Dipeptidyl peptidase IV, which probably plays important roles in Alzheimer disease (AD) pathology, is upregulated in AD brain neurons and associates with amyloid plaques Neurochem. Int. (IF 3.262) Pub Date : 2018-01-17 Hans-Gert Bernstein, Henrik Dobrowolny, Gerburg Keilhoff, Johann Steiner
There is evidence from in vitro experiments that dipeptidyl peptidase IV (DPP IV) might play role(s) in amyloid formation. However, nothing is known about the localization of the enzyme in brains of individuals with Alzheimer's disease. We herein show that in comparison to non-demented controls DPP IV is upregulated in AD brain neurons and occurs in multiple amyloid plaques.
Nicotine alleviates chronic stress-induced anxiety and depressive-like behavior and hippocampal neuropathology via regulating autophagy signaling Neurochem. Int. (IF 3.262) Pub Date : 2018-01-16 Xi Xiao, Xueliang Shang, Baohui Zhai, Hui Zhang, Tao Zhang
Recently, we reported that chronic nicotine significantly improved chronic stress-induced impairments of cognition and the hippocampal synaptic plasticity in mice, however, the underlying mechanism still needs to be explored. In the present study, 32 male C57BL/6 mice were divided into four groups: control (CON), stress (CUS), stress with chronic nicotine administration (CUS + Nic) and chronic nicotine administration (Nic). The anxiety-like behavior and neuropathological alteration of DG neurons were examined. Moreover, PC12 cells were examined with corticosterone in the presence or absence of nicotine. Both cell viability and apoptosis were determined. When treated simultaneously with an unpredictable chronic mild stress (CUS), nicotine (0.2 mg/kg/d) attenuated behavioral deficits and neuropathological alterations of DG neurons. Moreover, Western blotting showed that chronic nicotine also elevated the level of autophagy makers including Beclin-1 and LC3 II triggered by CUS. In addition, concomitant treatment with nicotine (10 μM) significantly attenuated the loss of PC12 cell viability (p < .01) and apoptosis compared to that of corticosterone treatment alone. Besides, chronic nicotine also enhanced the protein and RNA expression levels of autophagy makers triggered by corticosterone, such as Beclin-1, LC3 II and p62/SQSTM1. However, the above improvements were significantly blocked by autophagy inhibitor 3-MA. Importantly, the activation of the PI3K/Akt/mTOR signaling was carefully tested to illuminate the effects of chronic nicotine. Consequently, chronic nicotine played a role of neuroprotection in either CUS mice or corticosterone cells associating with the enhancement of the autophagy signaling, which was involved in activating the PI3K/Akt/mTOR signaling.
Curcumin potentiates the function of human α7-nicotinic acetylcholine receptors expressed in SH-EP1 cells Neurochem. Int. (IF 3.262) Pub Date : 2018-01-16 Eslam El Nebrisi, Lina T. Al Kury, Keun-Hang Susan Yang, Petrilla Jayaprakash, Frank C. Howarth, Nadine Kabbani, Murat Oz
Effects of curcumin, a biologically active ingredient of turmeric, were tested on the Ca2+ transients induced by the activation of α7 subunit of the human nicotinic acetylcholine (α7 nACh) receptor expressed in SH-EP1 cells. Curcumin caused a significant potentiation of choline (1 mM)-induced Ca2+ transients with an EC50 value of 133 nM. The potentiating effect of curcumin was not observed in Ca2+ transients induced by high K+ (60 mM) containing solutions or activation of α4β2 nACh receptors and the extent of curcumin potentiation was not altered in the presence of Ca2+ channel antagonists nifedipine (1 μM), verapamil (1 μM), ω-conotoxin (1 μM), and bepridil (10 μM). Noticeably the effect of curcumin was not observed when curcumin and choline were co-applied without curcumin pre-incubation. The effect of curcumin on choline-induced Ca2+ transients was not reversed by pre-incubation with inhibitors of protein C, A, and CaM kinases. Metabolites of curcumin such as tetrahydrocurcumin, demethylcurcumin, and didemethylcurcumin also caused potentiation of choline-induced Ca2+ transients. Notably, specific binding of [125I]-bungarotoxin was not altered in the presence of curcumin. Collectively, our results indicate that curcumin allosterically potentiate the function of the α7-nACh receptor expressed in SH-EP1 cells.
CDC42EP4, a perisynaptic scaffold protein in Bergmann glia, is required for glutamatergic tripartite synapse configuration Neurochem. Int. (IF 3.262) Pub Date : 2018-01-09 Natsumi Ageta-Ishihara, Kohtarou Konno, Maya Yamazaki, Manabu Abe, Kenji Sakimura, Masahiko Watanabe, Makoto Kinoshita
Configuration of tripartite synapses, comprising the pre-, post-, and peri-synaptic components (axon terminal or bouton, dendritic spine, and astroglial terminal process), is a critical determinant of neurotransmitter kinetics and hence synaptic transmission. However, little is known about molecular basis for the regulation of tripartite synapse morphology. Previous studies showed that CDC42EP4, an effector protein of a cell morphogenesis regulator CDC42, is expressed exclusively in Bergmann glia in the cerebellar cortex, that it forms tight complex with the septin heterooligomer, and that it interacts indirectly with the glutamate transporter GLAST and MYH10/nonmuscle myosin ΙΙB. Scrutiny of Cdc42ep4-/- mice had revealed that the CDC42EP4-septins-GLAST interaction facilitates glutamate clearance, while the role for CDC42EP4-septins-MYH10 interaction has remained unsolved. Here, we find anomalous configuration of the tripartite synapses comprising the parallel fiber boutons, dendritic spines of Purkinje cells, and Bergmann glial processes in Cdc42ep4-/- mice. The complex anomalies include 1) recession of Bergmann glial membranes from the nearest active zones, and 2) extension of nonactive synaptic contact around active zone. In line with the recession of Bergmann glial membranes by the loss of CDC42EP4, overexpression of CDC42EP4 in heterologous cells promotes cell spreading and partitioning of MYH10 to insoluble (i.e., active) fraction. Paradoxically, however, Cdc42ep4-/- cerebellum contained significantly more MYH10 and N-cadherin, which is attributed to secondary neuronal response mainly in Purkinje cells. Given cooperative actions of N-cadherin and MYH10 for adhesion between neurons, we speculate that their augmentation may reflect the extension of nonactive synaptic contacts in Cdc42ep4-/- cerebellum. Transcellular mechanism that links the absence of CDC42EP4 in Bergmann glia to the augmentation of N-cadherin and MYH10 in neurons is currently unknown, but the phenotypic similarity to GLAST-null mice indicates involvement of the glutamate intolerance. Together, the unique phenotype of Cdc42ep4-/- mice provides a clue to novel molecular network underlying tripartite synapse configuration.
Research progress in stroke-induced immunodepression syndrome (SIDS) and stroke-associated pneumonia (SAP) Neurochem. Int. (IF 3.262) Pub Date : 2018-01-06 Dan-Dan Liu, Shi-Feng Chu, Chen Chen, Peng-Fei Yang, Nai-Hong Chen, Xin He
In recent years, stroke-induced immunodepression syndrome (SIDS) and the resulting stroke-associated infection (SAI) have become a focus of current research efforts. Inflammatory reactions after stroke promote tissue healing and eliminate necrotic cells, whereas excessive inflammatory reactions may cause secondary damage. Stroke-induced immunodepression not only reduces inflammatory reactions and protects brain tissues but also weakens the resistance of the human body against pathogens and leads to infection. Changes in the local and systemic immune system in stroke patients may play an important role in prognosis. Infection is a leading cause of death in patients following stroke, and an evaluation of the prognosis of stroke patients is associated closely with the presence of infectious complications. Among these complications, pneumonia is the most common type of infection observed after acute stroke, which exhibits the greatest effect on the recovery of neurological function. SIDS is closely related to stroke-associated pneumonia (SAP), and the use of immunodepression as an entry point may provide an efficacious treatment target and drug development strategy. An improved understanding of the pathophysiological mechanisms leading to SAP is essential to develop new treatment strategies for improving the outcomes of stroke patients.
Circadian modification network of a core clock driver BMAL1 to harmonize physiology from brain to peripheral tissues Neurochem. Int. (IF 3.262) Pub Date : 2018-01-03 Teruya Tamaru, Ken Takamatsu
Circadian clocks dictate various physiological functions by brain SCN (a central clock) -orchestrating the temporal harmony of peripheral clocks of tissues/organs in the whole body, with adaptability to environments by resetting their timings. Dysfunction of this circadian adaptation system (CAS) occasionally causes/exacerbates diseases. CAS is based on cell-autonomous molecular clocks, which oscillate via a core transcriptional/translational feedback loop with clock genes/proteins, e.g., BMAL1: CLOCK circadian transcription driver and CRY1/2 and PER1/2 suppressors, and is modulated by various regulatory loops including clock protein modifications. Among mutants with a single clock gene, BMAL1-deficient mice exhibit the most drastic loss of circadian functions. Here, we highlight on numerous circadian protein modifications of mammalian BMAL1, e.g., multiple phosphorylations, SUMOylation, ubiquitination, acetylation, O-GlcNAcylation and S-nitrosylation, which mutually interplay to control molecular clocks and coordinate physiological functions from the brain to peripheral tissues through the input and output of the clocks.
Nicotinic acetylcholine receptor (nAChR) mediated dopamine release in larval Drosophila melanogaster Neurochem. Int. (IF 3.262) Pub Date : 2018-01-03 Poojan Pyakurel, Mimi Shin, B. Jill Venton
Pathological role of lipid interaction with α-synuclein in Parkinson's disease Neurochem. Int. (IF 3.262) Pub Date : 2018-01-03 Mari Suzuki, Kazunori Sango, Keiji Wada, Yoshitaka Nagai
Alpha-synuclein (αSyn) plays a central role in the pathogenesis of Parkinson's disease (PD) and dementia with Lewy bodies (DLB). In sporadic PD and DLB, normally harmless αSyn proteins without any mutations might gain toxic functions by unknown mechanisms. Thus, it is important to elucidate the factors promoting the toxic conversion of αSyn, towards understanding the pathogenesis of and developing disease-modifying therapies for PD and DLB. Accumulating biophysical and biochemical studies have demonstrated that αSyn interacts with lipid membrane, and the interaction influences αSyn oligomerization and aggregation. Furthermore, genetic and clinicopathological studies have revealed mutations in the glucocerebrosidase 1 (GBA1) gene, which encodes a degrading enzyme for the glycolipid glucosylceramide (GlcCer), as strong risk factors for PD and DLB, and we recently demonstrated that GlcCer promotes toxic conversion of αSyn. Moreover, pathological studies have shown the existence of αSyn pathology in lysosomal storage disorders (LSDs) patient’ brain, in which glycosphingolipids (GSLs) is found to be accumulated. In this review, we focus on the lipids as a key factor for inducing wild-type (WT) αSyn toxic conversion, we summarize the knowledge about the interaction between αSyn and lipid membrane, and propose our hypothesis that aberrantly accumulated GSLs might contribute to the toxic conversion of αSyn. Identifying the trigger for toxic conversion of αSyn would open a new therapeutic road to attenuate or prevent crucial events leading to the formation of toxic αSyn.
A refined concept: Alpha synuclein dysregulation disease Neurochem. Int. (IF 3.262) Pub Date : 2018-01-02 Hideki Mochizuki, Chi-Jing Choong, Eliezer Masliah
Alpha synuclein (αSyn) still remains a mysterious protein even two decades after SNCA encoding it was identified as the first causative gene of familial Parkinson's disease (PD). Accumulation of αSyn causes α-synucleinopathies including PD, dementia with Lewy bodies (DLB) and multiple system atrophy (MSA). Recent advances in therapeutic approaches offer new antibody-, vaccine-, antisense-oligonucleotide- and small molecule-based options to reduce αSyn protein levels and aggregates in patient's brain. Gathering research information of other neurological disease particularly Alzheimer's disease, recent disappointment of an experimental amyloid plaques busting antibody in clinical trials underscores the difficulty of treating people who show even mild dementia as damage in their brain may already be too extensive. Prodromal intervention to inhibit the accumulation of pathogenic protein may advantageously provide a better outcome. However, treatment prior to onset is not ethically justified as standard practice at present. In this review, we initiate a refined concept to define early pathogenic state of αSyn accumulation before occurrence of brain damage as a disease criterion for αSyn dysregulation disease.
Coronaridine congeners modulate mitochondrial α3β4* nicotinic acetylcholine receptors with different potency and through distinct intra-mitochondrial pathways Neurochem. Int. (IF 3.262) Pub Date : 2017-12-23 Hugo R. Arias, Olena Lykhmus, Kateryna Uspenska, Maryna Skok
In contrast to plasma membrane-expressed nicotinic acetylcholine receptors (nAChRs), mitochondrial nAChRs function in an ion-independent manner by triggering intra-mitochondrial kinases that regulate the release of cytochrome c (Cyt c), an important step in cellular apoptosis. The aim of this study is to determine the structural requirements for mitochondrial α3β4* nAChR activation by measuring the modulatory effects of two noncompetitive antagonists of these receptors, (+)-catharanthine and (±)-18-methoxycoronaridine [(±)-18-MC], on Cyt c release from wild-type and α7-/- mice mitochondria. The sandwich ELISA results indicated that α3β4* nAChRs are present in liver mitochondria in higher amounts compared to that in brain mitochondria and that these receptors are up-regulated in α7-/- mice. Correspondingly, (±)-18-MC decreased Cyt c release from liver mitochondria of wild-type mice and from brain and liver mitochondria of α7-/- mice. The effect in wild-type mice mitochondria was mediated mainly by the Src-dependent pathway, regulating the apoptogenic activity of reactive oxygen species, while in α7-/- mice mitochondria, (±)-18-MC strongly affected the calcium-calmodulin kinase II-dependent pathway. In contrast, (+)-catharanthine was much less potent than (±)-18-MC and triggered several signaling pathways, suggesting the involvement of multiple nAChR subtypes. These results show for the first time that noncompetitive antagonists can induce mitochondrial α3β4* nAChR signaling, giving a more comprehensive understanding on the function of intracellular nAChR subtypes.
The release and transmission of amyloid precursor protein via exosomes Neurochem. Int. (IF 3.262) Pub Date : 2017-12-23 Tingting Zheng, Xiaoqing Wu, Xiaojie Wei, Mingkai Wang, Baorong Zhang
Amyloid precursor protein (APP) processing is central in Alzheimer's disease (AD) pathogenesis. The healthy unaffected neurons suffer the transmission of amyloid protein from pathologically affected neurons, which may play an important role in the anatomical spread of the disease. Exosomes are appropriate candidates for transmission of amyloid species, because of their potential role as “intercellular transportation”. To address a role of secreted exosomes in neuronal homeostasis in AD, we harvested exosomes from the conditioned medium of HEK293-APP Swe/Ind cells. We have demonstrated that these exosomes contained APP and were capable of efficiently transferring APP to normal primary neurons. Moreover, these exosomes had dose-dependent detrimental effect on cultured neurons. Our results suggest a key mechanism underlying the spread of amyloid protein in the brain and the acceleration of pathology in AD; exosomes secretion serves to amplify and propagate Alzheimer's disease related pathology.
High-fat diet-induced hyperglutamatergic activation of the hippocampus in mice: A proton magnetic resonance spectroscopy study at 9.4T Neurochem. Int. (IF 3.262) Pub Date : 2017-12-21 Song-I. Lim, Kyu-Ho Song, Chi-Hyeon Yoo, Dong-Cheol Woo, Bo-Young Choe
The potential role of the novel hypothalamic neuropeptides nesfatin-1, phoenixin, spexin and kisspeptin in the pathogenesis of anxiety and anorexia nervosa Neurochem. Int. (IF 3.262) Pub Date : 2017-12-15 Artur Pałasz, Małgorzata Janas-Kozik, Amanda Borrow, Oscar Arias-Carrión, John J. Worthington
Due to the dynamic development of molecular neurobiology and bioinformatic methods several novel brain neuropeptides have been identified and characterized in recent years. Contemporary techniques of selective molecular detection e.g. in situ Real-Time PCR, microdiffusion and some bioinformatics strategies that base on searching for single structural features common to diverse neuropeptides such as hidden Markov model (HMM) have been successfully introduced. A convincing majority of neuropeptides have unique properties as well as a broad spectrum of physiological activity in numerous neuronal pathways including the hypothalamus and limbic system. The newly discovered but uncharacterized regulatory factors nesfatin-1, phoenixin, spexin and kisspeptin have the potential to be unique modulators of stress responses and eating behaviour. Accumulating basic studies revelaed an intriguing role of these neuropeptides in the brain pathways involved in the pathogenesis of anxiety behaviour. Nesfatin-1, phoenixin, spexin and kisspeptin may also distinctly affect the energy homeostasis and modulate food intake not only at the level of hypothalamic centres. Moreover, in patients suffered from anxiety and anorexia nervosa a significant, sex-related changes in the plasma neuropeptide levels occurred. It should be therefore taken into account that the targeted pharmacomodulation of central peptidergic signaling may be potentially helpful in the future treatment of certain neuropsychiatric and metabolic disorders. This article reviews recent evidence dealing with the hypothetical role of these new factors in the anxiety-related circuits and pathophysiology of anorexia nervosa.
Neuropathic pain inhibitor, RAP-103, is a potent inhibitor of microglial CCL1/CCR8 Neurochem. Int. (IF 3.262) Pub Date : 2017-12-14 Mami Noda, Daichi Tomonaga, Kota Kitazono, Yusaku Yoshioka, Jiadai Liu, Jean-Philippe Rouseau, Richard Kinkead, Michael R. Ruff, Candace B. Pert
Chemokine signalling is important in neuropathic pain, with microglial cells expressing chemokine (C-C motif) receptor CCR2, CCR5 and CCR8, all playing key roles. In the previous report (Padi et al., 2012), oral administration of a short peptide, RAP-103, for 7 days fully prevents mechanical allodynia and inhibits the development of thermal hyperalgesia after partial ligation of the sciatic nerve in rodents. As for the mechanism of the inhibiting effect of RAP-103, it was speculated to be due to dual blockade of CCR2 and CCR5. We report here that RAP-103 exhibits stronger antagonism for CCR8 (half maximal inhibitory concentration [IC50] 7.7 fM) compared to CCR5 (IC50 < 100 pM) in chemotaxis using primary cultured mouse microglia. In addition, RAP-103 at a concentration of 0.1 pM completely inhibits membrane ruffling and phagocytosis induced by chemokine (C-C motif) ligand 1 (CCL1), an agonist for CCR8. It has been shown that CCL1/CCR8 signaling is important in tactile allodynia induced by nerve ligation. Therefore, CCR8, among other chemokine receptors such as CCR2/CCR5, could be the most potent target for RAP-103. Inhibitory effects of RAP-103 on plural chemokine receptors may play important roles for broad clinical use in neuropathic pain treatment.
Sirt3 confers protection against acrolein-induced oxidative stress in cochlear nucleus neurons Neurochem. Int. (IF 3.262) Pub Date : 2017-12-14 Juan Qu, Yong-xiang Wu, Ting Zhang, Yang Qiu, Zhong-jia Ding, Ding-jun Zha
Acrolein is a ubiquitous dietary and environmental pollutant, which can also be generated endogenously during cellular stress. However, the molecular mechanisms underlying acrolein-induced neurotoxicity, especially in ototoxicity conditions, have not been fully determined. In this study, we investigated the mechanisms on acrolein-induced toxicity in primary cultured cochlear nucleus neurons with focus on Sirt3, a mitochondrial deacetylase. We found that acrolein treatment induced neuronal injury and programmed cell death (PCD) in a dose dependent manner in cochlear nucleus neurons, which was accompanied by increased intracellular reactive oxygen species (ROS) generation and lipid peroxidation. Acrolein exposure also significantly reduced the mitochondrial membrane potential (MMP) levels, promoted cytochrome c release and decreased mitochondrial ATP production. In addition, increased ER tracker fluorescence and activation of ER stress factors were observed after acrolein treatment, and the ER stress inhibitors were shown to attenuate acrolein-induced toxicity in cochlear nucleus neurons. The results of western blot and RT-PCR showed that acrolein markedly decreased the expression of Sirt3 at both mRNA and protein levels, and reduced the activity of downstream mitochondrial enzymes. Furthermore, overexpression of Sirt3 by lentivirus transfection partially prevented acrolein-induced neuronal injury in cochlear nucleus neurons. These results demonstrated that acrolein induces mitochondrial dysfunction and ER stress in cochlear nucleus neurons, and Sirt3 acts as an endogenous protective factor in acrolein-induced ototoxicity.
A potential impact of Helicobacter pylori-related galectin-3 in neurodegeneration Neurochem. Int. (IF 3.262) Pub Date : 2017-12-13 Marina Boziki, Stergios A. Polyzos, Georgia Deretzi, Evangelos Kazakos, Panagiotis Katsinelos, Michael Doulberis, Georgios Kotronis, Evaggelia Giartza-Taxidou, Leonidas Laskaridis, Dimitri Tzivras, Elisabeth Vardaka, Constantinos Kountouras, Nikolaos Grigoriadis, Thomann Robert, Jannis Kountouras
Trophic modulation of gamma oscillations: The key role of processing protease for Neuregulin-1 and BDNF precursors Neurochem. Int. (IF 3.262) Pub Date : 2017-12-09 Hideki Tamura, Sadao Shiosaka, Shota Morikawa
Gamma oscillations within the cerebral cortex and hippocampus are associated with cognitive processes, including attention, sensory perception, and memory formation; a deficit in gamma regulation is a common symptom of neurologic and psychiatric disorders. Accumulating evidence has suggested that gamma oscillations result from the synchronized activity of cell assemblies coordinated mainly by parvalbumin-positive inhibitory interneurons. The modulator molecules for parvalbumin-positive interneurons are major research targets and have the potential to control the specific oscillatory rhythm and behavior originating from neural coordination. Neuregulin-1 and brain-derived neurotrophic factor have been focused on as synaptic trophic factors that are associated with gamma oscillations. Synaptic activity converts precursor trophic factors into their biologically active forms by proteolytic cleavage, which could, in turn, modulate cell excitability and synaptic plasticity through each receptor's signaling. From these findings, the processing of trophic factors by proteases in a synaptic microenvironment might involve gamma oscillations during cognition. Here, we review the trophic modulation of gamma oscillations through extracellular proteolysis and its implications in neuronal diseases.
Strong sonic hedgehog signaling in the mouse ventral spinal cord is not required for oligodendrocyte precursor cell (OPC) generation but is necessary for correct timing of its generation Neurochem. Int. (IF 3.262) Pub Date : 2017-11-06 Hirokazu Hashimoto, Wen Jiang, Takeshi Yoshimura, Kyeong-Hye Moon, Jinwoong Bok, Kazuhiro Ikenaka
In the mouse neural tube, sonic hedgehog (Shh) secreted from the floor plate (FP) and the notochord (NC) regulates ventral patterning of the neural tube, and later is essential for the generation of oligodendrocyte precursor cells (OPCs). During early development, the NC is adjacent to the neural tube and induces ventral domains in it, including the FP. In the later stage of development, during gliogenesis in the spinal cord, the pMN domain receives strong Shh signaling input. While this is considered to be essential for the generation of OPCs, the actual role of this strong input in OPC generation remains unclear. Here we studied OPC generation in bromi mutant mice which show abnormal ciliary structure. Shh signaling occurs within cilia and has been reported to be weak in bromi mutants. At E11.5, accumulation of Patched1 mRNA, a Shh signaling reporter, is observed in the pMN domain of wild type but not bromi mutants, whereas expression of Gli1 mRNA, another Shh reporter, disappeared. Thus, Shh signaling input to the pMN domain at E12.5 was reduced in bromi mutant mice. In these mutants, induction of the FP structure was delayed and its size was reduced compared to wild type mice. Furthermore, while the p3 and pMN domains were induced, the length of the Nkx2.2-positive region and the number of Olig2-positive cells decreased. The number of OPCs was also significantly decreased in the E12.5 and E14.5 bromi mutant spinal cord. In contrast, motor neuron (MN) production, detected by HB9 expression, significantly increased. It is likely that the transition from MN production to OPC generation in the pMN domain is impaired in bromi mutant mice. These results suggest that strong Shh input to the pMN domain is not required for OPC generation but is essential for producing a sufficient number of OPCs.
Insulin expression in cultured astrocytes and the decrease by amyloid β Neurochem. Int. (IF 3.262) Pub Date : 2017-11-03 Katsura Takano, Keisuke Koarashi, Kenji Kawabe, Masanori Itakura, Hidemitsu Nakajima, Mitsuaki Moriyama, Yoichi Nakamura
Insulin resistance in brain has been reported in Alzheimer's diseases (AD). Insulin signaling is important for homeostasis in brain function and reported to be disturbed in neurons leading to tau phosphorylation and neurofibrillary tangles. Many investigations of insulin in neurons have been reported; however, it has not been reported whether astrocytes also produce insulin. In the present study, we assessed the expression of insulin in astrocytes cultured from rat embryonic brain and the effects of amyloid β1-42 (Aβ) and lipopolysaccharide (LPS) on the expression. We found that astrocytes expressed preproinsulin mRNAs and insulin protein, and that Aβ or LPS decreased these expressions. Antioxidants, glutathione and N-acetylcysteine, restored the decreases in insulin mRNA expression by Aβ and by LPS. Insulin protein was detected in astrocyte conditioned medium. These results suggest that astrocytes express and secrete insulin. Oxidative stress might be involved in the decreased insulin expression by Aβ or LPS. The insulin decrease by Aβ in astrocytes could be a novel disturbing mechanism for brain insulin signaling in AD.
Icariside II, a PDE5 inhibitor from Epimedium brevicornum, promotes neuron-like pheochromocytoma PC12 cell proliferation via activating NO/cGMP/PKG pathway Neurochem. Int. (IF 3.262) Pub Date : 2017-10-31 Jianmei Gao, Yingshu Xu, Ming Lei, Jingshan Shi, Qihai Gong
Icariside II (ICS II), a phosphodiesterase 5 inhibitor (PDE 5-I), is a major ingredient of Epimedium brevicornum, with wide spectrum of neuroprotective properties. However, little is known about the potential beneficial effect of ICS II on neuronal cell proliferation, and its possible underlying mechanism remains still unclear. We hypothesized that the beneficial effect of ICS II on neuron-like highly differentiated rat pheochromocytoma (PC12) cell proliferation is correlated with the nitric oxide (NO) signaling pathway and its upstream of PI3K/AKT pathway. PC12 cells were treated with ICS II alone or together with L-NMMA, H89, KT-5823, and/or LY294002 (the inhibitor of NOS, PKA, PKG, PI3K, respectively). It was found that ICS II concentration-dependently promoted PC12 cells proliferation, and cell cycle analysis showed that the proportion of ICS II-treated PC12 cells in S phase was higher than that of control. Moreover, ICS II at the appropriate concentration (100 μM) not only increased nNOS expression, NO production, but also enhanced cGMP content and PKG activity. The addition of L-NMMA and KT-5 823 significantly inhibited the effects of ICS II on nNOS expression, NO production and PKG activity. Furthermore, LY294002 significantly decreased p-AKT level, NOS activity, NO production and nNOS expression, but it did not affect iNOS expression. These findings demonstrate that the beneficial effect of ICS II on neuronal cell proliferation, and its possible underlying mechanisms are, at least partly, through activating AKT/nNOS/NO/cGMP/PKG signaling pathway.
Motoneuron degeneration in the trigeminal motor nucleus innervating the masseter muscle in Dystonia musculorum mice Neurochem. Int. (IF 3.262) Pub Date : 2017-10-21 M. Ibrahim Hossain, Masao Horie, Nozomu Yoshioka, Masayuki Kurose, Kensuke Yamamura, Hirohide Takebayashi
Dystonia musculorum (dt) mice, which have a mutation in the Dystonin (Dst) gene, are used as animal models to investigate the human disease known as hereditary sensory and autonomic neuropathy type VI. Massive neuronal cell death is observed, mainly in the peripheral nervous system (PNS) of dt mice. We and others have recently reported a histopathological feature of these mice that neurofilament (NF) accumulates in various areas of the central nervous system (CNS), including motor pathways. Although dt mice show motor disorder and growth retardation, the causes for these are still unknown. Here we performed histopathological analyses on motor units of the trigeminal motor nucleus (Mo5 nucleus), because they are a good system to understand neuronal responses in the mutant CNS, and abnormalities in this system may lead to problems in mastication, with subsequent growth retardation. We report that motoneurons with NF accumulation in the Mo5 nuclei of DstGt homozygous mice express the stress-induced genes CHOP, ATF3, and lipocalin 2 (Lcn2). We also show a reduced number of Mo5 motoneurons and a reduced size of Mo5 nuclei in DstGt homozygous mice, possibly due to apoptosis, given the presence of cleaved caspase 3-positive Mo5 motoneurons. In the mandibular (V3) branches of the trigeminal nerve, which contains axons of Mo5 motoneurons and trigeminal sensory neurons, there was infiltration of Iba1-positive macrophages. Finally, we report atrophy of the masseter muscles in DstGt homozygous mice, which showed abnormal nuclear localization of myofibrils and increased expression of atrogin-1 mRNA, a muscle atrophy-related gene and weaker masseter muscle strength with uncontrolled muscle activity by electromyography (EMG). Taken together, our findings strongly suggest that mastication in dt mice is affected due to abnormalities of Mo5 motoneurons and masseter muscles, leading to growth retardation at the post-weaning stages.
Release of soluble and vesicular purine nucleoside phosphorylase from rat astrocytes and microglia induced by pro-inflammatory stimulation with extracellular ATP via P2X7 receptors Neurochem. Int. (IF 3.262) Pub Date : 2017-10-20 Luis Emiliano Peña-Altamira, Elisabetta Polazzi, Patricia Giuliani, Alina Beraudi, Francesca Massenzio, Ilaria Mengoni, Alessandro Poli, Mariachiara Zuccarini, Renata Ciccarelli, Patrizia Di Iorio, Marco Virgili, Barbara Monti, Francesco Caciagli
Purine nucleoside phosphorylase (PNP), a crucial enzyme in purine metabolism which converts ribonucleosides into purine bases, has mainly been found inside glial cells. Since we recently demonstrated that PNP is released from rat C6 glioma cells, we then wondered whether this occurs in normal brain cells. Using rat primary cultures of microglia, astrocytes and cerebellar granule neurons, we found that in basal condition all these cells constitutively released a metabolically active PNP with Km values very similar to those measured in C6 glioma cells. However, the enzyme expression/release was greater in microglia or astrocytes that in neurons. Moreover, we exposed primary brain cell cultures to pro-inflammatory agents such as lipopolysaccharide (LPS) or ATP alone or in combination. LPS alone caused an increased interleukin-1β (IL-1β) secretion mainly from microglia and no modification in the PNP release, even from neurons in which it enhanced cell death. In contrast, ATP administered alone to glial cells at high micromolar concentrations significantly stimulated the release of PNP within 1 h, an effect not modified by LPS presence, whereas IL-1β secretion was stimulated by ATP only in cells primed for 2 h with LPS. In both cases ATP effect was mediated by P2X7 receptor (P2X7R), since it was mimicked by cell exposure to Bz-ATP, an agonist of P2X7R, and blocked by cell pre-treatment with the P2X7R antagonist A438079. Interestingly, ATP-induced PNP release from glial cells partly occurred through the secretion of lysosomal vesicles in the extracellular medium. Thus, during inflammatory cerebral events PNP secretion promoted by extracellular ATP accumulation might concur to control extracellular purine signals. Further studies could elucidate whether, in these conditions, a consensual activity of enzymes downstream of PNP in the purine metabolic cascade avoids accumulation of extracellular purine bases that might concur to brain injury by unusual formation of reactive oxygen species.
Calcium uptake and cytochrome c release from normal and ischemic brain mitochondria Neurochem. Int. (IF 3.262) Pub Date : 2017-10-16 Alexander Andreyev, Pratistha Tamrakar, Robert E. Rosenthal, Gary Fiskum
At abnormally elevated levels of intracellular Ca2+, mitochondrial Ca2+ uptake may compromise mitochondrial electron transport activities and trigger membrane permeability changes that allow for release of cytochrome c and other mitochondrial apoptotic proteins into the cytosol. In this study, a clinically relevant canine cardiac arrest model was used to assess the effects of global cerebral ischemia and reperfusion on mitochondrial Ca2+ uptake capacity, Ca2+ uptake-mediated inhibition of respiration, and Ca2+-induced cytochrome c release, as measured in vitro in a K+-based medium in the presence of Mg2+, ATP, and NADH-linked oxidizable substrates. Maximum Ca2+ uptake by frontal cortex mitochondria was significantly lower following 10 min cardiac arrest compared to non-ischemic controls. Mitochondria from ischemic brains were also more sensitive to the respiratory inhibition associated with accumulation of large levels of Ca2+. Cytochrome c was released from brain mitochondria in vitro in a Ca2+-dose-dependent manner and was more pronounced following both 10 min of ischemia alone and following 24 h reperfusion, in comparison to mitochondria from non-ischemic Shams. These effects of ischemia and reperfusion on brain mitochondria could compromise intracellular Ca2+ homeostasis, decrease aerobic and increase anaerobic cerebral energy metabolism, and potentiate the cytochrome c-dependent induction of apoptosis, when re-oxygenated mitochondria are exposed to abnormally high levels of intracellular Ca2+.
3-Iodothyroacetic acid (TA1), a by-product of thyroid hormone metabolism, reduces the hypnotic effect of ethanol without interacting at GABA-A receptors Neurochem. Int. (IF 3.262) Pub Date : 2017-10-12 Annunziatina Laurino, Elisa Landucci, Francesco Resta, Gaetano De Siena, Rosanna Matucci, Alessio Masi, Laura Raimondi
3-iodothyroacetic acid (TA1) is among the by-products of thyroid hormone metabolism suspected to mediate the non-genomic effects of the hormone (T3). We aim to investigate whether TA1 systemically administered to mice stimulated mice wakefulness, an effect already described for T3 and for another T3 metabolite (i.e. 3-iodothryonamine; T1AM), and whether TA1 interacted at GABA-A receptors (GABA-AR). Mice were pre-treated with either saline (vehicle) or TA1 (1.32, 4 and 11 μg/kg) and, after 10 min, they received ethanol (3.5 g/kg, i.p.). In another set of experiments, TA1 was administered 5 min after ethanol. The latency of sleep onset and the time of sleep duration were recorded. Voltage-clamp experiments to evaluate the effect of 1 μM TA1 on bicuculline-sensitive currents in acute rat hippocampal slice neurons and binding experiments evaluating the capacity of 1, 10, 100 μM TA1 to displace [3H]flumazenil from mice brain membranes were also performed. 4 μg/kg TA1 increases the latency of onset and at 1.32 and 4 μg/kg it reduces the duration of ethanol-induced sleep only if administered before ethanol. TA1 does not functionally interact at GABA-AR. Overall these results indicate a further similarity between the pharmacological profile of TA1 and that of T1AM.
Sitagliptin enhances the neuroprotective effect of pregabalin against pentylenetetrazole-induced acute epileptogenesis in mice: Implication of oxidative, inflammatory, apoptotic and autophagy pathways Neurochem. Int. (IF 3.262) Pub Date : 2017-10-12 Manar A. Nader, Hayam Ateyya, Mohamed El-Shafey, Nagla A. El-Sherbeeny
The current investigation aimed at studying the anti-epileptogenic effect of sitagliptin. The possible effect of the drug in combination with pregabalin in pentylenetetrazole (PTZ)- induced seizures was studied. In addition, the postulated mechanisms that could mediate such effect were explored namely, suppression of oxidative stress and neuro-inflammatory markers, autophagy and apoptosis. Seven days prior to PTZ (60 mg/kg, sc) injection, mice were treated with sitagliptin (5, 15, and 60 mg/kg, twice daily, orally) or pregabalin (30 mg/kg, once daily, orally) or their combination. At the end of the experiment, several parameters were assessed including: oxidative/nitro-oxidative stress such as superoxide dismutase (SOD), reduced glutathione (GSH), glutathione peroxidase (GP-x) catalase (CAT), and lipid peroxidation assessed as malondialdehyde (MDA), nitrate/nitrite (NOx), 3-nitrotyrosine (3-NT). Seizure latency was evaluated. Neuronal damage was also assessed by performing tissue staining by hematoxylin and eosin, estimating hippocampus level of glutamate, gamma-aminobutyric acid (GABA), glial fibrillary acidic protein (GFAP) and brain-derived neurotrophic factor (BDNF). Also, markers for inflammation, autophagy and apoptosis were measured, nuclear factor erythroid-derived 2- like 2 (Nrf2), nuclear factor kappa-B (NF-κB), phosphatidylethanolamine-conjugated form of microtubule-associated protein light chain-3 (LC3-II), casapase-3, Bcl-2-like protein 4 (BAX) and glucagon like peptide-1 (GLP-1) activity. Sitagliptin significantly suppressed epileptogenesis in PTZ-induced seizures. Sitagliptin counteracted neuronal damage and all biochemical, and histo-chemical alteration induced by PTZ. Also, a more significant protective effect was observed after combination with pregabalin. This study is indicative for the antiepileptogenic potential of sitagliptin with or without pregabalin in the PTZ model of epilepsy which is likely to be through its effect on antioxidant, anti-apoptotic and autophagic pathways.
Dual effects of insect nAChR chaperone RIC-3 on hybrid receptor: Promoting assembly on endoplasmic reticulum but suppressing transport to plasma membrane on Xenopus oocytes Neurochem. Int. (IF 3.262) Pub Date : 2017-10-12 Haibo Bao, Xixia Xu, Wei Liu, Na Yu, Zewen Liu
Resistance to inhibitors of cholinesterase (RIC) −3 promotes the maturation (folding and assembly) of neuronal nicotinic acetylcholine receptors (nAChRs) as a molecular chaperone. The modulation effects of RIC-3 on homomeric α7 nAChRs are always positive, but its effects on heteromeric subtypes are inconsistent among reports. In this study, five RIC-3 isoforms were identified from Locusta migratoria. Four isoforms showed obvious effects on hybrid receptor Locα1/rβ2 expressed in Xenopus oocytes. As a representative, the co-expression of RIC-3v4 exhibited the decreased agonist responses (Imax) on oocytes, lower specific [3H]epibatidine binding (Bmax) on plasma membrane protein (PMP), and reduced subunit levels in PMP, which showed that the mature Locα1/rβ2 on the plasma membrane was decreased by the co-expression of RIC-3. In contrast, the [3H]epibatidine binding and mature Locα1/rβ2 levels in the endoplasmic reticulum membrane protein (ERMP) were much increased when co-expressing with RIC-3v4. The [3H]epibatidine binding and mature Locα1/rβ2 levels in total membrane protein (TMP) gave the similar results as that in ERMP. Taking data together, the results showed that the co-expression of RIC-3 increased the mature Locα1/rβ2 receptor levels on ER of Xenopus oocytes, but these mature receptors were mostly kept on ER and suppressed to transport to plasma membrane.
Quantitative temporal changes in DTI values coupled with histological properties in cuprizone-induced demyelination and remyelination Neurochem. Int. (IF 3.262) Pub Date : 2017-10-10 Ryutaro Yano, Junichi Hata, Yoshifumi Abe, Fumiko Seki, Keitaro Yoshida, Yuji Komaki, Hideyuki Okano, Kenji F. Tanaka
Diffusion tensor imaging (DTI) is widely used to evaluate microstructural variations in brain tissue. In particular, fractional anisotropy (FA), reflecting the magnitude and orientation of anisotropic water diffusion, allows us to detect pathological events in white matter. An ex vivo DTI study coupled with histological assessment is an efficient strategy to evaluate the myelination process, i.e. demyelination and remyelination. The relationship between DTI values and myelin content or the individual cellular components such as oligodendrocytes, microglia, and astrocytes during both processes of demyelination and remyelination are not well-understood. To address this issue, we employed a cuprizone-inducible demyelination mouse model. Demyelination can be induced in this model during cuprizone exposure and termination of cuprizone exposure induces remyelination. We fed the mice cuprizone-containing chow for 4 weeks and then normal chow for an additional 4 weeks. The ex vivo DTI was performed to evaluate the white matter profiles observed by FA, mean diffusivity (MD), and radial diffusivity (RD) at both demyelinating and remyelinating time points, and then we evaluated histological properties at the same time points. The results indicated a gradual FA decrease during the cuprizone treatment (0, 2, 3, 4 weeks). A lower peak was seen at 1 week after the normal chow was resumed, with recovery to baseline at 2 and 4 weeks. MD and RD showed an opposing pattern to that of FA. These DTI values were positively or negatively correlated with myelin content regardless of the status of the white matter. The RD value was more sensitive to myelination status than FA and MD. We have clarified the temporal changes in the DTI values coupled with histological properties over both the demyelination and remyelination processes.
Resveratrol activation of AMPK-dependent pathways is neuroprotective in human neural stem cells against amyloid-beta-induced inflammation and oxidative stress Neurochem. Int. (IF 3.262) Pub Date : 2017-10-05 Ming-Chang Chiang, Christopher J. Nicol, Yi-Chuan Cheng
Alzheimer's disease (AD) is a neurodegenerative disorder with progressive memory loss resulting in dementia. Amyloid-beta (Aβ) peptides play a critical role in the pathogenesis of this disease, and are thought to promote inflammation and oxidative stress leading to neurodegeneration in the neocortex and hippocampus of the AD brains. AMP-activated protein kinase (AMPK) is a master regulator of cellular energy homeostasis, and cell survival in response to inflammation and oxidative stress. However, the neuroprotective mechanisms by which AMPK achieves these beneficial effects in human neural stem cells (hNSCs) exposed to Aβ is still not well understood. Resveratrol is a potent activator of AMPK suggesting it may have therapeutic potential against AD. Therefore, we will test the hypothesis that the AMPK activator resveratrol protects against Aβ mediated neuronal impairment (inflammation and oxidative stress) in hNSCs. Here, Aβ-treated hNSCs had significantly decreased cell viability that correlated with increased TNF-α and IL-1β inflammatory cytokine expression. Co-treatment with resveratrol significantly abrogated the Aβ-mediated effects in hNSCs, and was effectively blocked by the addition of the AMPK-specific antagonist (Compound C). These results suggest the neuroprotective effects of resveratrol are mediated by an AMPK-dependent pathway. In addition, resveratrol rescued the transcript expression levels of inhibitory kappa B kinase (IKK) in Aβ-treated hNSCs. NF-κB is a transcription factor with a key role in the expression of a variety of genes involved in inflammatory responses. Resveratrol prevented the Aβ-mediated increases in NF-κB mRNA and protein levels, and its nuclear translocation in hNSCs. Co-treatment with resveratrol also significantly restored iNOS and COX-2 levels in Aβ-treated hNSCs. Furthermore, hNSCs co-treated with resveratrol were significantly rescued from Aβ-induced oxidative stress, which correlated with reversal of the Aβ-induced mRNA decrease in oxidative defense genes (SOD-1, NRF2, Gpx1, Catalase, GSH and HO-1). Taken together, these novel findings show that activation of AMPK-dependent signaling by resveratrol rescues Aβ-mediated neurotoxicity in hNSCs, and provides evidence supporting a neuroprotective role for AMPK activating drugs in Aβ-related diseases such as AD.
Roles of CSGalNAcT1, a key enzyme in regulation of CS synthesis, in neuronal regeneration and plasticity Neurochem. Int. (IF 3.262) Pub Date : 2017-10-05 Michihiro Igarashi, Kosei Takeuchi, Sayaka Sugiyama
Chondroitin sulfate (CS) is a sulfated glycosaminoglycan composed of a long chain of repeating disaccharide units that are attached to core proteins, resulting in CS proteoglycans (CSPGs). In the mature brain, CS is concentrated in perineuronal nets (PNNs), which are extracellular structures that surround synapses and regulate synaptic plasticity. In addition, CS is rapidly synthesized after CNS injury to create a physical and chemical barrier that inhibits axon growth. Most previous studies used a bacterial CS-degrading enzyme to investigate the physiological roles of CS. Recent studies have shown that CS is synthesized by more than 15 enzymes, all of which have been characterized in vitro. Here we focus on one of those enzymes, CSGalNAcT1 (T1). We produced T1 knockout mice (KO), which show extensive axon regeneration following spinal cord injury, as well as the loss of onset of ocular dominance plasticity. These results from T1KO mice suggest important roles for extracellular CS in the brain regarding neuronal plasticity and axon regeneration.
Involvement of neuronal and glial activities in control of the extracellular d-serine concentrations by the AMPA glutamate receptor in the mouse medial prefrontal cortex Neurochem. Int. (IF 3.262) Pub Date : 2017-09-28 Sayuri Ishiwata, Asami Umino, Toru Nishikawa
It has been well accepted that d-serine may be an exclusive endogenous coagonist for the N-methyl-d-aspartate (NMDA)-type glutamate receptor in mammalian forebrain regions. We have recently found by using an in vivo dialysis method that an intra-medial prefrontal cortex infusion of S-α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (S-AMPA), a selective AMPA-type glutamate receptor agonist, causes a reduction in the extracellular levels of d-serine in a calcium-permeable AMPA receptor antagonist-sensitive manner. The inhibitory influence by the AMPA receptor on the extracellular d-serine, however, contradicts the data obtained from in vitro experiments that the AMPA receptor stimulation leads to facilitation of the d-serine liberation. This discrepancy appears to be due to the different cell setups between the in vivo and in vitro preparations. From the viewpoints of the previous reports indicating (1) the neuronal presence of d-serine synthesizing enzyme, serine racemase, and d-serine-like immunoreactivity and (2) the same high tissue concentrations of d-serine in the glia-enriched white matter and in the neuron-enriched gray matter of the mammalian neocortex, we have now investigated in the mouse medial prefrontal cortex, the effects of attenuation of neuronal and glial activities, by tetrodotoxin or fluorocitrate, respectively, on the S-AMPA-induced downregulation of the extracellular d-serine contents. In vivo dialysis studies revealed that a local infusion of tetrodotoxin or fluorocitrate eliminated the ability of S-AMPA given intra-cortically to cause a significant decrease in the dialysate concentrations of d-serine without affecting the elevating effects of S-AMPA on those of glycine, another intrinsic coagonist for the NMDA receptor. These findings suggest that the control by the AMPA receptor of the extracellular d-serine levels could be modulated by the neuronal and glial activities in the prefrontal cortex. It cannot be excluded that fluorocitrate would indirectly alter the modulation by changing synaptic neurotransmission via glial activity attenuation as previously reported.
Vesicular movements in the growth cone Neurochem. Int. (IF 3.262) Pub Date : 2017-09-27 Motohiro Nozumi, Michihiro Igarashi
Growth cones, which are the highly motile tips of extending neuronal processes in developing neurons, have many vesicles. These vesicles are likely essential for the membrane expansion that is required for nerve growth, and probably coordinate with rearrangement of the cytoskeletons. Such mechanisms are poorly understood from molecular and cell biological aspects. Recently, we used superresolution microscopic approaches and described new mechanisms that are involved in the interaction between the vesicles and F-actin in the leading edge of the peripheral domain. Vesicles mainly accumulate in the central domain of growth cones. However, the dynamics of vesicles in each domain, for example, clathrin dependency, are totally distinct from each other. Here, we discuss the diversity of the dynamics of vesicular and related proteins that play different roles in nerve growth.
Sex differences in the mitochondrial bioenergetics of astrocytes but not microglia at a physiologically relevant brain oxygen tension Neurochem. Int. (IF 3.262) Pub Date : 2017-09-06 Sausan M. Jaber, Evan A. Bordt, Niraj M. Bhatt, Daniel M. Lewis, Sharon Gerecht, Gary Fiskum, Brian M. Polster
Biological sex is thought to influence mitochondrial bioenergetic function. Previous respiration measurements examining brain mitochondrial sex differences were made at atmospheric oxygen using isolated brain mitochondria. Oxygen is 160 mm Hg (21%) in the atmosphere, while the oxygen tension in the brain generally ranges from ∼5 to 45 mm Hg (∼1–6% O2). This study tested the hypothesis that sex and/or brain physiological oxygen tension influence the mitochondrial bioenergetic properties of primary rat cortical astrocytes and microglia. Oxygen consumption was measured with a Seahorse XF24 cell respirometer in an oxygen-controlled environmental chamber. Strikingly, male astrocytes had a higher maximal respiration than female astrocytes when cultured and assayed at 3% O2. Three percent O2 yielded a low physiological dissolved O2 level of ∼1.2% (9.1 mm Hg) at the cell monolayer during culture and 1.2–3.0% O2 during assays. No differences in bioenergetic parameters were observed between male and female astrocytes at 21% O2 (dissolved O2 of ∼19.7%, 150 mm Hg during culture) or between either of these cell populations and female astrocytes at 3% O2. In contrast to astrocytes, microglia showed no sex differences in mitochondrial bioenergetic parameters at either oxygen level, regardless of whether they were non-stimulated or activated to a proinflammatory state. There were also no O2- or sex-dependent differences in proinflammatory TNF-α or IL-1β cytokine secretion measured at 18 h activation. Overall, results reveal an intriguing sex variance in astrocytic maximal respiration that requires additional investigation. Findings also demonstrate that sex differences can be masked by conducting experiments at non-physiological O2.
Alterations in the E3 ligases Parkin and CHIP result in unique metabolic signaling defects and mitochondrial quality control issues Neurochem. Int. (IF 3.262) Pub Date : 2017-08-26 Britney N. Lizama, Amy M. Palubinsky, BethAnn McLaughlin
E3 ligases are essential scaffold proteins, facilitating the transfer of ubiquitin from E2 enzymes to lysine residues of client proteins via isopeptide bonds. The specificity of substrate binding and the expression and localization of E3 ligases can, however, endow these proteins with unique features with variable effects on mitochondrial, metabolic and CNS function. By comparing and contrasting two E3 ligases, Parkin and C-terminus of HSC70-Interacting protein (CHIP) we seek to highlight the biophysical properties that may promote mitochondrial dysfunction, acute stress signaling and critical developmental periods to cease in response to mutations in these genes. Encoded by over 600 human genes, RING-finger proteins are the largest class of E3 ligases. Parkin contains three RING finger domains, with R1 and R2 separated by an in-between region (IBR) domain. Loss-of-function mutations in Parkin were identified in patients with early onset Parkinson's disease. CHIP is a member of the Ubox family of E3 ligases. It contains an N-terminal TPR domain and forms unique asymmetric homodimers. While CHIP can substitute for mutated Parkin and enhance survival, CHIP also has unique functions. The differences between these proteins are underscored by the observation that unlike Parkin-deficient animals, CHIP-null animals age prematurely and have significantly impaired motor function. These properties make these E3 ligases appealing targets for clinical intervention. In this work, we discuss how biophysical and metabolic properties of these E3 ligases have driven rapid progress in identifying roles for E3 ligases in development, proteostasis, mitochondrial biology, and cell health, as well as new data about how these proteins alter the CNS proteome.
Analysis of lipid raft molecules in the living brain slices Neurochem. Int. (IF 3.262) Pub Date : 2017-08-24 Norihiro Kotani, Takanari Nakano, Yui Ida, Rina Ito, Miki Hashizume, Arisa Yamaguchi, Makoto Seo, Tomoyuki Araki, Yasushi Hojo, Koichi Honke, Takayuki Murakoshi
Neuronal plasma membrane has been thought to retain a lot of lipid raft components which play important roles in the neural function. Although the biochemical analyses of lipid raft using brain tissues have been extensively carried out in the past 20 years, many of their experimental conditions do not coincide with those of standard neuroscience researches such as neurophysiology and neuropharmacology. Hence, the physiological methods for lipid raft analysis that can be compatible with general neuroscience have been required. Herein, we developed a system to physiologically analyze ganglioside GM1-enriched lipid rafts in brain tissues using the “Enzyme-Mediated Activation of Radical Sources (EMARS)” method that we reported (Kotani N. et al. Proc. Natl. Acad. Sci. U S A 105, 7405–7409 (2008)). The EMARS method was applied to acute brain slices prepared from mouse brains in aCSF solution using the EMARS probe, HRP-conjugated cholera toxin subunit B, which recognizes ganglioside GM1. The membrane molecules present in the GM1-enriched lipid rafts were then labeled with fluorescein under the physiological condition. The fluorescein-tagged lipid raft molecules called “EMARS products” distributed differentially among various parts of the brain. On the other hand, appreciable differences were not detected among segments along the longitudinal axis of the hippocampus. We further developed a device to label the lipid raft molecules in acute hippocampal slices under two different physiological conditions to detect dynamics of the lipid raft molecules during neural excitation. Using this device, several cell membrane molecules including Thy1, known as a lipid raft resident molecule in neurons, were confirmed by the EMARS method in living hippocampal slices.
P2Y12 shRNA treatment relieved HIV gp120-induced neuropathic pain in rats Neurochem. Int. (IF 3.262) Pub Date : 2017-08-18 Liran Shi, Bing Wu, Zhihua Yi, Shanhong Zhao, Lifang Zou, Lin Li, Huilong Yuan, Tianyu Jia, Shuangmei Liu, Hui Liu, Yun Gao, Guilin Li, Hong Xu, Chunping Zhang, Shangdong Liang
Human immunodeficiency virus (HIV) envelope glycoprotein (glycoprotein 120, gp120) can induce chronic neuropathic pain by directly stimulating primary sensory afferent neurons. Activation of satellite glial cells (SGCs) in dorsal root ganglia (DRG) plays an important role in the transmission of neuropathic pain. The P2Y12 receptor is expressed in SGCs of DRG. In this study, we investigated the role of the P2Y12 receptor in HIV gp120-induced neuropathic pain. The results showed that peripheral nerve exposure to HIV gp120 increased mechanical and thermal hyperalgesia in gp120-treated model rats. The gp120 treatment increased the expression of P2Y12 mRNA and protein in DRG SGCs. Treatment with P2Y12 short hairpin RNA (shRNA) in DRG SGCs decreased the upregulated expression of P2Y12 mRNA and protein in DRG SGCs as well as relieved mechanical and thermal hyperalgesia in gp120-treated rats. Reduction of P2Y12 receptor decreased co-expression of P2Y12 and glial fibrillary acidic protein (GFAP), expression of GFAP, interleukin (IL)-1β, tumor necrosis factor (TNF)-receptor 1 (TNF-R1), and phosphorylation of Akt (p-Akt) proteins in DRG of gp120-treated rats. Upregulation of GFAP is a marker of SGC activation. Therefore, P2Y12 shRNA treatment decreased HIV gp120-induced mechanical and thermal hyperalgesia in gp120-treated rats.
Alzheimer's disease as oligomeropathy Neurochem. Int. (IF 3.262) Pub Date : 2017-08-16 Kenjiro Ono
Alzheimer's disease (AD) is the most common age-related neurodegenerative disorder and is characterized by pathological aggregates of amyloid β-protein (Aβ) and tau protein. On the basis of genetic evidence, biochemical data, and animal models, Aβ has been suggested to be responsible for the pathogenesis of AD (the amyloid hypothesis). Aβ molecules tend to aggregate to form oligomers, protofibrils, and mature fibrils. Although mature fibrils in the final stage have been thought to be the cause of AD pathogenesis, recent studies using synthetic Aβ peptides, a cell culture model, Aβ precursor protein transgenic mice models, and human samples, such as cerebrospinal fluids and postmortem brains of AD patients, suggest that pre-fibrillar forms (oligomers of Aβ) are more deleterious than are extracellular fibril forms. Based on this recent evidence showing that oligomers have a central role in the pathogenesis of AD, the term “oligomeropathy” could be used to define AD and other protein-misfolding diseases. In this review, I discuss recent developments in the “oligomer hypothesis” including our research findings regarding the pathogenesis of AD.
4-Hydroperoxy-2-decenoic acid ethyl ester protects against 6-hydroxydopamine-induced cell death via activation of Nrf2-ARE and eIF2α-ATF4 pathways Neurochem. Int. (IF 3.262) Pub Date : 2017-08-16 Yuki Inoue, Hirokazu Hara, Yukari Mitsugi, Eiji Yamaguchi, Tetsuro Kamiya, Akichika Itoh, Tetsuo Adachi
Parkinson's disease (PD) is a neurodegenerative disorder characterized by progressive degeneration of dopaminergic neurons in the substantia nigra. Oxidative stress has been reported to be closely related to the pathogenesis and worsening of symptoms of PD. One therapeutic strategy is to alleviate neuronal injuries caused by oxidative stress. In this study, we investigated protective effects of royal jelly (RJ) fatty acids and their derivatives on oxidative stress-induced cell death using human neuroblastoma SH-SY5Y cells. 4-Hydroperoxy-2-decenoic acid ethyl ester (HPO-DAEE), a synthesized RJ fatty acid derivative, markedly induced antioxidant enzymes such as heme oxygenase-1 (HO-1). Pretreatment with HPO-DAEE protected against 6-hydroxydopamine (6-OHDA)-induced cell death. NF-E2-related factor 2 (Nrf2), a master regulator of antioxidative responses, plays a key role in the acquisition of resistance to oxidative stress. HPO-DAEE elicited nuclear accumulation of Nrf2 and activated antioxidant response element (ARE), a cis-activating regulatory element, indicating that HPO-DAEE induced expression of antioxidant genes through Nrf2-ARE signaling. Recently, the activating transcription factor-4 (ATF4) has been shown to cooperate with Nrf2 and modulate antioxidant gene expression. We also found that HPO-DAEE promoted phosphorylation of eukaryotic initiation factor 2α (eIF2α), which is an upstream effector of ATF4, and subsequent nuclear accumulation of ATF4. The eIF2α phosphatase inhibitor, salubrinal, augmented HPO-DAEE-induced HO-1 expression and protection against 6-OHDA-induced cell death. These results indicate that HPO-DAEE activates both the Nrf2-ARE and eIF2α-ATF4 pathways. Moreover, ROS generation occurred upon treatment of SH-SY5Y cells with HPO-DAEE, and the antioxidants N-acetylcysteine and glutathione suppressed HPO-DAEE-induced activation of the Nrf2-ARE and eIF2α-ATF4 pathways. Therefore, sublethal oxidative stress caused by HPO-DAEE is likely to activate both these pathways. Taken together, we conclude that HPO-DAEE elicits adaptive responses to oxidative stress through cooperative activation of the Nrf2-ARE and eIF2α-ATF4 pathways.
1,25-Dihydroxyvitamin-D3 induces brain proteomic changes in cuprizone mice during remyelination involving calcium proteins Neurochem. Int. (IF 3.262) Pub Date : 2017-08-14 Eystein Oveland, Agnes Nystad, Frode Berven, Kjell-Morten Myhr, Øivind Torkildsen, Stig Wergeland
Dietary supplementation of vitamin D is commonly recommended to patients with multiple sclerosis. We recently found that high-dose of the hormonally active 1,25-dihydroxyvitamin-D3 (1,25D) promotes myelin repair in the cuprizone model for de- and remyelination. In the present study, we quantified 5062 proteins, of which 125 were differentially regulated in brain tissue from 1,25D treated mice during remyelination, compared to placebo. Proteins upregulated in the early remyelination phase were involved in calcium binding, e.g. calretinin (>1.3 fold, p < 0.005), S10A5 and secretagogin, and involved in mitochondrial function, e.g. NADH-ubiquinone oxidoreductase chain 3, and acyl-coenzyme A synthetase. Calretinin, S10A5 and secretagogin expression levels were characterized using immunohistochemistry. Calretinin immunoreactivity was significantly increased (>3 fold, p = 0.016) in the medial septal nuclei of 1,25D treated mice in the early remyelination phase. Our results indicate that vitamin D may influence remyelination by mechanisms involving an increase in calretinin expression and potentially other calcium binding proteins.
Glutathione monoethyl ester prevents TDP-43 pathology in motor neuronal NSC-34 cells Neurochem. Int. (IF 3.262) Pub Date : 2017-08-14 Tong Chen, Bradley J. Turner, Philip M. Beart, Lucy Sheehan-Hennessy, Chinasom Elekwachi, Hakan Muyderman
Oxidative stress is recognised as central in a range of neurological diseases including Amyotrophic lateral sclerosis (ALS), a disease characterised by fast progressing death of motor neurons in the brain and spinal cord. Cellular pathology includes cytosolic protein aggregates in motor neurons and glia of which potentially cytotoxic hyper-phosphorylated fragments of the Transactive response DNA Binding Protein 43 kDa (TDP-43) constitute a major component. This is closely associated with an additional loss of nuclear TDP-43 expression indicating a “loss of function” mechanism, accelerating motor neuron (MN) loss. Furthermore, mutations in TDP-43 cause familial ALS and ALS-like disease in animal models. In this study, we investigated the role of glutathione (GSH) in modulating oxidative stress responses in TDP-43 pathology in motor neuron NSC-34 cells. Results demonstrate that depletion of GSH produces pathology similar to that of mutant TDP-43, including occurrence of cytosolic aggregates, TDP-43 phosphorylation and nuclear clearing of endogenous TDP-43. We also demonstrate that introduction of mutant TDP-43A315T and silencing of endogenous TDP-43, but not overexpression of wild-type TDP-43, result in similar pathology, including depletion of intracellular GSH, possibly resulting from a decreased expression of a regulatory subunit of ɣ-glutamylcysteine ligase (GCLM), a rate limiting enzyme in GSH synthesis. Importantly, treatment of mutant cells with GSH monoethyl ester (GSHe) that directly increases intracellular GSH and bypasses the need for GSH synthesis, protected against mutant-induced TDP-43 pathology, including reducing aggregate formation, nuclear clearance, reactive oxygen species (ROS) production and cell death. Our data strongly suggest that oxidative stress is central to TDP-43 pathology and may result from a loss of function affecting GSH synthesis and that treatments directly aimed at restoring cellular GSH content may be beneficial in preventing cell death in TDP-43-mediated ALS.
Antecedent ADHD, dementia, and metabolic dysregulation: A U.S. based cohort analysis Neurochem. Int. (IF 3.262) Pub Date : 2017-08-12 Keith Fluegge, Kyle Fluegge
Introduction Epidemiological and genetic studies have reported a link between antecedent ADHD and dementia. The underpinning mechanisms of these associations are not known and have generated considerable speculation. Methods We have extracted hospitalization discharge data on dementia and ADHD (representing a severe phenotype) from the Healthcare Cost and Utilization Project (HCUPnet) and utilized a Poisson regression with two-ways fixed effects to investigate this association. Results An unadjusted ten-year lagged measure of a severe ADHD phenotype increases hospitalization risk for an all-listed Lewy Body Dementia (LBD) diagnosis (IRR: 1.21, 95% C.I. 1.08–1.35) and Alzheimer's disease (AD) discharge diagnosis (IRR: 1.15, 95% C.I.: 1.05–1.27). However, these relationships may be dependent upon the extent of metabolic dysregulation in a subtype-specific manner, as controlling for diabetes removes the significant association between antecedent ADHD and risk of AD but not LBD. Discussion These results indicate that the association between antecedent ADHD and dementia risk may be uniquely influenced by metabolic dysregulation, building upon prior discussion in this journal of a purported link between AD and diabetes. We tie the current findings to environmental risk factors that we have previously implicated in the etiology of ADHD to generate testable hypotheses on the underlying brain neurochemistry that may facilitate the link between metabolic dysregulation and dementia subtype risk.
Mitophagy in neurodegenerative diseases Neurochem. Int. (IF 3.262) Pub Date : 2017-08-08 Carlo Rodolfo, Silvia Campello, Francesco Cecconi
Neurodegenerative diseases, such as Parkinson's disease (PD), Alzheimer's disease (AD), Huntington's disease (HD), and Amyotrophic Lateral Sclerosis (ALS), are a complex “family” of pathologies, characterised by the progressive loss of neurons and/or neuronal functions, leading to severe physical and cognitive inabilities in affected patients. These syndromes, despite differences in the causative events, the onset, and the progression of the disease, share as common features the presence of aggregate-prone neuro-toxic proteins, in the form of aggresomes and/or inclusion bodies, perturbing cellular homeostasis and neuronal function (Popovic et al., 2014), and the presence of dysfunctional mitochondria. The removal of protein aggregates and of damaged organelles, through the ubiquitin-proteasome system (UPS) and/or the autophagy/lysosome machinery, is a crucial step for the maintenance of neuronal homeostasis. Indeed, their impairment has been reported as associated with the development of these diseases. In this review, we focus on the role played by mitophagy, a specialised form of autophagy, in the onset and progression of major neurodegenerative diseases, as well as on possible therapeutic approaches involving mitophagy modulation.
Resveratrol loaded solid lipid nanoparticles attenuate mitochondrial oxidative stress in vascular dementia by activating Nrf2/HO-1 pathway Neurochem. Int. (IF 3.262) Pub Date : 2017-08-04 Aarti Yadav, Aditya Sunkaria, Nitin Singhal, Rajat Sandhir
Vascular dementia (VaD) is the leading cause of cognitive decline resulting from vascular lesions. Recent studies have shown that mitochondrial dysfunctions and oxidative stress are involved in cognitive decline. The aim of the present study was to evaluate the beneficial effects of resveratrol-loaded solid lipid nanoparticles (R-SLNs) in permanent bilateral common carotid artery occlusion (BCCAO) induced model of VaD. R-SLNs prepared had average size of 286 nm and 91.25% drug encapsulation efficiency with sustained release. Moreover, R-SLNs had 4.5 times higher levels of resveratrol (RSV) in brain compared to when administered as free RSV. Neurobehavioral analyses revealed that R-SLNs administration successfully ameliorated cognitive decline observed in BCCAO rats. Administration of R-SLNs to BCCAO animals showed significant reduction in mitochondrial reactive oxygen species (ROS) generation, lipid peroxidation, and protein carbonyls. In addition, R-SLNs significantly improved redox ratio and Mn-superoxide dismutase (Mn-SOD) activity. R-SLNs administration resulted in significant reduction in hypoxia-inducible factor 1α (HIF-1α) levels, whereas, nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and heme oxygenase 1 (HO-1) levels were increased after R-SLNs treatment. Taken together, the results demonstrate that R-SLNs could be a novel and promising therapeutic strategy in VaD as well in other age-related neurodegenerative disorders.
Mitochondrial dysfunction in the neuro-degenerative and cardio-degenerative disease, Friedreich's ataxia Neurochem. Int. (IF 3.262) Pub Date : 2017-08-04 Shannon Chiang, Danuta S. Kalinowski, Patric J. Jansson, Des R. Richardson, Michael L.-H. Huang
Mitochondrial homeostasis is essential for maintaining healthy cellular function and survival. The detrimental involvement of mitochondrial dysfunction in neuro-degenerative diseases has recently been highlighted in human conditions, such as Parkinson's, Alzheimer's and Huntington's disease. Friedreich's ataxia (FA) is another neuro-degenerative, but also cardio-degenerative condition, where mitochondrial dysfunction plays a crucial role in disease progression. Deficient expression of the mitochondrial protein, frataxin, is the primary cause of FA, which leads to adverse alterations in whole cell and mitochondrial iron metabolism. Dys-regulation of iron metabolism in these compartments, results in the accumulation of inorganic iron deposits in the mitochondrial matrix that is thought to potentiate oxidative damage observed in FA. Therefore, the maintenance of mitochondrial homeostasis is crucial in the progression of neuro-degenerative conditions, particularly in FA. In this review, vital mitochondrial homeostatic processes and their roles in FA pathogenesis will be discussed. These include mitochondrial iron processing, mitochondrial dynamics (fusion and fission processes), mitophagy, mitochondrial biogenesis, mitochondrial energy production and calcium metabolism.
ISG'ylation increases stability of numerous proteins including Stat1, which prevents premature termination of immune response in LPS-stimulated microglia Neurochem. Int. (IF 3.262) Pub Date : 2017-07-31 Piotr Przanowski, Stefan Loska, Dominik Cysewski, Michal Dabrowski, Bozena Kaminska
Microglia are myeloid cells in the central nervous system which maintain homeostasis and contribute to repair, but instigate neuroinflammation when are activated by infection, trauma or neurological diseases. Initiation of acute inflammatory responses could be mimicked in vitro by stimulation of microglial cultures with lipopolysaccharide (LPS). We have previously demonstrated Stat-dependent induction of the Uba7 mRNA expression in LPS stimulated microglia. Uba7 is an E1 enzyme crucial for posttranslational protein modifications. ISG'ylation is a process in which ISG15 is covalently attached to lysines of target proteins via the sequential action of three enzymes: the E1-activating enzyme UbE1L (UBA7), the E2-conjugating enzyme UBCH8, and E3 ligase HERC5. Here we use quantitative labeled-free mass spectrometry and gene silencing to determine the role of ISG'ylation in LPS-stimulated microglia. We found the increased mRNA levels of Isg15, Uba7, Ube2l6, Herc6 and profound ISG'ylation in inflammatory microglia. Silencing of Uba7 in BV2 microglial cells results in a profound decrease in the level of hundreds proteins as measured by mass spectrometry. There is statistically significant intersection of Uba7-dependent proteins in LPS-stimulated microglia and three datasets of ISG'ylated proteins reported in earlier studies. Stat1, a main activator of Uba7 expression, was modified by ISG15 after LPS stimulation. The level of both total and phospho-Stat1 is decreased after Uba7 knockdown leading to premature termination of immune responses as evidenced by the reduction of iNos and Ccl5 expression. Our results suggest that increased ISG'ylation in LPS-stimulated microglia supports stability of proteins, including Stat1, which prevents termination of immune responses during inflammation.
Recombinant neuroglobin ameliorates early brain injury after subarachnoid hemorrhage via inhibiting the activation of mitochondria apoptotic pathway Neurochem. Int. (IF 3.262) Pub Date : 2017-07-31 Fuxiang Chen, Jing Lu, Fan Chen, Zhangya Lin, Yuanxiang Lin, Lianghong Yu, Xingfen Su, Peisen Yao, Bin Cai, Dezhi Kang
Neuroglobin (Ngb) overexpression is considered as an intrinsic neuroprotective response. Therefore, exogenous Ngb increased in brain tissues has become a promising therapeutic strategy for neurological diseases. Previous studies demonstrated that transactivator of transcription (TAT) protein transduction domain was able to mediate synthetic Ngb entrance into neurons, and then protected brain from hypoxia-ischemic injury. However, the role of recombinant Ngb on early brain injury following subarachnoid hemorrhage (SAH) has not been elucidated. The objectives of this study were to investigate the expression of endogenous Ngb in brain using a rabbit model of SAH, and to verify whether TAT-Ngb fusion protein could be delivered into brain parenchyma, as well as to explore the neuroprotective effect of Ngb and its possible mechanisms. We found that Ngb expressions were up regulated in the transcript and protein levels in a similar time dependent manner after SAH as compared to the sham group. Moreover, TAT-Ngb fusion protein was successfully generated and transferred into brain neurons. Compared with the saline- and Ngb-treated group, neuronal viabilities and neurological outcomes were significantly improved 72 h post-SAH in the TAT-Ngb-treated group. Likewise, anti-apoptotic Bcl-2 protein was also elevated obviously. Conversely, pro-apoptotic factors including caspase 3, caspase 9 and Bax were greatly decreased after TAT-Ngb treatment. Our results suggest that Ngb plays a neuroprotective effect in rabbits suffering from SAH possibly through inhibiting the SAH-induced activation of mitochondria apoptotic pathway. Furthermore, TAT-mediated Ngb delivery into brain may be a promising therapeutic approach.
Defective methionine metabolism in the brain after repeated blast exposures might contribute to increased oxidative stress Neurochem. Int. (IF 3.262) Pub Date : 2017-07-31 Peethambaran Arun, William B. Rittase, Donna M. Wilder, Ying Wang, Irene D. Gist, Joseph B. Long
Blast-induced traumatic brain injury (bTBI) is one of the major disabilities in Service Members returning from recent military operations. The neurobiological underpinnings of bTBI, which are associated with acute and chronic neuropathological and neurobehavioral deficits, are uncertain. Increased oxidative stress in the brain is reported to play a significant role promoting neuronal damage associated with both brain injury and neurodegenerative disorders. In this study, brains of rats exposed to repeated blasts in a shock tube underwent untargeted profiling of primary metabolism by automatic linear exchange/cold injection GC-TOF mass spectrometry and revealed acute and sub-acute disruptions in the metabolism of the essential amino acid methionine and associated antioxidants. Methionine sulfoxide, the oxidized metabolite of methionine, showed a sustained increase in the brain after blast exposure which was associated with a significant decrease in cysteine, the amino acid derived from methionine. Glutathione, the antioxidant synthesized from cysteine, also concomitantly decreased as did the antioxidant ascorbic acid. Reductions in ascorbic acid were accompanied by increased levels of its oxidized metabolite, dehydroascorbic acid and other metabolites such as threonic acid, isothreonic acid, glycolic acid and oxalic acid. Fluorometric analysis of the brains showed acute and sub-acute increase in total reactive oxygen species. In view of the fundamental importance of glutathione in the brain as an antioxidant, including its role in the reduction of dehydroascorbic acid to ascorbic acid, the disruptions in methionine metabolism elicited by blast exposure might prominently contribute to neuronal injury by promoting increased and sustained oxidative stress.
Spatial organization of genome architecture in neuronal development and disease Neurochem. Int. (IF 3.262) Pub Date : 2017-07-28 Yuki Fujita, Toshihide Yamashita
Although mammalian genomes encode genetic information in their linear sequences, their fundamental function with regard to gene expression depends on the higher-order structure of chromosomes. Current techniques for the evaluation of chromosomal structure have revealed that genomes are arranged at several hierarchical levels in three-dimensional space. The spatial organization of genomes involves the formation of chromatin loops that bypass a wide range of genomic distances, providing a connection between enhancers and chromosomal domains. Furthermore, they form chromatin domains that are arranged into chromosome territories in the three-dimensional space of the cell nucleus. Recent studies have shown that the spatial organization of the genome is essential for normal brain development and function. Activity-dependent alterations in the spatial organization of the genome can regulate transcriptional activity related to neuronal plasticity. Disruptions in the higher-order chromatin architecture have been implicated in neuropsychiatric disorders, such as cognitive dysfunction and anxiety. Here, we discuss the growing interest in the role of genome organization in brain development and neurological disorders.
Can crosstalk between DOR and PARP reduce oxidative stress mediated neurodegeneration? Neurochem. Int. (IF 3.262) Pub Date : 2017-07-21 Rutika Raina, Dwaipayan Sen
The progressive loss of structure and function of neurons leads to neurodegenerative processes which become the causative reason for various neurodegenerative diseases such as Parkinson's disease (PD), Alzheimer's disease (AD) etc. These diseases are multifactorial in nature but they have been seen to possess similar causative agents to a certain extent. Oxidative Stress (OS) has been identified as a major stressor and a mediator in most of these diseases. OS not only leads to the generation of free radical species but if persistent, can possibly lead to lipid peroxidation, protein damage, DNA damage, and cell death. Anti-oxidants are endogenously present in our body to tackle oxygen metabolites but their levels reduce greatly under continuous OS conditions. In such a case, dietary supplements to replenish the anti-oxidant levels in our body is a good way of treatment but it is very slow and may not be as effective in chronic stress conditions. Thus, there is a need for more effective mechanisms to attenuate OS. Two such mechanisms which can be considered are the activation of Delta opioid receptor (DOR) and Inhibition of Poly (ADP-ribose)-polymerase1 (PARP1), which have been suggested to protect neurons and increase neuronal cell survivability in both in-vitro and in-vivo disease models. Various signaling pathways have been highlighted to probably play a significant role in attenuating OS by the activation of DOR. It would be an interesting topic of investigation to see if one of the probable mechanisms by which DOR attenuates OS could be by modulation of PARP through a cascade of intracellular signaling reactions.
Suppression of cortical TRPM7 protein attenuates oxidative damage after traumatic brain injury via Akt/endothelial nitric oxide synthase pathway Neurochem. Int. (IF 3.262) Pub Date : 2017-07-20 Hong-Liang Xu, Meng-Dong Liu, Xiao-Hong Yuan, Chun-Xi Liu
Neuronal death after traumatic brain injury (TBI) is a complex process resulting from a combination of factors, many of which are still unknown. Transient receptor potential melastatin 7 (TRPM7) is a transient receptor potential channel that has been demonstrated to mediate ischemic and traumatic neuronal injury in vitro. In the present study, TRPM7 was suppressed in the rat cerebral cortex by intracortical injections of viral vectors bearing shRNA specific for TRPM7 to investigate its potential role in an in vivo TBI model. We found that TRPM7 suppression significantly reduced brain edema, brain contusion volume and motor functional deficits, which was sustained for at least 2 weeks after the insult. These protective effects were accompanied by inhibited apoptosis in injured cortex. Also, TRPM7 suppression attenuated lipid peroxidation, decreased the expression of protein carbonyl, and preserved the endogenous antioxidant enzyme activities. The results of western blot analysis showed that TRPM7 suppression markedly increased the phosphorylation of Akt and endothelial nitric oxide synthase (eNOS). In addition, blocking Akt/eNOS pathway activation by the specific inhibitor LY294002 (LY, 10 μL, 10 mmol/L) or L-NIO (0.5 mg/kg) partially reversed the protective effects of TRPM7 suppression and its anti-oxidative activities. Taken together, these findings demonstrated that regional inhibition of TRPM7 in cerebral cortex exerts neuroprotective effects against TBI through activation of Akt/eNOS pathway. Thus, TRPM7 might represent a potential drug development target for the treatment of TBI.
Oxytocin release via activation of TRPM2 and CD38 in the hypothalamus during hyperthermia in mice: Implication for autism spectrum disorder Neurochem. Int. (IF 3.262) Pub Date : 2017-07-20 Haruhiro Higashida, Teruko Yuhi, Shirin Akther, Sarwat Amina, Jing Zhong, Mingkun Liang, Tomoko Nishimura, Hong-Xiang Liu, Olga Lopatina
Oxytocin (OT) is a critical molecule for social recognition that mediates social and emotional behaviors. OT is released during stress and acts as an anxiolytic factor. To know the precise molecular mechanisms underlying OT release into the brain during stress is important. It has been reported that intracellular concentrations of free calcium in the hypothalamic neurons are elevated by simultaneous stimulation of cyclic ADP-ribose (cADPR) and heat. We have reported in vitro and in vivo data that supports the idea that release of OT in the brain of male mice is regulated by cADPR and fever in relation to stress conditions. 1) Significantly higher levels of OT release were observed in hypothalamus cultures isolated from subordinate mice in group-housed males compared to dominant males after cage-switch stress; 2) OT concentrations in micro-perfusates at the paraventricular nucleus upon perfusion stimulation with cADPR were enhanced in subordinate mice compared to dominant mice; 3) The OT concentration in the cerebrospinal fluid (CSF) was higher in endotoxin-shock mice with fever compared to controls with no body temperature increase; and 4) In mice exposed to new environmental stress, the CSF OT level transiently increased 5 min after exposure, while the rectal temperature increased from 36.6 °C to 37.8 °C from 5 to 15 min after exposure. In this review, we examine whether or not cADPR and hyperthermia co-regulate hypothalamic OT secretion during social stress through the elevation of intracellular free Ca2+ concentrations involved in CD38-dependent Ca2+ mobilization and TRPM2-dependent Ca2+ influx. Finally, we propose that the interaction between CD38 and TRPM2 seems to be a new mechanism for stress-induced release of OT, which may result in anxiolytic effects for temporal recovery from social impairments in children with autism spectrum disorder during hyperthermia.
A brain-specific isoform of apoptosis-inducing factor 2 attenuates ischemia-induced oxidative stress in HT22 cells Neurochem. Int. (IF 3.262) Pub Date : 2017-07-18 Yuanyang Xie, Siyi Wanggou, Qing Liu, Xuejun Li, Jingping Liu, Ming Wu
Apoptosis-inducing factor (AIF) is a family of conserved mitochondrial flavoproteins that have both vital and lethal functions in cells. The function and regulation of AIF-1, the original described and most abundant isoform, has been extensively studied, whereas three other AIF isoforms have not been further characterized. Here, we investigated the role of AIF-2, a brain-specific isoform of AIF, in an in vitro ischemia model in neuronal HT22 cells. We showed that AIF-2 was constitutively expressed in HT22 cells, and the oxygen and glucose deprivation (OGD) did not alter AIF-2 expression. Downregulation of AIF-2 with specific siRNA aggravated OGD-induced lactate dehydrogenase (LDH) release, apoptosis and loss of cell viability, whereas overexpression of AIF-2 through lentivirus transfection exerted the opposite effects. In OGD-treated cells, AIF-2 overexpression promoted the endogenous antioxidant enzyme activities, preserved mitochondrial membrane potential (MMP), inhibited cytochrome c release, and thereby prevented reactive oxygen species (ROS) generation and lipid peroxidation. In addition, AIF-2 significantly prevented the OGD-induced AIF-1 translocation from cytoplasm to the nuclei. In view of these considerations, AIF-2 might represent an ideal strategy to avoid AIF-1 associated neurotoxicity, and could be tested against brain ischemia in animal models.
Pharmacologic modeling of primary mitochondrial respiratory chain dysfunction in zebrafish Neurochem. Int. (IF 3.262) Pub Date : 2017-07-18 James Byrnes, Rebecca Ganetzky, Richard Lightfoot, Michael Tzeng, Eiko Nakamaru-Ogiso, Christoph Seiler, Marni J. Falk
Mitochondrial respiratory chain (RC) disease is a heterogeneous and highly morbid group of energy deficiency disorders for which no proven effective therapies exist. Robust vertebrate animal models of primary RC dysfunction are needed to explore the effects of variation in RC disease subtypes, tissue-specific manifestations, and major pathogenic factors contributing to each disorder, as well as their pre-clinical response to therapeutic candidates. We have developed a series of zebrafish (Danio rerio) models that inhibit, to variable degrees, distinct aspects of RC function, and enable quantification of animal development, survival, behaviors, and organ-level treatment effects as well as effects on mitochondrial biochemistry and physiology. Here, we characterize four pharmacologic inhibitor models of mitochondrial RC dysfunction in early larval zebrafish, including rotenone (complex I inhibitor), azide (complex IV inhibitor), oligomycin (complex V inhibitor), and chloramphenicol (mitochondrial translation inhibitor that leads to multiple RC complex dysfunction). A range of concentrations and exposure times of each RC inhibitor were systematically evaluated on early larval development, animal survival, integrated behaviors (touch and startle responses), organ physiology (brain death, neurologic tone, heart rate), and fluorescence-based analyses of mitochondrial physiology in zebrafish skeletal muscle. Pharmacologic RC inhibitor effects were validated by spectrophotometric analysis of Complex I, II and IV enzyme activities, or relative quantitation of ATP levels in larvae. Outcomes were prioritized that utilize in vivo animal imaging and quantitative behavioral assessments, as may optimally inform the translational potential of pre-clinical drug screens for future clinical study in human mitochondrial disease subjects. The RC complex inhibitors each delayed early embryo development, with short-term exposures of these three agents or chloramphenicol from 5 to 7 days post fertilization also causing reduced larval survival and organ-specific defects ranging from brain death, behavioral and neurologic alterations, reduced mitochondrial membrane potential in skeletal muscle (rotenone), and/or cardiac edema with visible blood pooling (oligomycin). Remarkably, we demonstrate that treating animals with probucol, a nutrient-sensing signaling network modulating drug that has been shown to yield therapeutic effects in a range of other RC disease cellular and animal models, both prevented acute rotenone-induced brain death in zebrafish larvae, and significantly rescued early embryo developmental delay from either rotenone or oligomycin exposure. Overall, these zebrafish pharmacologic RC function inhibition models offer a unique opportunity to gain novel insights into diverse developmental, survival, organ-level, and behavioral defects of varying severity, as well as their individual response to candidate therapies, in a highly tractable and cost-effective vertebrate animal model system.
Application of the gene editing tool, CRISPR-Cas9, for treating neurodegenerative diseases Neurochem. Int. (IF 3.262) Pub Date : 2017-07-18 Nivya Kolli, Ming Lu, Panchanan Maiti, Julien Rossignol, Gary L. Dunbar
Increased accumulation of transcribed protein from the damaged DNA and reduced DNA repair capability contributes to numerous neurological diseases for which effective treatments are lacking. Gene editing techniques provide new hope for replacing defective genes and DNA associated with neurological diseases. With advancements in using such editing tools as zinc finger nucleases (ZFNs), meganucleases, and transcription activator-like effector nucleases (TALENs), etc., scientists are able to design DNA-binding proteins, which can make precise double-strand breaks (DSBs) at the target DNA. Recent developments with the CRISPR-Cas9 gene-editing technology has proven to be more precise and efficient when compared to most other gene-editing techniques. Two methods, non-homologous end joining (NHEJ) and homology-direct repair (HDR), are used in CRISPR-Cas9 system to efficiently excise the defective genes and incorporate exogenous DNA at the target site. In this review article, we provide an overview of the CRISPR-Cas9 methodology, including its molecular mechanism, with a focus on how in this gene-editing tool can be used to counteract certain genetic defects associated with neurological diseases. Detailed understanding of this new tool could help researchers design specific gene editing strategies to repair genetic disorders in selective neurological diseases.
Involvement of endoplasmic reticulum stress and neurite outgrowth in the model mice of autism spectrum disorder Neurochem. Int. (IF 3.262) Pub Date : 2017-07-12 Koichi Kawada, Seisuke Mimori, Yasunobu Okuma, Yasuyuki Nomura
Neurodevelopmental disorders are congenital impairments, impeding the growth and development of the central nervous system. These disorders include autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder in Diagnostic and Statistical Manual of Mental Disorders-5. ASD is caused by a gene defect and chromosomal duplication. Despite numerous reports on ASD, the pathogenic mechanisms are not clear. The optimal methods to prevent ASD and to treat it are also not clear. Other studies have reported that endoplasmic reticulum (ER) stress contributes to the pathogenesis of neurodegenerative diseases. In this study, we have investigated ER stress condition and neuronal maturation in an ASD mice model employing male ICR mice. An ASD mice model was established by injecting with valproic acid (VPA) into pregnant mice. The offspring born from VPA-treated mothers were subjected to the experiments as the ASD model mice. The cerebral cortex and hippocampus of ASD model mice were found to be under high ER stress. The mRNA levels of Hes1 and Pax6 were decreased in the cerebral cortex of the ASD model mice, but not in the hippocampus. In addition, the mRNA level in Math1 was increased in the cerebral cortex. ER stress inhibited dendrite and axon extension in primary culture derived from the cerebral cortex of E14.5 mice. Furthermore, dendrite outgrowth was suppressed in primary culture derived from the cerebral cortex of ASD model mice by the same method. These results indicated the possibility that ER stress induces abnormal neuronal maturation in the embryonal cerebral cortex of ASD model mice employing male ICR mice. Therefore, ER stress may contribute to the pathogenesis of ASD.
Upregulation of Cdh1 signaling in the hippocampus attenuates brain damage after transient global cerebral ischemia in rats Neurochem. Int. (IF 3.262) Pub Date : 2017-07-12 Bo Zhang, Kai Wei, Xuan Li, Rong Hu, Jin Qiu, Yue Zhang, Wenlong Yao, Chuanhan Zhang, Chang Zhu
Cerebral ischemia is a major cause of brain dysfunction. The E3 ubiquitin ligase anaphase-promoting complex and its coactivator Cdh1 have been reported to be involved in the regulation of neuronal survival, differentiation, axonal growth and synaptic development in the central nervous system. However, its role in the ischemic brain and the underlying mechanisms remain poorly understood. The present study aimed to investigate the effects of Cdh1 overexpression on the ischemic rat brain by direct intra-hippocampal injection of lentivirus-delivered Cdh1 before transient global cerebral ischemia reperfusion. Spatial memory acquisition and retention were assessed using a Morris water maze task. Neuronal damage, glial activation, oxidative stress and the synaptic ultrastructure were also examined. The results indicated that a recombinant Cdh1-encoding lentiviral vector can upregulate the expression of Cdh1 in the rat hippocampus. Cdh1 overexpression increased the survival rates of rats, reversed the abnormal accumulation of cyclin B1, alleviated neuronal death, inhibited glial activation, mitigated oxidative stress, modulated synaptic plasticity and improved neurological deficits caused by ischemia. Our study indicates that targeting the Cdh1 signaling pathway in the hippocampus may provide a promising therapeutic strategy for the clinical treatment of transient global cerebral ischemia.
Ubiquitination at the mitochondria in neuronal health and disease Neurochem. Int. (IF 3.262) Pub Date : 2017-07-12 Christian Covill-Cooke, Jack H. Howden, Nicol Birsa, Josef T. Kittler
The preservation of mitochondrial function is of particular importance in neurons given the high energy requirements of action potential propagation and synaptic transmission. Indeed, disruptions in mitochondrial dynamics and quality control are linked to cellular pathology in neurodegenerative diseases, such as Alzheimer's and Parkinson's disease. Here, we will discuss the role of ubiquitination by the E3 ligases: Parkin, MARCH5 and Mul1, and how they regulate mitochondrial homeostasis. Furthermore, given the role of Parkin and Mul1 in the formation of mitochondria-derived vesicles we give an overview of this area of mitochondrial homeostasis. We highlight how through the activity of these enzymes and MDV formation, multiple facets of mitochondrial biology can be regulated, ensuring the functionality of the mitochondrial network thus preserving neuronal health.
Traffic jam hypothesis: Relationship between endocytic dysfunction and Alzheimer's disease Neurochem. Int. (IF 3.262) Pub Date : 2017-07-08 Nobuyuki Kimura, Katsuhiko Yanagisawa
Membrane trafficking pathways, like the endocytic pathway, carry out fundamental cellular processes that are essential for normal functioning. One such process is regulation of cell surface receptor signaling. A growing body of evidence suggests that β-amyloid protein (Aβ) plays a key role in Alzheimer's disease (AD) pathogenesis. Cleavage of Aβ from its precursor, β-amyloid precursor protein (APP), occurs through the endocytic pathway in neuronal cells. In early-stage AD, intraneuronal accumulation of abnormally enlarged endosomes is common, indicating that endosome trafficking is disrupted. Strikingly, genome-wide association studies reveal that several endocytosis-related genes are associated with AD onset. Also, recent studies demonstrate that alteration in endocytosis induces not only Aβ pathology but also the propagation of tau protein pathology, another key pathological feature of AD. Endocytic dysfunction can disrupt neuronal physiological functions, such as synaptic vesicle transport and neurotransmitter release. Thus, “traffic jams” in the endocytic pathway may be involved in AD pathogenesis and may serve as a novel target for the development of new therapeutics.
Neuroprotection of edaravone on the hippocampus of kainate-induced epilepsy rats through Nrf2/HO-1 pathway Neurochem. Int. (IF 3.262) Pub Date : 2017-07-08 Zhiguang Liu, Chengzhi Yang, Xinyan Meng, Zaili Li, Cunling Lv, Peiwei Cao
Epilepsy is a severe and chronic neurological disease. Edaravone is an effective free radical scavenger and has been reported to prevent neuronal loss induced by Kainate (KA). However, the molecular mechanisms by which edaravone inhibits KA-induced neuron injury remain elusive. Seventy adult male Wistar rats were randomly divided into 7 groups. For KA treatment, Kainate (4 μg/kg) were administrated in the right hippocampus CA3 region with sereotactic technique. And for edaravone treatment, the rats were intraperitoneal injection with edaravone (10 mg kg - 1 d – 1). All rats were sacrificed on the seven day after the injection of KA. Histological changes of the hippocampus, CA1, CA3 and CA4 were observed under thionine staining. Histological changes of CA1 and CA3 were divided into the following 4 grades (histological grade,HG) under light microscope. The release of inflammatory cytokines was measured by ELISA assay. The inflammatory proteins and Nrf2 and HO-1 expression were determined by quantitative real time PCR (qRT-PCR) and Western blots analysis. Treatment with edaravone increased the neuronal density and decreased the neuronal damage degree in the CA1, CA3 subfield induced by KA. Besides, edaravone reduced the downregulation of the mRNA and protein expression levels of Nrf2 and HO-1 induced by KA. Moreover, edaravone decreased the levels of NF-κB (P65) and proinflammatory cytokines TNF-α, IL-1β and IL-6 and the inflammatory proteins expression levels, HMGB1, nNOS, iNOS and eNOS in the hippocampus. However, introduction of Nrf2-siRNA and HO-1 inhibitor (Znpp) reversed the effects of edaravone on KA-injected rats. Edaravone can protect hippocampal neurons from damage in KA-induced epilepsy rats through Nrf2/HO-1 pathway.
Pathophysiological role of prostaglandin E2-induced up-regulation of the EP2 receptor in motor neuron-like NSC-34 cells and lumbar motor neurons in ALS model mice Neurochem. Int. (IF 3.262) Pub Date : 2017-07-04 Yasuhiro Kosuge, Hiroko Miyagishi, Yuki Yoneoka, Keiko Yoneda, Hiroshi Nango, Kumiko Ishige, Yoshihisa Ito
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by selective degeneration of motor neurons. The primary triggers for motor neuronal death are still unknown, but inflammation is considered to be an important factor contributing to the pathophysiology of ALS both clinically and in ALS models. Prostaglandin E2 (PGE2) and its corresponding four E-prostanoid receptors play a pivotal role in the degeneration of motor neurons in human and transgenic models of ALS. It has also been shown that PGE2-EP2 signaling in glial cells (astrocytes or microglia) promotes motor neuronal death in G93A mice. The present study was designed to investigate the levels of expression of EP receptors in the spinal motor neurons of ALS model mice and to examine whether PGE2 alters the expression of EP receptors in differentiated NSC-34 cells, a motor neuron-like cell line. Immunohistochemical staining demonstrated that EP2 and EP3 immunoreactivity was localized in NeuN-positive large cells showing the typical morphology of motor neurons in mice. Semi-quantitative analysis showed that the immunoreactivity of EP2 in motor neurons was significantly increased in the early symptomatic stage in ALS model mice. In contrast, the level of EP3 expression remained constant, irrespective of age. In differentiated NSC-34 cells, bath application of PGE2 resulted in a concentration-dependent decrease of MTT reduction. Although PGE2 had no effect on cell survival at concentrations of less than 10 μM, pretreatment with 10 μM PGE2 significantly up-regulated EP2 and concomitantly potentiated cell death induced by 30 μM PGE2. These results suggest that PGE2 is an important effector for induction of the EP2 subtype in differentiated NSC-34 cells, and that not only EP2 up-regulation in glial cells but also EP2 up-regulation in motor neurons plays a pivotal role in the vulnerability of motor neurons in ALS model mice.
The broad spectrum of signaling pathways regulated by unfolded protein response in neuronal homeostasis Neurochem. Int. (IF 3.262) Pub Date : 2017-06-28 Atsushi Saito, Kazunori Imaizumi
The protein folding capabilities in the endoplasmic reticulum (ER) are disturbed by alternations in the cellular homeostasis such as the disruption of calcium ion homeostasis, the expression of mutated proteins and oxidative stress. In response to these ER dysfunctions, eukaryotic cells activate canonical branches of signal transduction cascades to restore the protein folding capacity and avoid irreversible damages, collectively termed the unfolded protein response (UPR). Prolonged ER dysfunctions and the downregulation of UPR signaling pathways have been accepted as a crucial trigger for the pathogenesis of various neurodegenerative diseases. Furthermore, recent studies have revealed that the UPR has a wide spectrum of signaling pathways for unique physiological roles in the diverse developmental, differential and lipidomic processes. A developed and intricate ER network exists in the neurites of neurons. Neuronal ER functions and ER-derived signaling mediate efficient communication between cell soma and distal sites through local protein synthesis, sorting and lipogenesis. However, relevant of ER-derived UPR signaling pathways in the elaborate mechanisms regulating neuronal activities, synaptic functions and protective responses against injury is not fully elucidated. In this review, we summarized our current understanding of how the UPR functions provide the appropriate signals for neuronal capabilities. We also reviewed how UPR dysfunctions lead to the pathogenesis of neurodegenerative diseases, and the possibilities ameliorating their toxic effects by targeting UPR components.
Some contents have been Reproduced by permission of The Royal Society of Chemistry.
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