Blockade and reversal of swimming-induced paralysis in C. elegans by the antipsychotic and D2-type dopamine receptor antagonist azaperone Neurochem. Int. (IF 3.262) Pub Date : 2018-05-22 Osama Refai, Randy D. Blakely
The catecholamine neurotransmitter dopamine (DA) exerts powerful modulatory control of physiology and behavior across phylogeny. Perturbations of DA signaling in humans are associated with multiple neurodegenerative and behavioral disorders, including Parkinson's disease, attention-deficit/hyperactivity disorder, addiction and schizophrenia. In the nematode C. elegans, DA signaling regulates mating behavior, learning, food seeking and locomotion. Previously, we demonstrated that loss of function mutations in the dat-1 gene that encodes the presynaptic DA transporter (DAT-1) results in a rapid cessation of movement when animals are placed in water, termed Swimming Induced Paralysis (Swip). Mutations in genes supporting DA biosynthesis, vesicular packaging and DA signaling suppresses Swip in dat-1 animals, consistent with paralysis as arising from excessive DA signaling at the extrasynaptic D2-type DA receptor DOP-3. Although animals grown on the vesicular monoamine transporter antagonist reserpine diminish Swip, the drug must be applied chronically, can impact the signaling of multiple biogenic amines, and has been reported to have penetrant, off-target actions. Here, we demonstrate that the antipsychotic drug azaperone potently and rapidly suppresses Swip behavior in either dat-1 mutants, as well as in wildtype animals treated with the DAT-1 antagonist nisoxetine, with genetic experiments consistent with DOP-3 antagonism as the mechanism of Swip suppression. Reversal of Swip in previously paralyzed dat-1 animals by azaperone application demonstrates an otherwise functionally-intact swimming circuit in these mutants. Finally, whereas azaperone suppresses DA-dependent Swip, the drug fails to attenuate the DA-independent paralysis induced by βPEA, aldicarb or genetic disruption of γ-aminobutyric acid (GABA) signaling. We discuss our findings with respect to the use of azaperone as a potent and selective tool in the identification and analysis of presynaptic mechanisms that regulate DA signaling.
Fisetin alleviates oxidative stress after traumatic brain injury via the Nrf2-ARE pathway Neurochem. Int. (IF 3.262) Pub Date : 2018-05-22 Li Zhang, Handong Wang, Yali Zhou, Yihao Zhu, Maoxin Fei
Fisetin, a natural flavonoid, has neuroprotection properties in many brain injury models. However, its role in traumatic brain injury (TBI) has not been fully explained. In the present study, we aimed to explore the neuroprotective effects of fisetin in a mouse model of TBI. We found that fisetin improved neurological function, reduced cerebral edema, attenuated brain lesion and ameliorated blood-brain barrier (BBB) disruption after TBI. Moreover, the up-regulation of malondialdehyde (MDA) and the activity of glutathione peroxidase (GPx) were reversed by fisetin treatment. Furthermore, administration of fisetin suppressed neuron cell death and apoptosis, increased the expression of B-cell lymphoma 2 (Bcl-2), while decreased the expression of Bcl-2-associated X protein (Bax) and caspase-3 after TBI. In addition, fisetin activated the nuclear factor erythroid 2-related factor 2 (Nrf2)-antioxidant response element (ARE) pathway following TBI. However, fisetin only failed to suppress oxidative stress in Nrf2−/− mice. In conclusion, our data provided the first evidence that fisetin played a critical role in neuroprotection after TBI partly through the activation of the Nrf2-ARE pathway.
Increased brain docosahexaenoic acid has no effect on the resolution of neuroinflammation following intracerebroventricular lipopolysaccharide injection Neurochem. Int. (IF 3.262) Pub Date : 2018-05-22 Marc-Olivier Trépanier, Kathryn E. Hopperton, Vanessa Giuliano, Mojgan Masoodi, Richard P. Bazinet
Resolution of inflammation in the periphery was once thought to be a passive process, but new research now suggests it is an active process mediated by specialized pro-resolving lipid mediators (SPM) derived from omega-3 polyunsaturated fatty acids (n-3 PUFA). However, this has yet to be illustrated in neuroinflammation. The purpose of this study was to measure resolution of neuroinflammation and to test whether increasing brain docosahexaenoic acid (DHA) affects the resolution of neuroinflammation.C57Bl/6 mice, fat-1 mice and their wildtype littermates, fed either fish oil or safflower oil, received lipopolysaccharide (LPS) in the left lateral ventricle. Animals were then euthanized at various time points for immunohistochemistry, gene expression, and lipidomic analyses.Peak microglial activation was observed at 5 days post-surgery and the resolution index was 10 days. Of the approximately 350 genes significantly changed over the 28 days post LPS injection, 130 were uniquely changed at 3 days post injection. No changes were observed in the bioactive mediator pools. However, a few lysophospholipid species were decreased at 24hr post surgery. When brain DHA is increased, microglial cell density did not resolve faster and did not alter gene expression.In conclusion, resolution of neuroinflammation appears to be independent of SPM. Increasing brain DHA had no effect in this model.
Protective effect of S-nitrosoglutathione administration against hyperglycemia induced disruption of blood brain barrier is mediated by alterations in tight junction proteins and cell adhesion molecules Neurochem. Int. (IF 3.262) Pub Date : 2018-05-21 Aanchal Aggarwal, Inderjit Singh, Rajat Sandhir
Diabetes is associated with increased blood brain barrier (BBB) permeability resulting in neurological deficits. The present study investigated the role of S-nitrosoglutathione (GSNO) on tight junction proteins and cell adhesion molecules in streptozotocin-induced diabetic mice. Diabetes was induced by intraperitoneal injection of streptozotocin (40 mg/kg body weight) for 5 days in mice. GSNO was administered daily (100 μg/kg body weight, orally) for 8 weeks after the induction of diabetes. A significant decline was observed in the cognitive ability of diabetic animals assessed using radial arm maze test. A significant increase was observed in nitrotyrosine levels in cortex and hippocampus of diabetic mice. Relative mRNA and protein expression of tight junction proteins viz; zona occludens-1 (ZO-1) and occludin were significantly lower in the microvessels isolated from cortex and hippocampus of diabetic animals, whereas expression of claudin-5 mRNA and protein was unaltered. Immunofluorescence of tight junction proteins confirmed loss of ZO-1 and occludin in the diabetic brain. Furthermore, significant increase in interstitial cell adhesion molecule (ICAM)-1 and vascular cell adhesion molecule (VCAM)-1 mRNA and protein expression was observed in diabetic animals. Ultrastructure of microvessels from diabetic brain was also altered thereby confirming BBB disruption. GSNO administration to diabetic animals, on the other hand, was able to ameliorate loss of ZO-1 and occludin as well as normalize ICAM-1 and VCAM-1 expression, restore BBB integrity and vascular inflammation, and improve cognitive deficits. Therefore, our findings clearly suggest that GSNO is a therapeutic with potential to protect BBB and thereby preventing diabetes induced neurological deficits.
Tumor necrosis factor receptor 2 is required for ischemic preconditioning-mediated neuroprotection in the hippocampus following a subsequent longer transient cerebral ischemia Neurochem. Int. (IF 3.262) Pub Date : 2018-05-17 Jae-Chul Lee, Chan Woo Park, Myoung Cheol Shin, Jun Hwi Cho, Hyang-Ah Lee, Young-Myeong Kim, Joon Ha Park, Ji Hyeon Ahn, Jeong Hwi Cho, Hyun-Jin Tae, In Koo Hwang, Tae-Kyeong Lee, Moo-Ho Won, Il Jun Kang
Tumor Necrosis Factor-α (TNF-α) is a proinflammatory cytokine implicated in neuronal damage in response to cerebral ischemia. Ischemic preconditioning (IPC) provides neuroprotection against a subsequent severer or longer transient ischemia by ischemic tolerance. Here, we focused on the role of TNF-α in IPC-mediated neuroprotection against neuronal death following a subsequent longer transient cerebral ischemia (TCI). Gerbils used in this study were randomly assigned to eight groups; sham group, TCI operated group, IPC plus (+) sham group, IPC + TCI operated group, sham + etanercept (an inhibitor of TNF-a) group, TCI + etanercept group, IPC + sham + etanercept group, and IPC + TCI + etanercept group. IPC was induced by a 2-min sublethal transient ischemia, which was operated 1 day prior to a longer (5-min) TCI. A significant death of neurons was found in the stratum pyramidale (SP) in the CA1 area (CA1) of the hippocampus 5 days after TCI; however, IPC protected SP neurons from TCI. We found that TNF-α immunoreactivity was significantly increased in CA1 pyramidal neurons in the TCI and IPC + TCI groups compared to the sham group. TNF-R1 expression in CA1 pyramidal neurons of the TCI group was also increased 1 and 2 days after TCI; however, in the IPC + TCI group, TNF-R1 expression was significantly lower than that in the TCI group. On the other hand, we did not detect TNF-R2 immunoreactivity in CA1 pyramidal neurons 1 and 2 days after TCI; meanwhile, in the IPC + TCI group, TNF-R2 expression was significantly increased compared to TNF-R2 expression at 1 and 2 days after TCI. In addition, in this group, TNF-R2 was newly expressed in pericytes, which are important cells in the blood brain barrier, from 1 day after TCI. When we treated etanercept to the IPC + TCI group, IPC-induced neuroprotection was significantly weakened. In brief, this study indicates that IPC confers neuroprotection against TCI by TNF-α signaling through TNF-R2 and suggests that the enhancement of TNF-R2 expression by IPC may be a legitimate strategy for a therapeutic intervention of TCI.
Agmatine potentiates neuroprotective effects of subthreshold concentrations of ketamine via mTOR/S6 kinase signaling pathway Neurochem. Int. (IF 3.262) Pub Date : 2018-05-12 Mauren K. Tavares, Suellen dos Reis, Nicolle Platt, Isabella A. Heinrich, Ingrid A.V. Wolin, Rodrigo B. Leal, Manuella P. Kaster, Ana Lúcia S. Rodrigues, Andiara E. Freitas
Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis is one of the most robust neurobiological findings in the pathophysiology of major depressive disorder (MDD) over the last 40 years. The persistent increase in glucocorticoids levels induces morphological and anatomical changes in the brain, especially in the hippocampus. Ketamine represents a major advance for the treatment of MDD, however the psychotomimetic effects of this compound limit its widespread use. Agmatine is a neuromodulator that has been shown to be a putative novel and well-tolerated antidepressant/augmenter drug. In this study, the exposure of HT22 hippocampal neuronal cell line to corticosterone (50 μM) induced a significant neuronal cell death. Interestingly, the incubation of HT22 cells with the fast-acting antidepressant drug ketamine (1 μM) prevented the corticosterone-induced toxicity. Similarly, agmatine caused a significant cytoprotection at the concentration of 0.1 μM against corticosterone (50 μM) cell damage. Notably, the incubation with a subthreshold concentration of ketamine (0.01 μM) in combination with a subthreshold concentration of agmatine (0.001 μM) prevented the neuronal damage elicited by corticosterone (50 μM). A 24 h co-incubation with subthreshold concentrations of ketamine (0.01 μM) and agmatine (0.001 μM) was able to cause a significant increase in the phosphorylation levels of Akt (Ser473) and p70S6 kinase (Thr389) as well as PSD95 immunocontent. Neither glycogen synthase kinase-3β (Ser9) phosphorylation nor β catenin immunocontent were altered by a 24 h co-incubation period. Finally, the co-incubation of cells for 30 min did not produce any effect in the phosphorylation or immunocontent of any protein investigated. Taken together, our results support the notion that the combination of subthreshold concentrations of ketamine and agmatine has cytoprotective effects against corticosterone-induced cell death. This effect is accompanied by its ability to activate Akt and mTOR/S6 kinase signaling pathway, and increase the expression of synaptic proteins.
Serum 25-hydroxyvitamin D deficiency predicts poor outcome among acute ischemic stroke patients without hypertension Neurochem. Int. (IF 3.262) Pub Date : 2018-05-03 Bingjun Zhang, Yuge Wang, Yi Zhong, Siyuan Liao, Zhengqi Lu
25-Hydroxyvitamin D (25(OH)D) deficiency is a frequent condition in patients who suffer acute ischemic stroke (AIS), and several studies suggested that it may be associated with a poorer prognosis. Whether this association is affected by hypertension is unclear. Our aim was to investigate the association between 25(OH)D levels and both clinical severity and outcome after 3 months in AIS patients stratified by the history of hypertension. Consecutive first-ever AIS patients admitted to the Third Affiliated Hospital of Sun Yat-sen University, China were identified. Clinical information was collected. Serum 25(OH)D levels were measured at baseline. Stroke severity was assessed at admission using the National Institutes of Health Stroke Scale (NIHSS) score. Functional outcome was evaluated after 3 months of onset using the modified Rankin Scale (mRS). Multivariate analyses were performed using logistic regression models. During the study period, 377 patients were diagnosed as AIS and were included in the analysis. 25(OH)D deficiency was not associated with the risk of NIHSS at admission and 3 months mRS both in total patients and the hypertension subgroup. Among AIS without hypertension, 25(OH)D deficiency subjects had a significantly higher of NIHSS at admission and 3 months mRS compared with those with 25(OH)D ≥ 50 nmol/L. The odds ratios (95% confidence interval) were 5.51(1.83–16.60) and 4.63(1.53–14.05) in the multivariable adjusted model (P for linear trend < 0.05). Serum lower 25(OH)D levels can be seen as an independent prognostic factor of functional outcome in AIS without hypertension. Additional studies about improving prognosis of AIS by vitamin D supplementation could be first applied to these patients.
Huntington's disease pattern of transcriptional dysregulation in the absence of mutant huntingtin is produced by knockout of neuronal GLT-1 Neurochem. Int. (IF 3.262) Pub Date : 2018-04-27 Robert B. Laprairie, Geraldine T. Petr, Yan Sun, Kathryn D. Fischer, Eileen M. Denovan-Wright, Paul A. Rosenberg
GLT-1 is the major glutamate transporter in the brain, and is expressed in astrocytes and in axon terminals in the hippocampus, cortex, and striatum. Neuronal GLT-1 accounts for only 5–10% of total brain GLT-1 protein, and its function is uncertain. In HD, synaptic dysfunction of the corticostriate synapse is well-established. Transcriptional dysregulation is a key feature of HD. We hypothesized that deletion of neuronal GLT-1, because it is expressed in axon terminals in the striatum, might produce a synaptopathy similar to that present in HD. If true, then some of the gene expression changes observed in HD might also be observed in the neuronal GLT-1 knockout. In situ hybridization using 33P labeled oligonucleotide probes was carried out to assess localization and expression of a panel of genes known to be altered in expression in HD. We found changes in the expression of cannabinoid receptors 1 and 2, preproenkaphalin, and PDE10A in the striatum of mice in which the GLT-1 gene was inactivated in neurons by expression of synapsin-Cre, compared to wild-type littermates. These changes in expression were observed at 12 weeks of age but not at 6 weeks of age. No changes in DARPP-32, PDE1B, NGFIA, or β-actin expression were observed. In addition, we found widespread alteration in expression of the dynamin 1 gene. The changes in expression in the neuronal GLT-1 knockout of genes thought to exemplify HD transcriptional dysregulation suggest an overlap in the synaptopathy caused by neuronal GLT-1 deletion and HD. These data further suggest that specific changes in expression of cannabinoid receptors, preproenkephalin, and PDE10A, considered to be the hallmark of HD transcriptional dysregulation, may be produced by an abnormality of glutamate homeostasis under the regulation of neuronal GLT-1, or a synaptic disturbance caused by that abnormality, independently of mutation in huntingtin.
Endogenous acetylcholine regulates neuronal and astrocytic vascular endothelial growth factor expression levels via different acetylcholine receptor mechanisms Neurochem. Int. (IF 3.262) Pub Date : 2018-04-26 Kyoko Kimura, Kinzo Matsumoto, Hironori Ohtake, Jun-Ichiro Oka, Hironori Fujiwara
Vascular endothelial growth factor (VEGF), a signaling molecule involved in angiogenesis, plays an important role in neuroprotection and neurogenesis. In the present study, we aimed to elucidate the mechanisms underlying endogenous acetylcholine (ACh)-induced VEGF expression in neurons and astrocytes, and identify the neuronal cells contributing to its expression in the medial septal area, a nuclear origin of cholinergic neurons mainly projecting to the hippocampus. The mRNA expression and secretion of VEGF were measured by RT-PCR and ELISA using mouse primary cultured cortical neurons and astrocytes. VEGF expression in the medial septal area was assessed by RT-PCR and immunostaining using mice treated with tacrine [9-amino-1,2,3,4-tetrahydro-acridine HCl (THA); 2.5 mg/kg, i.p.] once daily for 7 days. The THA treatment increased VEGF mRNA expression in neurons in a manner that was reversed by mecamylamine, a nicotinic ACh receptor (AChR) antagonist, whereas in mouse primary cultured astrocytes, carbachol, but not THA dose-dependently increased VEGF mRNA expression and secretion in a manner that was inhibited by scopolamine, a muscarinic AChR inhibitor. In in vivo studies, the administration of THA significantly increased the expression of VEGF in medial septal cholinergic neurons and the effects of THA were significantly blocked by mecamylamine. THA also significantly increased the expression levels of a phosphorylated form of VEGF receptor 2 (p-VEGFR2), an activated form of VEGFR2. The present results suggest that endogenous ACh plays an up-regulatory role for VEGF expression in neurons and astrocytes via different mechanisms. Moreover, endogenous ACh-induced increases in VEGF levels appear to activate VEGFR2 on medial septal cholinergic neurons via an autocrine mechanism.
Mitochondrial alterations in Parkinson's disease human samples and cellular models Neurochem. Int. (IF 3.262) Pub Date : 2018-04-26 Mara Zilocchi, Giovanna Finzi, Marta Lualdi, Fausto Sessa, Mauro Fasano, Tiziana Alberio
Mitochondrial impairment is one of the most important hallmarks of Parkinson's disease (PD) pathogenesis. In this work, we wanted to verify the molecular basis of altered mitochondrial dynamics and disposal in Substantia nigra specimens of sporadic PD patients, by the comparison with two cellular models of PD. Indeed, SH-SY5Y cells were treated with either dopamine or 1-methyl-4-phenylpyridinium (MPP+) in order to highlight the effect of altered dopamine homeostasis and of complex I inhibition, respectively. As a result, we found that fusion impairment of the inner mitochondrial membrane is a common feature of both PD human samples and cellular models. However, the effects of dopamine and MPP+ treatments resulted to be different in terms of the mitochondrial damage induced. Opposite changes in the levels of two mitochondrial protein markers (voltage-dependent anion channels (VDACs) and cytochrome c oxidase subunit 5β (COX5β)) were observed. In this case, dopamine treatment better recapitulated the molecular picture of patients' samples. Moreover, the accumulation of PTEN-induced putative kinase 1 (PINK1), a mitophagy marker, was not observed in both PD patients samples and cellular models. Eventually, in transmission electron microscopy images, small electron dense deposits were observed in mitochondria of PD subjects, which are uniquely reproduced in dopamine-treated cells. In conclusion, our study suggests that the mitochondrial molecular landscape of Substantia nigra specimens of PD patients can be mirrored by the impaired dopamine homeostasis cellular model, thus supporting the hypothesis that alterations in this process could be a crucial pathogenetic event in PD.
Protective influences of N-acetylcysteine against alcohol abstinence-induced depression by regulating biochemical and GRIN2A, GRIN2B gene expression of NMDA receptor signaling pathway in rats Neurochem. Int. (IF 3.262) Pub Date : 2018-04-25 Rutuja Yawalkar, Harish Changotra, Girdhari Lal Gupta
Evidences have indicated a high degree of comorbidity of alcoholism and depression. N-acetylcysteine (NAC) has shown its clinical efficiency in the treatment of several psychiatric disorders and is identified as a multi-target acting drug. The ability of NAC to prevent alcohol abstinence-induced depression-like effects and underlying mechanism(s) have not been adequately addressed. This study was aimed to investigate the beneficial effects of NAC in the alcohol abstinence-induced depression developed following long-term voluntary alcohol intake. For evaluation of the effects of NAC, Sprague–Dawley rats were enabled to voluntary drinking of 4.5%, 7.5% and 9% v/v alcohol for fifteen days. NAC (25, 50, and 100 mg/kg) and fluoxetine (5 mg/kg) were injected intraperitoneally for three consecutive days during the alcohol abstinence period on the days 16, 17, 18. The behavioral studies were conducted employing forced swim test (FST), and tail suspension test (TST) on day 18 to determine the effects of N-acetylcysteine and fluoxetine in the ethanol withdrawal induced-depression. Blood alcohol concentration, alcohol biomarkers like SGPT, SGOT, ALP, GGT, and MCV were estimated by using commercially available kits. Serotonin concentrations were measured in the plasma, hippocampus and pre-frontal cortex using the rat ELISA kit. The expression of GRIN1, GRIN2A, GRIN2B genes for the N-methyl d-aspartate receptors (NMDAR) subunits in the hippocampus and the prefrontal cortex were also examined by reverse-transcription quantitative polymerase chain reaction. The results revealed that alcohol abstinence group depicted increased immobility time in FST and TST. Further, NAC exerted significant protective effect at the doses 50 mg/kg and 100 mg/kg, but 25 mg/kg showed insignificant protection against alcohol abstinence-induced depression. The increased level of biochemical parameters following ethanol abstinence were also reversed by NAC at the dose of 100 mg/kg. The significant reversal effect of NAC on the serotonin level following alcohol abstinence was greater in the hippocampus as compared to the third-day alcohol withdrawal group. The increased expression levels of GRIN2A and GRIN2B following ethanol abstinence were reversed with a higher dose of NAC (100 mg/kg) treatment. In conclusion, the results of the study reveal that NAC has remarkable protective effects in the alcohol abstinence-induced depression by modulating alcohol markers, serotonin levels and GRIN2A, GRIN2B gene expression of NMDAR signaling pathway in rats.
Regulation of the ARE-binding proteins, TTP (tristetraprolin) and HuR (human antigen R), in inflammatory response in astrocytes Neurochem. Int. (IF 3.262) Pub Date : 2018-04-24 Alina A. Astakhova, Dmitry V. Chistyakov, Marina G. Sergeeva, Georg Reiser
Control of decay of mRNA containing the adenine-uridine rich elements (AREs) is an important post-transcriptional mechanism involved in the regulation of inflammatory gene expression. Two widely recognized proteins in this machinery are HuR (human antigen R) – a protein that stabilizes ARE-containing mRNA and TTP (tristetraprolin) – a protein that shortens half-lives of ARE-containing mRNA. Although HuR and TTP regulation mechanisms have been well studied in cells of hematopoietic origin, there are no respective data in astrocytes, cells of ectodermal origin which play an important role in neuroinflammation. Therefore we evaluated the existence of TTP and HuR in primary astrocytes and characterized the features of their regulation after stimulation by the proinflammatory stimuli thrombin, ATP, and agonists of TLR4, TLR2. All proinflammatory stimuli increased levels of TTP mRNA, but not HuR mRNA. Transcripts of both HuR and TTP underwent stabilization upon lipopolysaccharide (LPS) treatment, measured with the actinomycin D protocol. This effect was abolished by treatment with SB203580, an inhibitor of р38 МАРК. Both TTP and HuR transcripts were sensitive to modulation by anisomycin and cycloheximide. LPS induced translocation of HuR protein from nucleus to cytoplasm. TTP is localized in the cytosolic fraction and localization is not sensitive to LPS treatment. Our data for the first time reveal specificity of regulation of ARE-binding proteins in astrocytes. We propose possibilities to manipulate brain inflammatory processes via post-transcription regulatory steps in astrocytes.
Activation of M2 muscarinic acetylcholine receptors by a hybrid agonist enhances cytotoxic effects in GB7 glioblastoma cancer stem cells Neurochem. Int. (IF 3.262) Pub Date : 2018-04-24 Ilaria Cristofaro, Zaira Spinello, Carlo Matera, Mario Fiore, Luciano Conti, Marco De Amici, Clelia Dallanoce, Ada Maria Tata
In previous studies, we found that the orthosteric muscarinic agonist arecaidine propargyl ester (APE) (100 μM) induced a decreased cell proliferation and severe apoptosis in glioblastoma cancer stem cells (GSCs). In this report, we have investigated the effects mediated by hybrid (orthosteric/allosteric) muscarinic agonists P-6-Iper and N-8-Iper on GSCs survival. At variance with APE, the agonist N-8-Iper inhibited cell growth in a dose dependent manner and also impaired cell survival at low doses. The inhibitory effects of the N-8-Iper action appear to be mediated by M2 receptor activation, since they were strongly reduced by co-administration of the selective M2 receptor antagonist methoctramine as well as upon M2 receptor silencing. Moreover, analysis of the expression of phosphorylated histone H2AX (γ-H2AX) indicated that the treatment with N-8-Iper produced a decreased cell survival by induction of DNA damage. The ability of N-8-Iper to produce a cytotoxic effect and apoptosis at low doses indicates that this muscarinic agonist is a suitable probe in a putative therapeutic intervention on glioblastoma through M2 receptor activation.
Mitochondria in the nervous system: From Health to disease, part II Neurochem. Int. (IF 3.262) Pub Date : 2018-04-10 Maria Teresa Carrì, Brian M. Polster, Philip M. Beart
In Part II of this Special Issue on "Mitochondria in the Nervous System: From Health to Disease", the editors bring together more reviews and original articles from researchers in the field of mitochondrial metabolism in the healthy and diseased nervous system. Subjects span from basic mitochondrial physiology to papers on mitochondrial dynamics and to those altered states of the nervous system that can be considered “mitopathologies”. Finally, a few papers approach aspects of mitochondrial biology linked to the feasibility and validity of a mitochondrial therapy.
Restorative effect of l-Dopa treatment against Ochratoxin A induced neurotoxicity Neurochem. Int. (IF 3.262) Pub Date : 2018-04-05 Pratiksha V. Bhat, T. Anand, Manu T. Mohan, Farhath Khanum
The toxic effects of Ochratoxin A (OTA), a fungal secondary metabolite of the genera Aspergillus and Penicillium with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) a Parkinson inducing drug were investigated to evaluate the neurotoxic effects exerted by OTA. OTA is known to contaminate food and feedstuff leading to a wide range of toxicity like nephrotoxicity, hepatotoxicity, and immunotoxicity. However, due to the dearth of available information on the possible mechanisms of OTA neurotoxicity and neurodegeneration the current study was undertaken. Hence, in this study, we examined the neurotoxic effects and the possible mechanism of action of neurodegeneration by OTA toxicity on mice brain by conducting a battery of behavioural studies and reviewing neurotransmitter levels and neuronal apoptotic pathways. Further, they were treated with l-Dopa, a precursor of dopamine (DA) to explore its ameliorative effects against OTA. The results of behavioural studies like gait analysis, spontaneous activity, cylinder test and pole test showed that OTA exhibits Parkinsonian physiognomies which were stabilized with l-Dopa treatment. Also, OTA toxicity showed insults on neurotransmitter levels and general brain function parameters that were normalized with l-Dopa treatment. The results of the present study suggest that OTA promotes neurodegeneration by targeting neuronal pathway leading to the development of Parkinson's diseases.
The antipsychotic drug quetiapine stimulates oligodendrocyte differentiation by modulating the cell cycle Neurochem. Int. (IF 3.262) Pub Date : 2018-04-05 Guiyun Mi, Yituo Wang, Enmao Ye, Yunyun Gao, Qiaowei Liu, Pinhong Chen, Yuyang Zhu, Hongju Yang, Zheng Yang
Recent studies have revealed that oligodendrocyte differentiation deficits and de-myelination occur in the brains of schizophrenic patients. Cell cycle proteins play a critical role in modulating oligodendrocyte proliferation and differentiation. In our previous studies, we found that cuprizone, a copper chelant, induces oligodendrocyte loss and demyelination, and this effect can be alleviated by using the atypical antipsychotic drug quetiapine. To explore the mechanisms of quetiapine in oligodendrocyte development, we examined the effects of quetiapine on cell cycle progression. Quetiapine promoted cell cycle exit and blocked the mitogenic effect of PDGF in cultured rat cortical oligodendrocyte progenitor cells (OPCs). Quetiapine accelerated OPC differentiation in vitro. Moreover, the systemic administration of quetiapine up-regulated p21 mRNA expression, a cyclin-dependent kinase inhibitor, in mice. Knocking down p21 expression by RNA interference enhanced proliferation and delayed differentiation. Our results suggest that cell cycle regulation may contribute to the differentiation-promoting effect of quetiapine.
12/15 lipoxygenase: A crucial enzyme in diverse types of cell death Neurochem. Int. (IF 3.262) Pub Date : 2018-04-05 Qiu-Qi Li, Qin-Li, Ji-Ning Jia, Zhao-Qian Liu, Hong-Hao Zhou, Xiao-Yuan Mao
The 12/15-lipoxygenase (12/15-LOX) enzymes react with polyunsaturated fatty acids producing active lipid metabolites that are involved in plethora of human diseases including neurological disorders. A great many of elegant studies over the last decades have contributed to unraveling the mechanism how 12/15-lipoxygenase play a role in these diseases. And the way it works is mainly through apoptosis. However, recent years have found that the way 12/15-lipoxygenase works is also related to autophagy and ferroptosis, a newly defined type of cell death by Stockwell's lab in 2012. Figuring out how 12/15-lipoxygenase participate in these modes of cell death is of vital importance to understand its role in disease. The review aims to give a sight on our current knowledge on the role of this enzyme in apoptosis, autophagy and ferroptosis. And the relevant diseases that 12/15-lipoxygenase may be involved.
Repeated peripheral administration of lipidized prolactin-releasing peptide analog induces c-fos and FosB expression in neurons of dorsomedial hypothalamic nucleus in male C57 mice Neurochem. Int. (IF 3.262) Pub Date : 2018-03-27 Zdenko Pirník, Mária Kolesárová, Blanka Železná, Lenka Maletínská
Previous studies indicate that hypothalamic prolactin-releasing peptide (PrRP), signaling via GPR10 and neuropeptide FF2 receptor, is involved in energy homeostasis, stress responses, and cardiovascular regulation. Energy homeostasis depends on the balance between food intake regulation and energy expenditure, in which the hypothalamus plays a key role. The lipidization of PrRP31 with palmitoyl acid allows it to produce its anorexigenic effect after repeated peripheral administration and to reduce body weight and improve metabolic parameters in diet-induced obese (DIO) mice. The aim of this study was to reveal the transient and long-lasting changes in neuronal activity via c-Fos and FosB immunohistochemistry in brain nuclei related to food intake regulation and energy homeostasis during the first days of treatment with a newly designed lipidized analog of PrRP31 (palm11-PrRP31) with promising antiobesity effects. The data revealed that the anorexigenic effect of repeated application of palm11-PrRP31 was associated with delayed but gradually significantly reduced cumulative food intake in mice as well as with a significant reduction in their body weight. Moreover, while the repeated application of palm11-PrRP31 was associated with a significant reduction in acute cell activity in the paraventricular hypothalamic nucleus (PVN) and nucleus of the solitary tract (NTS) compare to its acute treatment, both acute and long-lasting cell activity in the dorsomedial hypothalamic nucleus (DMN) were increased. The data indicate that DMN neurons might be tonically activated after repeated administration of lipidized PrRP analogs that may be associated with the process of long-term adaptation to modified energy homeostasis.
Activity dependent internalization of the glutamate transporter GLT-1 requires calcium entry through the NCX sodium/calcium exchanger Neurochem. Int. (IF 3.262) Pub Date : 2018-03-21 Ignacio Ibáñez, David Bartolomé-Martín, Dolores Piniella, Cecilio Giménez, Francisco Zafra
GLT-1 is the main glutamate transporter in the brain and its trafficking controls its availability at the cell surface, thereby shaping glutamatergic neurotransmission under physiological and pathological conditions. Extracellular glutamate is known to trigger ubiquitin-dependent GLT-1 internalization from the surface of the cell to the intracellular compartment, yet here we show that internalization also requires the participation of calcium ions. Consistent with previous studies, the addition of glutamate (1 mM) to mixed primary cultures (containing neurons and astrocytes) promotes GLT-1 internalization, an effect that was suppressed in the absence of extracellular Ca2+. The pathways of Ca2+ mobilization by astrocytes were analyzed in these mixed cultures using the genetically encoded calcium sensor GCaMP6f. A complex pattern of calcium entry was activated by glutamate, with a dramatic and rapid rise in the intracellular Ca2+ concentration partially driven by glutamate transporters, especially in the initial stages after exposure to glutamate. The Na+/Ca2+ exchanger (NCX) plays a dominant role in this Ca2+ mobilization and its blockade suppresses the glutamate induced internalization of GLT-1, both in astrocytes and in a more straightforward experimental system like HEK293 cells transiently transfected with GLT-1. This regulatory mechanism might be relevant to control the amount of GLT-1 transporter at the cell surface in conditions like ischemia or traumatic brain injury, where extracellular concentrations of glutamate are persistently elevated and they promote rapid Ca2+ mobilization.
Long noncoding RNA DANCR mediates cisplatin resistance in glioma cells via activating AXL/PI3K/Akt/NF-κB signaling pathway Neurochem. Int. (IF 3.262) Pub Date : 2018-03-21 Yangang Ma, Guanghua Zhou, Mengyou Li, Dianfeng Hu, Lianqun Zhang, Peng Liu, Kai Lin
Malignant glioma is an aggressive type of brain tumor with poor prognosis and mostly incurable. Although cisplatin is used for adjuvant chemotherapy against glioma, intrinsic and acquired resistance restricts the application of cisplatin. Long noncoding RNA (lncRNA) DANCR is reported to regulate the differentiation and progression of several cancers. However, whether DANCR participates in cisplatin resistance of glioma is still unknown. In this study, we found that DANCR expression was negatively correlated with cisplatin sensitivity in glioma cells. Gain-of and loss-of function assays revealed that DNACR attenuated cisplatin-induced cell proliferation inhibition in vitro and xenograft growth suppression in vivo. Furthermore, DNACR also attenuated cisplatin-induced cell apoptosis in vitro and in vivo. Mechanistically, we found that DANCR upregulated AXL via competitively binding miR-33a-5p, miR-33b-5p, miR-1-3p, miR-206, and miR-613. Through upregulating AXL, DANCR activated PI3K/Akt/NF-κB signaling pathway in glioma cells. Inhibiting AXL/PI3K/Akt/NF-κB signaling pathway reversed the effects of DANCR on cisplatin resistance. In conclusion, we identified a cisplatin-resistance associated lncRNA DANCR. DANCR promotes cisplatin resistance via activating AXL/PI3K/Akt/NF-κB signaling pathway in glioma. Our data suggested that DANCR would be a potential biomarker for predicting cisplatin sensitivity and a therapeutic target for enhancing cisplatin efficacy in glioma.
Exposure to far-infrared rays attenuates methamphetamine-induced recognition memory impairment via modulation of the muscarinic M1 receptor, Nrf2, and PKC Neurochem. Int. (IF 3.262) Pub Date : 2018-03-20 Huynh Nhu Mai, Naveen Sharma, Eun-Joo Shin, Bao Trong Nguyen, Phuong Tram Nguyen, Ji Hoon Jeong, Choon Gon Jang, Eun-Hee Cho, Seung Yeol Nah, Nam Hun Kim, Toshitaka Nabeshima, Hyoung-Chun Kim
We demonstrated that activation of protein kinase Cδ (PKCδ) and inactivation of the glutathione peroxidase-1 (GPx-1)-dependent systems are critical for methamphetamine (MA)-induced recognition memory impairment. We also demonstrated that exposure to far-infrared rays (FIR) causes induction of the glutathione (GSH)-dependent system, including induction of the GPx-1 gene. Here, we investigated whether exposure to FIR rays affects MA-induced recognition memory impairment and whether it modulates PKC, cholinergic receptors, and the GSH-dependent system. Because the PKC activator bryostatin-1 mainly induces PKCα, PKCε, and PKCδ, we assessed expression of these proteins after MA treatment. MA treatment selectively increased PKCδ expression and its phosphorylation. Exposure to FIR rays significantly attenuated MA-induced increases in PKCδ phosphorylation. Importantly, bryostatin-1 potentiated MA-induced phosphorylation of PKCδ. MA treatment significantly decreased M1, M3, and M4 muscarinic acetylcholine receptors (mAChRs) and β2 nicotinic acetylcholine receptor expression. Of these, the decrease was most pronounced in M1 mAChR. Exposure to FIR significantly attenuated MA-induced decreases in the M1 mAChR and phospho-ERK1/2, while it facilitated Nrf2-dependent GSH induction. Dicyclomine, an M1 mAChR antagonist, and L-buthionine-(S, R)-sulfoximine (BSO), an inhibitor of GSH synthesis, counteracted against the protective potentials mediated by FIR. More importantly, the memory-enhancing potential of FIR rays was significantly counteracted by bryostatin-1, dicyclomine, and BSO. Our results suggest that exposure to FIR rays attenuates MA-induced impairment in recognition memory via up-regulation of M1 mAChR, Nrf2-dependent GSH induction, and ERK1/2 phosphorylation by inhibiting PKCδ phosphorylation by bryostatin-1.
Botulinum toxin type A and gabapentin attenuate postoperative pain and NK1 receptor internalization in rats Neurochem. Int. (IF 3.262) Pub Date : 2018-03-20 Xueyang Li, Ruijuan Guo, Yuqing Sun, Huili Li, Danxu Ma, Chen Zhang, Yun Guan, Junfa Li, Yun Wang
Treatment of postoperative pain remains a challenge in clinic. Botulinum toxin type A (BoNT/A) and gabapentin regulate the release of neurotransmitters from primary afferent neurons, but their effects of on postoperative pain are not clear. In the current study, using pain behavioral tests, Western blot analysis, and immunocytochemistry, we examined whether BoNT/A, alone or in combination with intrathecal gabapentin, inhibited pain hypersensitivity and attenuated the increase in neurokinin 1 (NK1) receptor internalization in dorsal horn neurons after plantar incision. Our data showed that pretreatment of rats with an intraplantar (2 U) 24 h before plantar incision or intrathecal (0.5 U) injection of BoNT/A 48 h before plantar incision induced a prolonged (3–5 days) decrease in pain scores and mechanical hypersensitivity, as compared to those observed with saline pretreatment. Both intraplantar and intrathecal BoNT/A pretreatment reduced synaptosomal-associated protein 25 levels in the ipsilateral lumbar dorsal root ganglia and spinal cord dorsal horn, and attenuated the increase in NK1 receptor internalization in dorsal horn neurons. Intrathecal administration of a sub-effective dose of gabapentin (50 μg) with BoNT/A (0.5 U) induced greater inhibition of pain hypersensitivity and NK1 receptor internalization than BoNT/A alone. These findings suggest that pretreatment with BoNT/A, alone or in combination with intrathecal gabapentin, may present a promising multimodal analgesia regimen for postoperative pain treatment.
Current perspective of mitochondrial biology in Parkinson's disease Neurochem. Int. (IF 3.262) Pub Date : 2018-03-14 Navneet Ammal Kaidery, Bobby Thomas
Parkinson's disease (PD) is one of the most common neurodegenerative movement disorder characterized by preferential loss of dopaminergic neurons of the substantia nigra pars compacta and the presence of Lewy bodies containing α-synuclein. Although the cause of PD remains elusive, remarkable advances have been made in understanding the possible causative mechanisms of PD pathogenesis. An explosion of discoveries during the past two decades has led to the identification of several autosomal dominant and recessive genes that cause familial forms of PD. The investigations of these familial PD gene products have shed considerable insights into the molecular pathogenesis of the more common sporadic PD. A growing body of evidence suggests that the etiology of PD is multifactorial and involves a complex interplay between genetic and environmental factors. Substantial evidence from human tissues, genetic and toxin-induced animal and cellular models indicates that mitochondrial dysfunction plays a central role in the pathophysiology of PD. Deficits in mitochondrial functions due to bioenergetics defects, alterations in the mitochondrial DNA, generation of reactive oxygen species, aberrant calcium homeostasis, and anomalies in mitochondrial dynamics and quality control are implicated in the underlying mechanisms of neuronal cell death in PD. In this review, we discuss how familial PD-linked genes and environmental factors interface the pathways regulating mitochondrial functions and thereby potentially converge both familial and sporadic PD at the level of mitochondrial integrity. We also provide an overview of the status of therapeutic strategies targeting mitochondrial dysfunction in PD. Unraveling potential pathways that influence mitochondrial homeostasis in PD may hold the key to therapeutic intervention for this debilitating neurodegenerative movement disorder.
Deletion of serine racemase confers D-serine –dependent resilience to chronic social defeat stress Neurochem. Int. (IF 3.262) Pub Date : 2018-03-14 Chao Dong, Ji-Chun Zhang, Qian Ren, Min Ma, Youge Qu, Kai Zhang, Wei Yao, Tamaki Ishima, Hisashi Mori, Kenji Hashimoto
The N-methyl-D-aspartate receptor (NMDAR) plays a key role in the pathophysiology of depression. Serine racemase (SRR, encoded by Srr) converts L-serine to D-serine, an endogenous co-agonist at the glycine site of the NMDAR. Knock-out (KO) of Srr did not alter behavioral signs of depression compared with wild-type (WT) mice as evaluated by locomotion, tail suspension, forced swimming, and 1% sucrose preference tests. However, chronic social defeat stress (CSDS: 10 days) caused a depression-like phenotype as measured by these same tests in WT mice but not in Srr KO mice, suggesting that decreased D-serine co-agonist activity confers resilience against CSDS. In WT mice, CSDS decreased brain-derived neurotrophic factor (BDNF) expression and phosphorylation/activation of its receptor TrkB in prefrontal cortex (PFC), dentate gyrus (DG), and the CA3 region of the hippocampus, but increased BDNF and phosphorylated TrkB in the nucleus accumbens (NAc). Conversely, CSDS did not alter BDNF or TrkB phosphorylation in any brain region of Srr KO mice. Administration of D-serine through drinking water (600 mg/L for 20 days) 10 days prior to and during CSDS restored the depression-like phenotype in Srr KO mice. These findings suggest that reducing brain D-serine may improve stress resilience, thereby reducing depression risk.
X-ray irradiation induces disruption of the blood–brain barrier with localized changes in claudin-5 and activation of microglia in the mouse brain Neurochem. Int. (IF 3.262) Pub Date : 2018-03-12 Yukari Yoshida, Yukihiko Sejimo, Masashi Kurachi, Yasuki Ishizaki, Takashi Nakano, Akihisa Takahashi
X-ray irradiation (X-irradiation) induces disruption of the blood–brain barrier (BBB). However, the mechanisms underlying the permeability changes are unclear. Therefore, in the present study, we examined the cellular and molecular changes produced by X-irradiation of the brain. Male ICR mice were irradiated locally on their head, posterior to the bregma, except for the eyes, with a single dose of 60 Gy. BBB permeability was assessed using Evans blue dye. We also examined vascular endothelial growth factor (VEGF) expression, microglial morphology, and the expression of the tight junction protein claudin-5 from 0.5 to 7 days after irradiation. An increase in BBB permeability and a decrease in the expression of VEGF protein occurred in a time-dependent manner. In addition, the number of activated microglia (CD68+/Iba-1+ double-positive cells), the amount of tumor necrosis factor (TNF)-α protein and immunoreactivity of NF-κB increased by irradiation, while the expression of claudin-5 on vascular endothelial cells diminished markedly in the cerebral cortex starting 0.5 days after irradiation. These results suggest that the downregulation of claudin-5 expression mediated by activated microglia may contribute to the BBB disruption induced by X-irradiation.
Neuromuscular synapse degeneration without muscle function loss in the diaphragm of a murine model for Huntington's Disease Neurochem. Int. (IF 3.262) Pub Date : 2018-03-10 Priscila A.C. Valadão, Matheus P.S.M. Gomes, Bárbara C. Aragão, Hermann A. Rodrigues, Jéssica N. Andrade, Rubens Garcias, Julliane V. Joviano-Santos, Murilo A. Luiz, Wallace L. Camargo, Lígia A. Naves, Christopher Kushmerick, Walter L.G. Cavalcante, Márcia Gallacci, Itamar C.G. de Jesus, Silvia Guatimosim, Cristina Guatimosim
Huntington's disease (HD) is an autosomal dominant neurodegenerative disease characterized by chorea, incoordination, and psychiatric and behavioral symptoms. The leading cause of death in HD patients is aspiration pneumonia, associated with respiratory dysfunction, decreased respiratory muscle strength and dysphagia. Although most of the motor symptoms are derived from alterations in the central nervous system, some might be associated with changes in the components of motor units (MU). To explore this hypothesis, we evaluated morphofunctional aspects of the diaphragm muscle in a mouse model of HD (BACHD). We showed that the axons of the phrenic nerves were not affected in 12-months-old BACHD mice, but the axon terminals that form the neuromuscular junctions (NMJs) were more fragmented in these animals in comparison with the wild-type mice. In BACHD mice, the synaptic vesicles of the diaphragm NMJs presented a decreased exocytosis rate. Quantal content and quantal size were smaller and there was less synaptic depression whereas the estimated size of the readily releasable vesicle pool was not changed. At the ultrastructure level, the diaphragm NMJs of these mice presented fewer synaptic vesicles with flattened and oval shapes, which might be associated with the reduced expression of the vesicular acetylcholine transporter protein. Furthermore, mitochondria of the diaphragm muscle presented signs of degeneration in BACHD mice. Interestingly, despite all these cellular alterations, BACHD diaphragmatic function was not compromised, suggesting a higher resistance threshold of this muscle. A putative resistance mechanism may be protecting this vital muscle. Our data contribute to expanding the current understanding of the effects of mutated huntingtin in the neuromuscular synapse and the diaphragm muscle function.
Investigating the metabolic alterations in a depressive-like rat model of chronic forced swim stress: An in vivo proton magnetic resonance spectroscopy study at 7T Neurochem. Int. (IF 3.262) Pub Date : 2018-03-09 Chi-Hyeon Yoo, Song-I. Lim, Kyu-Ho Song, Dong-Cheol Woo, Bo-Young Choe
Although recent investigations of major depressive disorder (MDD) have focused on the monoaminergic system, accumulating evidences suggest that alternative pathophysiological models of MDD and treatment options for patients with MDD are needed. Animals subjected to chronic forced swim stress (CFSS) develop behavioral despair. The purpose of this study was to investigate the in vivo effects of CFSS on systems other than the monoamine system in the rat prefrontal cortex (PFC) with 7T and short-echo-time (16.3 ms) proton magnetic resonance spectroscopy (1H MRS). Ten male Wistar rats underwent 14 days of CFSS, and in vivo1H MRS and forced swim tests were performed before and after CFSS. Point-resolved spectroscopy was used to quantify metabolite levels in the rat PFC. To investigate spectral overlap in glutamate and glutamine, spectral analyses in the spectra obtained in the in vivo1H MRS, parametrically matched spectral simulation, and in vitro experiments were performed. The results of the spectral analyses showed that the glutamate/glutamine spectral overlap was not critical, which suggested that in vivo1H MRS can be used to reliably assess the glutamate system. The rats showed significantly increased immobility times and decreased climbing times in the FST after CFSS, which suggested that the rats developed behavioral despair. The pre-CFSS and post-CFSS glutamate and glutamine levels did not significantly differ (p > 0.050). The levels of myo-inositol, total choline, and N-acetylaspartate, myo-inositol/creatine, and total choline/creatine increased significantly (p < 0.050). Similar findings have been reported in patients with MDD. Taken together, these results suggest that the CFSS-induced metabolic alterations were similar to those found in patients and that high-field and short-echo-time in vivo1H MRS can be used to investigate depression-induced metabolic alterations. Such investigations might provide alternative insights into the nonmonoaminergic pathophysiology and treatment of depression.
Tert-butylhydroquinone post-treatment attenuates neonatal hypoxic-ischemic brain damage in rats Neurochem. Int. (IF 3.262) Pub Date : 2018-03-09 Juan Zhang, Lorelei Donovan Tucker, DongYan, Yujiao Lu, Luodan Yang, Chongyun Wu, Yong Li, Quanguang Zhang
Hypoxic-ischemic (HI) encephalopathy is a leading cause of dire mortality and morbidity in neonates. Unfortunately, no effective therapies have been developed as of yet. Oxidative stress plays a critical role in pathogenesis and progression of neonatal HI. Previously, as a Nrf2 activator, tert-butylhydroquinone (TBHQ) has been demonstrated to exert neuroprotection on brain trauma and ischemic stroke models, as well as oxidative stress-induced cytotoxicity in neurons. It is, however, still unknown whether TBHQ administration can protect against oxidative stress in neonatal HI brain injury. This study was undertaken to determine the neuroprotective effects and mechanisms of TBHQ post-treatment on neonatal HI brain damage. Using a neonatal HI rat model, we demonstrated that TBHQ markedly abated oxidative stress compared to the HI group, as evidenced by decreased oxidative stress indexes, enhanced Nrf2 nuclear accumulation and DNA binding activity, and up-regulated expression of Nrf2 downstream antioxidative genes. Administration of TBHQ likewise significantly suppressed reactive gliosis and release of inflammatory cytokines, and inhibited apoptosis and neuronal degeneration in the neonatal rat cerebral cortex. In addition, infarct size and neuronal damage were attenuated distinctly. These beneficial effects were accompanied by improved neurological reflex and motor coordination as well as amelioration of spatial learning and memory deficits. Overall, our results provide the first documentation of the beneficial effects of TBHQ in neonatal HI model, in part conferred by activation of Nrf2 mediated antioxidative signaling pathways.
Glial glutamate transporters expression, glutamate uptake, and oxidative stress in an experimental rat model of intracerebral hemorrhage Neurochem. Int. (IF 3.262) Pub Date : 2018-03-09 J.D. Neves, A. Vizuete, F. Nicola, C. Da Ré, A.F. Rodrigues, F. Schmitz, R.G. Mestriner, D. Aristimunha, A.T. Wyse, C.A. Netto
Glial glutamate transporters (EAAT1 and EAAT2), glutamate uptake, and oxidative stress are important players in the pathogenesis of ischemic brain injury. However, the changes in EAAT1 and EAAT2 expression, glutamate uptake and the oxidative profile during intracerebral hemorrhage (ICH) development have not been described. The present study sought to investigate the changes of the above-mentioned variables, as well as the Na+/K+- ATPase and glutamine synthetase activities (as important contributors of glutamate homeostasis) and the percentage of neuronal cells after 6 h, 24 h, 72 h and 7 days of ICH. An injection of 0.2U of bacterial collagenase in the ipsilateral striatum was used to induce ICH in male Wistar rats; naïve animals were used as controls. EAAT1 and EAAT2 expression and glutamate uptake in the ipsilateral striatum were assessed. Additionally, the percentage of MAP2+ cells, Na+/K+-ATPase and GS activities, as well as the oxidative profile were analyzed. It is shown a decrease of EAAT1 expression and glutamate uptake 6 h post-ICH, whereas EAAT2 decreased 72 h after the event; conversely EAAT2 and glutamate uptake were increased after 7 days. The oxidative stress and endogenous defense system exhibited a remarkable response at 72 h of injury. ICH also increased Na+/K+-ATPase activity and selectively decreased GS activity, variables known to be important contributors of glial glutamate transporters activities. Altogether, present findings indicate that ICH induces different temporal EAAT1 and EAAT2 responses, culminating with an imbalance of glutamate uptake capacity, increased oxidative stress and sustained neuronal loss.
Axon-terminals expressing EAAT2 (GLT-1; Slc1a2) are common in the forebrain and not limited to the hippocampus Neurochem. Int. (IF 3.262) Pub Date : 2018-03-09 Yun Zhou, Bjørnar Hassel, Tore Eid, Niels Christian Danbolt
The excitatory amino acid transporter type 2 (EAAT2) represents the major mechanism for removal of extracellular glutamate. In the hippocampus, there is some EAAT2 in axon-terminals, whereas most of the protein is found in astroglia. The functional importance of the neuronal EAAT2 is unknown, and it is debated whether EAAT2 expressing nerve terminals are present in other parts of the brain. Here we selectively deleted the EAAT2 gene in neurons (by crossing EAAT2-flox mice with synapsin 1-Cre mice in the C57B6 background). To reduce interference from astroglial EAAT2, we measured glutamate accumulation in crude tissue homogenates. EAAT2 proteins levels were measured by immunoblotting. Although synapsin 1-Cre mediated gene deletion only reduced the forebrain tissue content of EAAT2 protein to 95.5 ± 3.4% of wild-type (littermate) controls, the glutamate accumulation in homogenates of neocortex, hippocampus, striatum and thalamus were nevertheless diminished to, respectively, 54 ± 4, 46 ± 3, 46 ± 2 and 65 ± 7% of controls (average ± SEM, n = 3 pairs of littermates). GABA uptake was unaffected. After injection of U-13C-glucose, lack of neuronal EAAT2 resulted in higher 13C-labeling of glutamine and GABA in the hippocampus suggesting that neuronal EAAT2 is partly short-circuiting the glutamate-glutamine cycle in wild-type mice. Crossing synapsin 1-Cre mice with Ai9 reporter mice revealed that Cre-mediated excision occurred efficiently in hippocampus CA3, but less efficiently in other regions and hardly at all in the cerebellum. Conclusions: (1) EAAT2 is expressed in nerve terminals in multiple brain regions. (2) The uptake catalyzed by neuronal EAAT2 plays a role in glutamate metabolism, at least in the hippocampus. (3) Synapsin 1-Cre does not delete floxed genes in all neurons, and the contribution of neuronal EAAT2 is therefore likely to be larger than revealed in the present study.
Neuroprotective potential of spermidine against rotenone induced Parkinson's disease in rats Neurochem. Int. (IF 3.262) Pub Date : 2018-03-06 Sunaina Sharma, Puneet Kumar, Rahul Deshmukh
Parkinson's disease is a leading hypokinetic disorder characterized by selective loss of dopaminergic neurons in substantia nigra pars compacta (SNpc) region of mid-brain. Degeneration of dopaminergic neurons is considered to be due to oxidative stress, neuroinflammation, disturbed calcium homeostasis and glutamate excitotoxicity etc. Spermidine is a polyamine which counteracts age associated cell death by scavenging free radical formation, activates authophagic machinery by enhancing formation of autophagosome, and antagonizes NMDA receptor. In the current study we investigated the neuroprotective potential of spermidine against rotenone induced PD in rats. Rats were treated subcutaneously with rotenone 1.5 mg/kg daily for 28 days. Spermidine 5&10 mg/kg was administered orally 1 h prior to rotenone administration from 15 to 28. Rotenone caused significant reduction in motor functioning and elevated levels of oxidative stress markers and proinflammatory cytokines levels (IL-1β, IL6 and TNF-α). The neurochemical analysis revealed a significant decrease in serotonin, norepinephrine, dopamine and their metabolites accompanied by a significant loss of dopaminergic neurons in the SNpc following ROT injection. However, treatment with spermidine rescued DAergic neurons in SNpc and nerve terminals in the striatum following ROT insult. Spermidine treatment also attenuated oxidative stress, neuroinflammation and restored striatal neurochemistry. Results of our study suggest that spermidine has promising neuroprotective effect against degenerative changes in experimental PD, and the protective effects are mediated through its antioxidant and anti-inflammatory properties.
1H NMR metabolic signature of cerebrospinal fluid following repetitive lower-limb remote ischemia preconditioning Neurochem. Int. (IF 3.262) Pub Date : 2018-02-22 Hailiang Wang, Zhiyong He, Yijue Zhang, Jun Zhang
Background Objective The cerebral ischemia/reperfusion greatly influences brain metabolism. Remote ischemia preconditioning (RIPC) is reported to confer neuroprotective effects against cerebral ischemia in animal models and human. This study aims to investigate the metabolomic profiles of cerebrospinal fluid (CSF) in patients treated with repetitive lower limb RIPC and provides an insight into possible mechanism underlying RIPC-induced neuroprotection. Method Fifty healthy patients undergoing minor surgery under spinal anesthesia were randomly allocated to 2 groups: control group (Group C, n = 25) and RIPC treatment group (Group T,n = 25). Repetitive limb RIPC were performed 3 sessions, consisting of three 5-min cycles per session from the day before surgery to the morning on the surgery day. The CSF samples were collected from 48 patients before intrathecal injection of local anesthetic. A proton nuclear magnetic resonance (1H NMR)-based metabonomics approach was used to obtain the CSF metabolic profiles of the samples (n = 24 each). The acquired data were processed with MestReNova and followed by statistical analysis with SIMCA-P. Results The model obtained with the orthogonal partial least-squares discriminant analysis (OPLS-DA) identified difference of metabolite profiles between two groups. The validation of the discriminant analysis showed that the accuracy of the OPLS-DA model was 81.3%. Sixteen metabolites including glucose, amino-acids and organic acids et al. were identified as the most influential CSF biomarkers for the discrimination between two groups, which are involved in pathways of energy metabolism and amino-acids metabolism. Conclusion 1H NMR spectra combined with pattern recognition analysis offers a new and promising platform to investigate metabolic signatures in patients treated with RIPC. Our results suggest repetitive RIPC mainly changes energy metabolism and amino-acid metabolism in brain, which provides a potential mechanistic understanding of RIPC-induced tolerance to cerebral ischemia.
Lanthionine ketimine-5-ethyl ester provides neuroprotection in a zebrafish model of okadaic acid-induced Alzheimer's disease Neurochem. Int. (IF 3.262) Pub Date : 2018-02-21 Daniel Koehler, Zahoor A. Shah, Kenneth Hensley, Frederick E. Williams
Okadaic acid (OKA) is a protein phosphatase-2A inhibitor that is used to induce neurodegeneration and study disease states such as Alzheimer's disease (AD). Lanthionine ketimine-5-ethyl ester (LKE) is a bioavailable derivative of the naturally occurring brain sulfur metabolite, lanthionine ketimine (LK). In previously conducted studies, LKE exhibited neuroprotective and neurotrophic properties in murine models but its mechanism of action remains to be clarified. In this study, a recently established zebrafish OKA-induced AD model was utilized to further elucidate the neuroprotective and neurotrophic properties of LKE in the context of an AD-like condition. The fish were divided into 3 groups containing 8 fish per group. Group #1 = negative control, Group #2 = 100 nM OKA, Group #3 = 100 nM OKA +500 μM LKE. OKA caused severe cognitive impairments in the zebrafish, but concomitant treatment with LKE protected against cognitive impairments. Further, LKE significantly and substantially reduced the number of apoptotic brain cells, increased brain-derived neurotrophic factor (BDNF), and increased phospho-activation of the pro-survival factors pAkt (Ser 473) and pCREB (Ser133). These findings clarify the neuroprotective and neurotrophic effects of LKE by highlighting particular survival pathways that are bolstered by the experimental therapeutic LKE.
Astaxanthin protects against kainic acid-induced seizures and pathological consequences Neurochem. Int. (IF 3.262) Pub Date : 2018-02-21 Yi Chang, Cheng Wei Lu, Yi Jing Chen, Tzu Yu Lin, Shu Kuei Huang, Su Jane Wang
Excitotoxic damage caused by increased glutamate levels is involved in the pathogenesis of neurodegenerative diseases. Astaxanthin, a natural carotenoid with multiple health benefits, inhibits glutamate release from the brain tissue; however, whether it possesses the ability to affect glutamate-induced brain injury is unknown. The present study investigated the neuroprotective effects of astaxanthin on kainic acid (KA)-induced excitotoxicity in rats and the possible underlying intracellular signaling pathway. The rats were orally administrated with astaxanthin (50 or 100 mg/kg) for 7 days (once a day), and KA (15 mg/kg) was administered intraperitoneally at 1 h after the final administration. The results revealed that KA induced seizures, increased the hippocampal glutamate levels, caused considerable neuronal death and microglial activation in the hippocampal CA3 regions, and increased the production of proinflammatory cytokines. Astaxanthin pretreatment prevented these changes. Furthermore, astaxanthin pretreatment increased the expression of neuronal cell survival-related factors, including phosphorylated Akt, phosphorylated glycogen synthase kinase-3β, and Bcl-2 in the hippocampus of KA-injected rats. These results suggested that astaxanthin can attenuate seizures, mitigate inflammation, augment survival signals, and prevent hippocampal neuronal damage in the animal model of KA-induced excitotoxicity.
Brain bioenergetics in rats with acute hyperphenylalaninemia ☆ Neurochem. Int. (IF 3.262) Pub Date : 2018-02-14 Nádia Weber Dimer, Bruna Klippel Ferreira, Jotele Fontana Agostini, Maria Luiza Gomes, Luiza Wilges Kist, Fernanda Malgarin, Milena Carvalho-Silva, Lara Mezari Gomes, Joyce Rebelo, Marisa Jádna Silva Frederico, Fátima Regina Mena Barreto Silva, Eduardo Pacheco Rico, Mauricio Reis Bogo, Emilio Luiz Streck, Gustavo Costa Ferreira, Patrícia Fernanda Schuck
Phenylketonuria (PKU) is a disorder of phenylalanine (Phe) metabolism caused by deficient phenylalanine hydroxylase activity. The deficiency results in increased levels of Phe and its metabolites in fluids and tissues of patients. PKU patients present neurological signals and symptoms including hypomyelination and intellectual deficit. This study assessed brain bioenergetics at 1 h after acute Phe administration to induce hyperphenylalaninemia (HPA) in rats. Wistar rats were randomized in two groups: HPA animals received a single subcutaneous administration of Phe (5.2 μmol/g) plus p-Cl-Phe (PAH inhibitor) (0.9 μmol/g); control animals received a single injection of 0.9% NaCl. In cerebral cortex, HPA group showed lower mitochondrial mass, lower glycogen levels, as well as lower activities of complexes I-III and IV, ATP synthase and citrate synthase. Higher levels of free Pi and phospho-AMPK, and higher activities of LDH, α-ketoglutarate dehydrogenase and isocitrate dehydrogenase were also reported in cerebral cortex of HPA animals. In striatum, HPA animals had higher LDH (pyruvate-lactate) and isocitrate dehydrogenase activities, and lower activities of α-ketoglutarate dehydrogenase and complex IV, as well as lower phospho-AMPK immunocontent. In hippocampus, HPA rats had higher mRNA expression for MFN1 and higher activities of α-ketoglutarate dehydrogenase and isocitrate dehydrogenase, but decreased activities of pyruvate dehydrogenase and complexes I and IV. In conclusion, our data demonstrated impaired bioenergetics in cerebral cortex, striatum and hippocampus of HPA rats.
Cholinergic tone in ventral tegmental area: Functional organization and behavioral implications Neurochem. Int. (IF 3.262) Pub Date : 2018-02-10 Changzheng Zhang, Xiaodong Liu, Peiling Zhou, Junjie Zhang, Wuming He, Ti-Fei Yuan
The ventral tegmental area (VTA), a pivotal brain region of the mesocorticolimbic dopaminergic system, is substantially innervated and modulated by cholinergic projections from the pedunculopontine tegmental nucleus and laterodorsal tegmental nucleus. In this review, we focus mainly on the current findings on VTA cholinergic compositions and functions, including VTA cholinergic innervations and synaptic connectivity, acetylcholine receptor expression and functional characteristics, cholinergic modulation of neuronal activity and dopamine efflux, cholinergic modulation of VTA-mediated behaviors such as reward and addiction, stress and depression, locomotion, etc. Taken together, these findings indicate that cholinergic transmission to the VTA plays an important role in modulation of the VTA circuit, which is implicated in regulation of multiple behaviors.
Peroxiredoxin-3 attenuates traumatic neuronal injury through preservation of mitochondrial function Neurochem. Int. (IF 3.262) Pub Date : 2018-02-08 Wei Hu, Xing-Bo Dang, Gang Wang, Shuai Li, Yue-Lin Zhang
Peroxiredoxins (PRDXs) are a highly conserved family of thiol peroxidases that scavenge peroxides in cells. PRDX3 is one member of PRDXs localized in the mitochondria, and has been shown to be involved in antioxidant defense and redox signaling. In this study, we investigated the role of PRDX3 in neuronal trauma using a traumatic neuronal injury (TNI) model in primary cultured cortical neurons. We found that TNI significantly decreased the expression of PRDX3 at both mRNA and protein levels. Overexpression of PRDX3 by lentivirus (LV-PRDX3) transfection attenuated lactate dehydrogenase (LDH) release and neuronal apoptosis after TNI. The results of immunostaining showed that LV-PRDX3 transfection markedly reduced TNI-induced intracellular ROS production, protein radical formation and lipid peroxidation. In addition, overexpression of PRDX3 preserved mitochondrial membrane potential (MMP) levels and ATP generation, and inhibited mitochondrial cytochrome c release in TNI-injured neurons. The results of polymerase chain reaction (PCR) showed that PRDX3 overexpression also increased mitochondrial DNA (mtDNA) content and upregulated the expression of mitochondrial biogenesis-related factors. Taken together, our data demonstrate that PRDX3 protects against TNI insult by preserving mitochondrial function and mitochondrial biogenesis, and may have potential therapeutic value for traumatic brain injury (TBI).
The small heat shock proteins, especially HspB4 and HspB5 are promising protectants in neurodegenerative diseases Neurochem. Int. (IF 3.262) Pub Date : 2018-02-07 Zhihui Zhu, Georg Reiser
Alterations of L-type voltage dependent calcium channel alpha 1 subunit in the hippocampal CA3 region during and after pilocarpine-induced epilepsy Neurochem. Int. (IF 3.262) Pub Date : 2018-02-07 Jie hua Xu, Hui Wang, Wen Zhang, Feng ru Tang
Voltage-dependent calcium channels (VDCC) have been shown to regulate neuronal excitability and their antagonists have been used clinically for the control of seizures. While functional studies of VDCC in epileptogenesis in the CA1 area of hippocampus or the dentate gyrus have been done, few studies were carried out in the CA3 area. Given the bursting characteristics of the CA3 neurons, we speculated that VDCC in the CA3 area might play an important role in the epileptogenesis. In the present study in the mouse pilocarpine model of temporal lobe epilepsy, we investigated the alterations of alpha 1 subunits of L-type VDCC in the CA3 area of the hippocampus at different stages of epileptogenesis, i.e., acute stage from 10 min to 1 day during and after pilocapine-induced status epilepticus (SE), latent period at 1 week, and chronic stage with spontaneous recurrent seizures at 2 months after SE. We found that an immediate redistribution of alpha 1 subunits in the CA3 area occurred during SE which might be involved in the seizure occurrence indicated by the Racine score record. Alterations of alpha 1 subunits were also demonstrated in the latent period and chronic stage, which might be related to the epileptogenesis and occurrence of epilepsy. Cav1.3, but not Cav1.2, was expressed in reactive astrocytes of the CA3 area, indicating the involvement of Cav1.3 in the modulation of astrocytic Ca2+ homeostasis during epileptogenesis.
New roles of reactive astrocytes in the brain; an organizer of cerebral ischemia Neurochem. Int. (IF 3.262) Pub Date : 2018-02-02 Schuichi Koizumi, Yuri Hirayama, Yosuke M. Morizawa
The brain consists of neurons and much higher number of glial cells. They communicate each other, by which they control brain functions. The brain is highly vulnerable to several insults such as ischemia, but has a self-protective and self-repairing mechanisms against these. Ischemic tolerance or preconditioning is an endogenous neuroprotective phenomenon, where a mild non-lethal ischemic episode can induce resistance to a subsequent severe ischemic injury in the brain. Because of its neuroprotective effects against cerebral ischemia or stroke, ischemic tolerance has been widely studied. However, almost all studies have been performed from the viewpoint of neurons. Glial cells are structurally in close association with synapses. Recent studies have uncovered the active roles of astrocytes in modulating synaptic connectivity, such as synapse formation, elimination and maturation, during development or pathology. However, glia-mediated ischemic tolerance and/or neuronal repairing have received only limited attention. We and others have demonstrated that glial cells, especially astrocytes, play a pivotal role in regulation of induction of ischemic tolerance as well as repairing/remodeling of neuronal networks by phagocytosis. Here, we review our current understanding of (1) glial-mediated ischemic tolerance and (2) glia-mediated repairing/remodeling of the penumbra neuronal networks, and highlight their mechanisms as well as their potential benefits, problems, and therapeutic application.
A role for KCC3 in maintaining cell volume of peripheral nerve fibers Neurochem. Int. (IF 3.262) Pub Date : 2018-01-31 Bianca Flores, Cara C. Schornak, Eric Delpire
The potassium chloride cotransporter, KCC3, is an electroneutral cotransporter expressed in the peripheral and central nervous system. KCC3 is responsible for the efflux of K+ and Cl− in neurons to help maintain cell volume and intracellular chloride levels. A loss-of- function (LOF) of KCC3 causes Hereditary Motor Sensory Neuropathy with Agenesis of the Corpus Callosum (HMSN/ACC) in a population of individuals in the Charlevoix/Lac-Saint-Jean region of Quebec, Canada. A variety of mouse models have been created to understand the physiological and deleterious effects of a KCC3 LOF. Though this KCC3 LOF in mouse models has recapitulated the peripheral neuropathy phenotype of HMSN/ACC, we still know little about the development of the disease pathophysiology. Interestingly, the most recent KCC3 mouse model that we created recapitulated a peripheral neuropathy-like phenotype originating from a KCC3 gain-of-function (GOF). Despite the past two decades of research in attempting to understand the role of KCC3 in disease, we still do not understand how dysfunction of this cotransporter can lead to the pathophysiology of peripheral neuropathy. This review focuses on the function of KCC3 in neurons and its role in human and health and disease.
S-oxiracetam ameliorates ischemic stroke induced neuronal apoptosis through up-regulating α7 nAChR and PI3K / Akt / GSK3β signal pathway in rats Neurochem. Int. (IF 3.262) Pub Date : 2018-01-19 Wenxiang Fan, Xiang Li, Liangliang Huang, Shucheng He, Zhicheng Xie, Yuxin Fu, Weirong Fang, Yunman Li
Ischemic stroke, the main reason for severe disabilities in the world, is associated with a high incidence of sensorimotor and cognitive dysfunction. In this study, we use the middle cerebral artery occlusion/reperfusion (MCAO/R) model in rats and oxygen glucose deprivation/reoxygenation (OGD/R) model in fetal rat primary cortical neurons to investigate whether and how S-oxiracetam (S-ORC) protect brain injury from ischemic stroke. The results revealed that S-ORC reduced brain infarct size and lessened neurological dysfunction after stroke. Further study demonstrated that S-ORC diminished TUNEL positive cells, increased cell viability, decreased LDH activity, and inhibited cell apoptotic rate. Furthermore, S-ORC inhibited neuronal apoptosis by activating the PI3K/Akt/GSK3β signaling pathway via α7 nAChR, which was evidenced by α7 nAChR siRNA. In conclusion, our findings strongly suggest that S-ORC could be used as an effective neuroprotective agent for ischemic stroke due to its effect in preventing neuronal apoptosis.
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.
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