Identification of the benztropine analog [125I]GA II 34 binding site on the human dopamine transporter Neurochem. Int. (IF 3.603) Pub Date : 2018-08-17 Michael J. Tomlinson, Danielle Krout, Akula Bala Pramod, John R. Lever, Amy Hauck Newman, L. Keith Henry, Roxanne A. Vaughan
The dopamine transporter (DAT) is a neuronal membrane protein that is responsible for reuptake of dopamine (DA) from the synapse and functions as a major determinant in control of DA neurotransmission. Cocaine and many psychostimulant drugs bind to DAT and block reuptake, inducing DA overflow that forms the neurochemical basis for euphoria and addiction. Paradoxically, however, some ligands such as benztropine (BZT) bind to DAT and inhibit reuptake but do not produce these effects, and it has been hypothesized that differential mechanisms of binding may stabilize specific transporter conformations that affect downstream neurochemical or behavioral outcomes. To investigate the binding mechanisms of BZT on DAT we used the photoaffinity BZT analog [125I]N-[n-butyl-4-(4‴-azido-3‴-iodophenyl)]-4′,4″-difluoro-3α-(diphenylmethoxy)tropane ([125I]GA II 34) to identify the site of cross-linking and predict the binding pose relative to that of previously-examined cocaine photoaffinity analogs. Biochemical findings show that adduction of [125I]GA II 34 occurs at residues Asp79 or Leu80 in TM1, with molecular modeling supporting adduction to Leu80 and a pharmacophore pose in the central S1 site similar to that of cocaine and cocaine analogs. Substituted cysteine accessibility method protection analyses verified these findings, but identified some differences in structural stabilization relative to cocaine that may relate to BZT neurochemical outcomes.
CXCR7+ and CXCR4+ stem cells and neuron specific enolase in acute ischemic stroke patients Neurochem. Int. (IF 3.603) Pub Date : 2018-08-17 Anna Gójska-Grymajło, Maciej Zieliński, Anna Wardowska, Dariusz Gąsecki, Michał Pikuła, Bartosz Karaszewski
Stroke causes an efflux of various groups of progenitor/stem cells from bone marrow to bloodstream and a rise in neuron specific enolase (NSE) serum concentrations. The aim of this study was to identify activity of chosen stem/progenitor cells during first 7 days after stroke through correlations between these cells levels and NSE values. Additional goal was to confirm the role of NSE as a prognostic marker of ischemic stroke. Venous blood was collected repeatedly from 67 acute ischemic stroke patients and 15 control subjects, in order to assess NSE with ELISA, and CD45−CD34 + CD271+, CD45−CD34 + CXCR4+, CD45−CD34 + CXCR7+ and CD45−CD34 + CD133 + stem/progenitor cells by means of flow cytometry. Patients underwent repeated assessment with the National Ischemic Stroke Scale and modified Rankin Scale. Ischemic lesion volumes were assessed twice by MRI-DWI (day 1 and 5 ± 2). NSE correlated negatively with MFI levels of the CD45−CD34 + CXCR7+ cells, and percentage levels of the CD45−CD34 + and CD45−CD34 + CXCR4+ cells. NSE concentrations were significantly higher in patients compared to control subjects. NSE on day 2 positively correlated with lesion volume on both MRI. NSE on day 2 and 6–7 correlated positively with initial NIHSS scores, and on day 1 with mRS score on day 9. In conclusion, in this study NSE indicated some activity of the CD45−CD34 + CXCR7+, CD45−CD34 + and CD45−CD34 + CXCR4+ stem/progenitor cells in the first 7 days after ischemic stroke. Additionally, this study supports the thesis that NSE might be a valuable prognostic marker in acute ischemic stroke.
Pregabalin and lacosamide ameliorate paclitaxel-induced peripheral neuropathy via inhibition of JAK/STAT signaling pathway and Notch-1 receptor Neurochem. Int. (IF 3.603) Pub Date : 2018-08-15 Khaled F. Al-Massri, Lamiaa A. Ahmed, Hanan S. El-Abhar
α-(phenylselanyl) acetophenone abolishes acute restraint stress induced-comorbid pain, depression and anxiety-related behaviors in mice Neurochem. Int. (IF 3.603) Pub Date : 2018-08-13 Fernanda Severo Sabedra Sousa, Paloma Taborda Birmann, Renata Balaguez, Diego Alves, César Augusto Brüning, Lucielli Savegnago
Unhealthy gut, unhealthy brain: The role of the intestinal microbiota in neurodegenerative diseases Neurochem. Int. (IF 3.603) Pub Date : 2018-08-14 Lindsay Joy Spielman, Deanna Lynn Gibson, Andis Klegeris
The number of bacterial cells living within the human body is approximately equal to, or greater than, the total number of human cells. This dynamic population of microorganisms, termed the human microbiota, resides mainly within the gastrointestinal tract. It is widely accepted that highly diverse and stable microbiota promote overall human health. Colonization of the gut with maladaptive and pathogenic microbiota, a state also known as dysbiosis, is associated with a variety of peripheral diseases ranging from type 2 diabetes mellitus to cardiovascular and inflammatory bowel disease. More recently, microbial dysbiosis has been associated with a number of brain pathologies, including autism spectrum disorder, Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), suggesting a direct or indirect communication between intestinal bacteria and the central nervous system (CNS). In this review, we illustrate two pathways implicated in the crosstalk between gut microbiota and CNS involving 1) the vagus nerve and 2) transmission of signaling molecules through the circulatory system and across the blood-brain barrier (BBB). We summarize the available evidence of the specific changes in the intestinal microbiota, as well as microorganism-induced modifications to intestinal and BBB permeability, which have been linked to several neurodegenerative disorders including ALS, AD, and PD. Even though each of these diseases arises from unique pathogenetic mechanisms, all are characterized, at least in part, by chronic neuroinflammation. We provide an interpretation for the substantial evidence that healthy intestinal microbiota have the ability to positively regulate the neuroimmune responses in the CNS. Even though the evidence is mainly associative, it has been suggested that bacterial dysbiosis could contribute to an adverse neuroinflammatory state leading to increased risk of neurodegenerative diseases. Thus, developing strategies for regulating and maintaining healthy intestinal microbiota could be a valid approach for lowering individual risk and prevalence of neurodegenerative diseases.
Yeast red pigment modifies cloned human α-synuclein pathogenesis in Parkinson disease models in Saccharomyces cerevisiae and Drosophila melanogaster Neurochem. Int. (IF 3.603) Pub Date : 2018-08-09 O.V. Nevzglyadova, E.V. Mikhailova, A.V. Artemov, Y.E. Ozerova, P.A. Ivanova, I.M. Golomidov, O.I. Bolshakova, V.V. Zenin, E.I. Kostyleva, T.R. Soidla, S.V. Sarantseva
Recently, we identified the yeast red pigment (RP), a polymer of 1-(5′-Phosphoribosyl)-5-aminoimidazole, as a novel potential anti-amyloid agent for the therapy of neurodegenerative diseases. The purpose of this study was to further validate RP for treatment of Parkinson's disease (PD) and to clarify molecular mechanisms involved in the reduction of amyloid cytotoxicity. We investigated RP effects in vivo using Saccharomyces cerevisiae and Drosophila melanogaster PD models. Western blot analysis revealed reduction in the levels of insoluble α-synuclein in both models, while soluble α-synuclein decreased only in Drosophila. In both models RP significantly reduced α-synuclein cytotoxicity, as was revealed by immunohistochemistry in Drosophila (p < 0.001, n = 27 flies per genotype/assay) and by flow cytometry in yeast (p < 0.05). Data obtained from the yeast PD model suggests that RP antitoxic effects are associated with a drop in ROS accumulation, and slower cellular transition from the early to late apoptotic stage. Using Drosophila brain tissue sections, we have demonstrated that RP helps to compensate for an α-synuclein-mediated reduction in the number of dopaminergic neurons and leads to better performance in animal climbing tests (p < 0.001, n = 120–150 flies per genotype/assay). Taken together, these results demonstrate the potential of RP for the treatment of PD, at least in model systems.
Pyrethroid bifenthrin induces oxidative stress, neuroinflammation, and neuronal damage, associated with cognitive and memory impairment in murine hippocampus Neurochem. Int. (IF 3.603) Pub Date : 2018-08-10 Brahim Gargouri, Nizar M. Yousif, Abdelraheim Attaai, Michèle Bouchard, Yassine Chtourou, Bernd L. Fiebich, Hamadi Fetoui
Exposure to synthetic pyrethroid (SPs) pesticides such as bifenthrin (BF) has been associated with adverse neurodevelopmental outcomes and cognitive impairments, but the underlying neurobiological mechanism is poorly understood so far. The present study has been designed to evaluate changes in behavior and in biomarkers of oxidative stress and neuroinflammation in the hippocampus of rats subchronically treated with BF. Rats exposed daily to BF at doses of 0.6 and 2.1 mg/kg b. w. for 60 days exhibited spatial and cognitive impairments as well as memory dysfunction after 60 days. This repeated BF treatment also significantly increased mRNA expression of pro-inflammatory cytokines tumor necrosis factor (TNF-α), interleukin (IL-1β), (IL-6), nuclear factor erythroid-2 (Nrf2), cyclooxygenase-2 (COX-2), nuclear factor-kappaB pathway (NF-kappaB), and prostaglandin E2 (PGE2) in the hippocampus. It further resulted in a significant increase in protein levels of Nrf2, COX-2, microsomal prostaglandin synthase-1 (mPGES-1) and NF-kappaB. This was accompanied by oxidative/nitrosative stress in the hippocampus of treated rats, as shown by increased levels of malondialdehyde (MDA), protein carbonyls (PCO), and nitric oxide (NO), and reduced levels of enzymatic (catalase, superoxide dismutase, and glutathione peroxidase) and non-enzymatic (reduced glutathione) antioxidants. The data are in line with those obtained in organotypic hippocampal slice cultures (OHSCs) isolated from mouse brain and exposed to BF for 72 h, showing neuronal death only at the high dose of 20 μM when compared to controls. These findings suggest that exposure to BF induces neuronal damage, alters redox state, and causes neuroinflammation in the hippocampus, which might lead to cognitive and memory impairment.
Phenylpropanoids and Alzheimer's disease: A potential therapeutic platform Neurochem. Int. (IF 3.603) Pub Date : 2018-08-08 Igri Kolaj, S. Imindu Liyanage, Donald F. Weaver
Alzheimer's disease (AD) is a neurodegenerative disorder, characterized by progressive dementia, neuroinflammation and the accumulation of intracellular neurofibrillary tangles and extracellular plaques. The etiology of AD is unclear, but is generally attributed to four leading hypotheses: (i) abnormal folding and aggregation of amyloid-β (Aβ)/tau proteins (ii) activation of the innate immune system, (iii) mitochondrial dysfunction, and (iv) oxidative stress. To date, therapeutic strategies have largely focused on Aβ-centric targets; however, the repeated failure of clinical trials and the continued lack of a disease-modifying therapy demand novel, multifaceted approaches. Natural products are common molecular platforms in drug development; in AD, compounds from the plant phenylpropanoid metabolic pathway have yielded promising associations. Herein, we review developments in the pathogenesis of AD and the metabolism of phenylpropanoids in plants. We further discuss the role of these metabolites as relevant to the four leading mechanisms of AD pathogenesis, and observe multiple protective effects among phenylpropanoids against AD onset and progression.
Gastrodin attenuates microglia activation through renin-angiotensin system and Sirtuin3 pathway Neurochem. Int. (IF 3.603) Pub Date : 2018-07-31 Shun-Jin Liu, Xiao-Yu Liu, Jing-Hui Li, Jing Guo, Fan Li, Yang Gui, Xiu-Hua Li, Li Yang, Chun-Yun Wu, Yun Yuan, Juan-Juan Li
Microglia activation and its mediated production of proinflammatory mediators play important roles in different neurodegenerative diseases; hence, modulation of microglia activation has been considered a potential therapeutic strategy to ameliorate neurodegeneration. This study was aimed to determine whether Gastrodin, a common herbal agent known to possess neuroprotective property, can attenuate production of proinflammatory mediators in activated microglia through the renin-angiotensin system (RAS) and Sirtuin3 (SIRT3). Expression of various members of the RAS including ACE, AT1, AT2, and SIRT3 in activated microglia was assessed by immunofluorescence and Western blot in hypoxic-ischemia brain damage (HIBD) in postnatal rats, and in BV-2 microglia in vitro challenged with lipopolysaccharide (LPS) with or without Gastrodin treatment. Expression of NOX-2, a subunit of NADPH oxidase, and proinflammatory mediators including iNOS and TNF-α, was also evaluated. The present results showed that expression of ACE, AT1, NOX-2, iNOS and TNF-α was markedly increased in activated microglia in the corpus callosum of HIBD rats, and in LPS stimulated BV-2 microglia. Remarkably, the expression was markedly attenuated following Gastrodin treatment. Conversely, Gastrodin enhanced AT2 and SIRT3 protein expression. In BV-2 microglia treated with Azilsartan, a specific inhibitor of AT1 (AT1I group), NOX-2 expression was decreased whereas that of SIRT3 in LPS + AT1I and LPS + Gastrodin group was increased when compared with the controls. In LPS + AT1I + Gastrodin group, SIRT3 expression was further augmented. More importantly, Gastrodin effectively reduced caspase 3 protein expression level in the HIBD rats coupled with a significant decrease in caspase 3 positive cells. We conclude that Gastrodin can exert its protective effects against the hypoxic-ischemia brain damage in the present experimental HIBD model. It is suggested that this is mainly through suppression of expression of RAS (except for AT2 and SIRT3) and proinflammatory mediators e.g. TNF-α in activated microglia.
Inhibition of VEGF-Flk-1 binding induced profound biochemical alteration in the hippocampus of a rat model of BBB breakdown by spider venom. A preliminary assessment using FT-IR spectroscopy Neurochem. Int. (IF 3.603) Pub Date : 2018-07-31 Maria Helena Rodrigues Mesquita Britto, Monique Culturato Padilha Mendonça, Edilene Siqueira Soares, Kumiko Koibuchi Sakane, Maria Alice da Cruz-Höfling
Hydrogen sulfide attenuates homocysteine-induced neurotoxicity by preventing mitochondrial dysfunction and oxidative damage: In vitro and in vivo studies Neurochem. Int. (IF 3.603) Pub Date : 2018-07-26 Mohit Kumar, Ratan Singh Ray, Rajat Sandhir
Elevated homocysteine (Hcy) levels have been implicated in neurodevelopmental and neurodegenerative disorders. Induction of oxidative stress and apoptosis has been reported as major mechanism in Hcy-induced neurotoxicity. Hydrogen sulfide (H2S), as an antioxidant molecule has been reported to exhibit novel protective effect against Hcy-induced cell damage. However, the mechanisms involved in protective effect of H2S against Hcy-induced toxicity in neurons have not been fully elucidated. Herein, effect of sodium hydrogen sulfide (NaHS, a source of H2S) on Hcy-induced neurotoxicity was studied in Neuro-2a (N2a) cells in vitro and in animals subjected to hyperhomocysteinemia. DCFH-DA staining revealed that NaHS effectively attenuated Hcy-induced oxidative damage via reducing intracellular reactive oxygen species (ROS) generation. JC-1 staining and western blot results showed that NaHS pre-treatment prevented Hcy-induced mitochondrial dysfunctions and mitochondria-mediated apoptosis. The MTT assay, cell cycle analysis, ethidium bromide/acridine orange (EB/AO) and Hoechst staining results demonstrated that NaHS significantly alleviated Hcy-induced cytotoxicity in N2a cells by preventing oxidative damage. Importantly, the results from agarose gel electrophoresis, comet and TUNEL assay indicated that NaHS prevented neurodegeneration by preventing DNA damage and apoptotic cell death in animals with hyperhomocysteinemia. Taken together, the results demonstrate the protective potential of H2S against Hcy-induced neurotoxicity by preventing oxidative DNA damage and mitochondrial dysfunctions. The findings validate that H2S is a promising therapeutic molecule in neurodegenerative conditions associated with hyperhomocysteinemia.
Roles for the uptake2 transporter OCT3 in regulation of dopaminergic neurotransmission and behavior Neurochem. Int. (IF 3.603) Pub Date : 2018-07-25 Paul J. Gasser
Transporter-mediated uptake determines the peak concentration, duration, and physical spread of released monoamines. Most studies of monoamine clearance focus on the presynaptic uptake1 transporters SERT, NET and DAT. However, recent studies have demonstrated the expression of the uptake2 transporter OCT3 (organic cation transporter 3), throughout the rodent brain. In contrast to NET, DAT and SERT, OCT3 has higher capacity and lower affinity for substrates, is sodium-independent, and is multi-specific, with the capacity to transport norepinephrine, dopamine, serotonin and histamine. OCT3 is insensitive to inhibition by cocaine and antidepressant drugs but is inhibited directly by the glucocorticoid hormone corticosterone. Thus, OCT3 represents a novel, stress hormone-sensitive, monoamine transport mechanism. Incorporating this transporter into current models of monoaminergic neurotransmission requires information on: A) the cellular and subcellular localization of the transporter; B) the effects of OCT3 inhibitors on monoamine clearance; and C) the consequences of decreased OCT3-mediated transport on physiology and/or behavior. This review summarizes studies describing the anatomical distribution of OCT3, its cellular and subcellular localization, its contribution to the regulation of dopaminergic signaling, and its roles in the regulation of behavior. Together, these and other studies suggest that both Uptake1 and Uptake2 transporters play key roles in regulating monoaminergic neurotransmission and the effects of monoamines on behavior.
Selective deletion of glutamine synthetase in the mouse cerebral cortex induces glial dysfunction and vascular impairment that precede epilepsy and neurodegeneration Neurochem. Int. (IF 3.603) Pub Date : 2018-07-24 Yun Zhou, Roni Dhaher, Maxime Parent, Qiu-Xiang Hu, Bjørnar Hassel, Siu-Pok Yee, Fahmeed Hyder, Shaun E. Gruenbaum, Tore Eid, Niels Christian Danbolt
Glutamate-ammonia ligase (glutamine synthetase; Glul) is enriched in astrocytes and serves as the primary enzyme for ammonia detoxification and glutamate inactivation in the brain. Loss of astroglial Glul is reported in hippocampi of epileptic patients, but the mechanism by which Glul deficiency might cause disease remains elusive. Here we created a novel mouse model by selectively deleting Glul in the hippocampus and neocortex. The Glul deficient mice were born without any apparent malformations and behaved unremarkably until postnatal week three. There were reductions in tissue levels of aspartate, glutamate, glutamine and GABA and in mRNA encoding glutamate receptor subunits GRIA1 and GRIN2A as well as in the glutamate transporter proteins EAAT1 and EAAT2. Adult Glul-deficient mice developed progressive neurodegeneration and spontaneous seizures which increased in frequency with age. Importantly, progressive astrogliosis occurred before neurodegeneration and was first noted in astrocytes along cerebral blood vessels. The responses to CO2-provocation were attenuated at four weeks of age and dilated microvessels were observed histologically in sclerotic areas of cKO. Thus, the abnormal glutamate metabolism observed in this model appeared to cause epilepsy by first inducing gliopathy and disrupting the neurovascular coupling.
Riparin II ameliorates corticosterone-induced depressive-like behavior in mice: Role of antioxidant and neurotrophic mechanisms Neurochem. Int. (IF 3.603) Pub Date : 2018-07-21 Iardja Stéfane Lopes, Iris Cristina Maia Oliveira, Victor Celso Cavalcanti Capibaribe, José Tiago Valentim, Daniel Moreira Alves da Silva, Alana Gomes de Souza, Mariana Albuquerque de Araújo, Raquell de Castro Chaves, Stanley Juan Chaves Gutierrez, José Maria Barbosa Filho, Danielle Silveira Macêdo, Francisca Cléa Florenço de Sousa
Riparin II (RIP II) is an alkamide isolated from Aniba riparia that has presented antidepressant and anxiolytic effects in acute stress behavioral models. This study aimed to investigate the activity of RIP II in a corticosterone-induced depression mice model. Corticosterone (20 mg/kg, s.c.) was administered once a day for 21 days. RIP II (50 mg/kg, p.o.) or fluvoxamine (FLU, 50 mg/kg, standard antidepressant, p.o.) was administered after corticosterone (CORT) injection, for the last 7 days of CORT treatment. Mice were exposed to the following behavioral tests: forced swimming, tail suspension, open field, sucrose preference, elevated plus maze and ymaze. After behavioral evaluation, brain areas (prefrontal cortex, hippocampus and striatum) were dissected for neurochemical evaluation: oxidative stress parameters (MDA, nitrite and GSH) and BDNF dosage. Repeated CORT administration caused depressive-like behavior in mice as indicated by increased despair effects in forced swimming and tail suspension tests and anhedonia in sucrose preference test. In addition, CORT decreased BDNF levels in the mice hippocampus and induced oxidative load in the brain with significative increase in pro-oxidant markers (lipid peroxidation and nitrite levels) and a decline in anti-oxidant defense system (reduced glutathione levels), indicating a direct effect of stress hormones in the induction of the brain oxidative stress. On the other hand, RIP II treatment reversed CORT-induced depressive-like behavior. Furthermore, this treatment reversed the impairment in BDNF levels and oxidative brain insults caused by CORT. This may demonstrate the mechanisms involved in antidepressant-like effect of RIP II. These findings further support that RIP II may be implicated as pharmacological intervention targeting depression associated with HPA-axis dysregulation.
Oligodendrocyte differentiation from human neural stem cells: A novel role for c-Src Neurochem. Int. (IF 3.603) Pub Date : 2018-07-21 Le Wang, Caitlin R. Schlagal, Junling Gao, Yan Hao, Tiffany J. Dunn, Erica L. McGrath, Javier Allende Labastida, Yongjia Yu, Shi-qing Feng, Shao-yu Liu, Ping Wu
Human neural stem cells (hNSCs) can differentiate into an oligodendrocyte lineage to facilitate remyelination in patients. Molecular mechanisms underlying oligodendrocyte fate specification remains unknown, hindering the development of efficient methods to generate oligodendrocytes from hNSCs. We have found that Neurobasal-A medium (NB) is capable of inducing hNSCs to oligodendrocyte progenitor cells (OPCs). We identified several signaling molecules are altered after cultivation in NB medium, including Akt, ERK1/2 and c-Src. While sustained activation of Akt and ERK1/2 during both NB induction and subsequent differentiation was required for OPC differentiation, c-Src phosphorylation was increased temporally during the period of NB induction. Both pharmacological inhibition and RNA interference confirmed that a transient elevation of phospho-c-Src is critical for OPC induction. Furthermore, inactivation of c-Src inhibited phosphorylation of Akt and ERK1/2. In summary, we identified a novel and critical role of c-Src in guiding hNSC differentiation to an oligodendrocyte lineage.
Voltammetric evidence for discrete serotonin circuits, linked to specific reuptake domains, in the mouse medial prefrontal cortex Neurochem. Int. (IF 3.603) Pub Date : 2018-07-19 A. West, J. Best, A. Abdalla, F. Nijhout, M. Reed, P. Hashemi
The medial prefrontal cortex (mPFC) is an important brain region, that controls a variety of behavioral and functional outputs. As an important step in characterizing mPFC functionality, In this paper we focus on chemically defining serotonin transmission in this area. We apply cutting-edge analytical methods, fast-scan cyclic voltammetry (FSCV) and fast-scan controlled adsorption cyclic voltammetry (FSCAV), pioneered in our laboratory, for the first real-time in vivo analysis of serotonin in the mPFC. In prior in vivo work in the substantia nigra, pars reticulata, we found that our sub-second measurements of a single evoked serotonin release were subject to two clearance mechanisms. These mechanisms were readily modeled via Uptake 1, mediated by the serotonin transporters (SERTs), and Uptake 2, mediated by monoamine transporters (dopamine transporters (DATs), norepinephrine transporters (NETs), and organic cation transporters (OCTs)). Here in the mPFC, for the first time to our knowledge, we observe two release events in response to a single stimulation of the medial forebrain bundle (MFB). Of particular note is that each response is tied to a discrete reuptake profile comprising both Uptake 1 and 2. We hypothesize that two distinct populations of serotonin axons traverse the MFB and terminate in different domains with specific reuptake profiles. We test and confirm this hypothesis using a multifaceted pharmacological, histological and mathematical approach. We thus present evidence for a highly elaborate biochemical organization that regulates serotonin chemistry in the mPFC. This knowledge provides a solid foundation on which to base future studies of the involvement of the mPFC in brain function and behavior.
Adrenergic β receptor activation in the basolateral amygdala, which is intracellular Zn2+-dependent, rescues amyloid β1-42-induced attenuation of dentate gyrus LTP Neurochem. Int. (IF 3.603) Pub Date : 2018-07-17 Haruna Tamano, Mitsuyasu Kubota, Yuki Fujise, Ryota Shimaya, Ryusei Itoh, Miki Suzuki, Paul A. Adlard, Ashley I. Bush, Atsushi Takeda
On the basis of the evidence that the basolateral amygdala (BLA) modulates hippocampal memory processes via synaptic plasticity, here we report that adrenergic β receptor activation in the BLA rescues amyloid β1-42 (Aβ1-42)-induced attenuation of long-term potentiation (LTP) at perforant pathway-dentate granule cell (DGC) synapses. When 500 μM isoproterenol (2 μl), an adrenergic β receptor agonist, was injected into the BLA 20 min before LTP induction, LTP was enhanced. Isoproterenol-mediated enhancement of LTP was blocked by co-injection with 100 μM ZnAF-2DA, an intracellular Zn2+ chelator, suggesting that intracellular Zn2+ is required for the intracellular signaling cascade after adrenergic β receptor activation in the BLA. Aβ1-42-induced attenuation of LTP, which was induced by Aβ1-42 injection into the dentate gyrus 60 min before LTP induction, was rescued by isoproterenol injection into the BLA 20 min before LTP induction, but not by 500 μM phenylephrine (2 μl), an adrenergic α1 receptor agonist, injection into the BLA, which did not enhance LTP unlike the case of isoproterenol injection. Interestingly, Aβ1-42-induced attenuation of LTP was also rescued by 100 μM isoproterenol injection into the BLA 20 min before LTP induction, which did not enhance LTP. The present study demonstrates that adrenergic β receptor activation in the BLA, which is linked with intracellular Zn2+ signaling, rescues Aβ1-42-induced attenuation of dentate gyrus LTP. It is likely that adrenergic β receptor activation in the BLA is a strategy for rescuing Aβ1-42-induced cognitive decline that is associated with hippocampal synaptic plasticity.
The antipsychotic drug quetiapine stimulates oligodendrocyte differentiation by modulating the cell cycle Neurochem. Int. (IF 3.603) 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.
Restorative effect of l-Dopa treatment against Ochratoxin A induced neurotoxicity Neurochem. Int. (IF 3.603) Pub Date : 2018-04-05 Pratiksha V. Bhat, T. Anand, T. Mohan Manu, 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.
A Comparative study for striatal-direct and -indirect pathway neurons to DA depletion-induced lesion in a PD rat model Neurochem. Int. (IF 3.603) Pub Date : 2018-04-16 Xuefeng Zheng, Jiajia Wu, Yaofeng Zhu, Si Chen, Zhi Chen, Tao Chen, Ziyun Huang, Jiayou Wei, Yanmei Li, Wanlong Lei
Striatal-direct and -indirect Pathway Neurons showed different vulnerability in basal ganglia disorders. Therefore, present study aimed to examine and compare characteristic changes of densities, protein and mRNA levels of soma, dendrites, and spines between striatal-direct and -indirect pathway neurons after DA depletion by using immunohistochemistry, Western blotting, real-time PCR and immunoelectron microscopy techniques. Experimental results showed that: 1) 6OHDA-induced DA depletion decreased the soma density of striatal-direct pathway neurons (SP+), but no significant changes for striatal-indirect pathway neurons (ENK+). 2) DA depletion resulted in a decline of dendrite density for both striatal-direct (D1+) and -indirect (D2+) pathway neurons, and D2+ dendritic density declined more obviously. At the ultrastructure level, the densities of D1+ and D2+ dendritic spines reduced in the 6OHDA groups compared with their control groups, but the density of D2+ dendritic spines reduced more significant than that of D1. 3) Striatal DA depletion down-regulated protein and mRNA expression levels of SP and D1, on the contrary, ENK and D2 protein and mRNA levels of indirect pathway neurons were up-regulated significantly. Present results suggested that indirect pathway neurons be more sensitive to 6OHDA-induced DA depletion.
Huntington's disease pattern of transcriptional dysregulation in the absence of mutant huntingtin is produced by knockout of neuronal GLT-1 Neurochem. Int. (IF 3.603) 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.
Fast and slow-twitching muscles are differentially affected by reduced cholinergic transmission in mice deficient for VAChT: A mouse model for congenital myasthenia Neurochem. Int. (IF 3.603) Pub Date : 2018-07-09 Matheus P.S. Magalhães-Gomes, Daisy Motta-Santos, Luana P.L. Schetino, Jéssica N. Andrade, Cristiane P. Bastos, Diogo A.S. Guimarães, Sydney K. Vaughan, Patrícia M. Martinelli, Silvia Guatimosim, Grace S. Pereira, Candido C. Coimbra, Vânia F. Prado, Marco A.M. Prado, Gregorio Valdez, Cristina Guatimosim
Congenital myasthenic symdromes (CMS) result from reduced cholinergic transmission at neuromuscular junctions (NMJs). While the etiology of CMS varies, the disease is characterized by muscle weakness. To date, it remains unknown if CMS causes long-term and irreversible changes to skeletal muscles. In this study, we examined skeletal muscles in a mouse line with reduced expression of Vesicular Acetylcholine Transporter (VAChT, mouse line herein called VAChT-KDHOM). We examined this mouse line for several reasons. First, VAChT plays a central function in loading acetylcholine (ACh) into synaptic vesicles and releasing it at NMJs, in addition to other cholinergic nerve endings. Second, loss of function mutations in VAChT causes myasthenia gravis in humans. Importantly, VAChT-KDHOM present with reduced ACh and muscle weakness, resembling CMS. We evaluated the morphology, fiber type (myosin heavy chain isoforms), and expression of muscle-related genes in the extensor digitorum longus (EDL) and soleus muscles. This analysis revealed that while muscle fibers atrophy in the EDL, they hypertrophy in the soleus muscle of VAChT-KDHOM mice. Along with these cellular changes, skeletal muscles exhibit altered levels of markers for myogenesis (Pax-7, Myogenin, and MyoD), oxidative metabolism (PGC1-α and MTND1), and protein degradation (Atrogin1 and MuRF1) in VAChT-KDHOM mice. Importantly, we demonstrate that deleterious changes in skeletal muscles and motor deficits can be partially reversed following the administration of the cholinesterase inhibitor pyridostigmine VAChT-KDHOM mice. These findings reveal that fast and slow type muscles differentially respond to cholinergic deficits. Additionally, this study shows that the adverse effects of cholinergic transmission, as in the case of CMS, on fast and slow type skeletal muscles are reversible.
Protein kinase C-mediated impairment of glutamine outward transport and SN1 transporter distribution by ammonia in mouse cortical astrocytes Neurochem. Int. (IF 3.603) Pub Date : 2018-07-03 Katarzyna Dąbrowska, Jan Albrecht, Magdalena Zielińska
SN1, a system N amino acid transporter specific for astrocytes, is mainly responsible for export of newly synthesized L-glutamine from the cells. Astrocytic retention of glutamine which plays a critical role in ammonia-induced astrocytic swelling resulting in brain edema, could be tentatively attributed to the impaired L-glutamine export from astrocytes. The present study demonstrates that treatment of cultured mouse cortical astrocytes for 24 h with 5 mM ammonium chloride (“ammonia”) inhibits the system N-mediated glutamine transport out of the cell, and that this inhibition is related to the reduced presence of the SN1 transporter on the cell membrane. Ammonia decreased total protein kinase C (PKC) activity in the absence but not in the presence of PKC activator, phorbol 12-myristate 13-acetate (PMA), and activation of PKC by PMA reversed both the ammonia-induced decrease of system N-mediated L-glutamine release and ammonia-induced SN1 deficit in the membrane fraction. However, while ammonia did not change the protein level of PKCα isoform, it decreased the protein content of PKCδ. Moreover, ammonia treatment increased the cell surface expression of SN1 in cells with silenced PKCα and PKCδ. Silencing of PKCδ abrogated the decrease of system N (SN1)-mediated glutamine release by ammonia. The results implicate the involvement of PKCδ in the inhibition of SN1 membrane expression and activity by ammonia.
RESP18 deficiency has protective effects in dopaminergic neurons in an MPTP mouse model of Parkinson's disease Neurochem. Int. (IF 3.603) Pub Date : 2018-06-28 Jing Su, Haoyue Wang, Yufang Yang, Jinghui Wang, Heng Li, Dongping Huang, Li Huang, Xiaochen Bai, Mei Yu, Jian Fei, Fang Huang
Regulated endocrine-specific protein, 18 kDa (RESP18) was first cloned in 1994. Its function in the brain especially in neurodegenerative diseases remains unclear. In this study, RESP18 knockout (KO) and littermate wild-type (WT) mice were comprehensively analyzed. The dopaminergic toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was applied to generate subchronic Parkinson's disease model. We found that KO mice displayed a reduction in locomotor activity and motor coordination under physiological conditions. Five and six days after MPTP administration, the behavioral impairments were detected in MPTP-treated WT mice, whereas such impairments were not detected in MPTP-treated KO mice. The depletion of tyrosine hydroxylase-positive nerve fibers in the striatum was similar between MPTP-treated KO mice and WT littermates. Furthermore, the striatal level of α-synuclein protein was increased by treatment with MPTP in WT mice, but not in KO mice. The loss of dopaminergic neurons was markedly alleviated, and the activation of glial cells was inhibited in the substantia nigra of KO mice challenged with MPTP. These results suggested that RESP18 deficiency might protect dopaminergic neurons against MPTP toxicity.
Basic fibroblast growth factor increased glucocorticoid receptors in cortical neurons through MAP kinase pathway Neurochem. Int. (IF 3.603) Pub Date : 2018-06-26 Tadahiro Numakawa, Haruki Odaka, Naoki Adachi, Shuichi Chiba, Yoshiko Ooshima, Hitomi Matsuno, Shingo Nakajima, Aya Yoshimura, Kazuhiro Fumimoto, Yohei Hirai, Hiroshi Kunugi
Prolonged and intense stress chronically increases blood concentration of glucocorticoids, which in turn causes downregulation of glucocorticoid receptor (GR) in the central nervous system (CNS). This process has been suggested to be involved in the pathogenesis of major depressive disorder (MDD). Here, we found that basic fibroblast growth factor (bFGF) increased the expression of GR in the rat cerebral cortex and cultured cortical neurons and restored the reduced GR expression caused by glucocorticoid exposure. Among intracellular signaling pathways stimulated by bFGF, extracellular signal–regulated kinase/mitogen-activated protein kinase (ERK/MAPK) pathway was responsible for the upregulation of GR. The bFGF-induced GR was functional as a transcription factor to enhance transcription of a target gene. Because high stress augments bFGF levels in the brain, it is likely that bFGF plays a compensating role for reduced GR expression after stress and thus should be studied as a therapeutic target for the treatment of MDD.
A dibenzoylmethane derivative inhibits lipopolysaccharide-induced NO production in mouse microglial cell line BV-2 Neurochem. Int. (IF 3.603) Pub Date : 2017-04-05 Katsura Takano, Natsumi Ishida, Kenji Kawabe, Mitsuaki Moriyama, Satoshi Hibino, Tominari Choshi, Osamu Hori, Yoichi Nakamura
Microglial activation has been suggested to play important roles in various neurodegenerative diseases by phagocytosis and producing various factors such as nitric oxide (NO), proinflammatory cytokines. Excessive production of NO, as a consequence of increased inducible nitric oxide synthase (iNOS) in microglia, contributes to the neurodegeneration. During a search for compounds that regulate endoplasmic reticulum (ER) stress, a dibenzoylmethane derivative, 2,2’-dimethoxydibenzoylmethane (DBM 14–26) was identified as a novel neuroprotective agent (Takano et al., Am. J. Physiol. Cell Physiol. 293, C1884-1894, 2007). We previously reported in cultured astrocytes that DBM 14–26 protected hydrogen peroxide-induced cell death and inhibited lipopolysaccharide (LPS)-induced NO production (Takano et al., J. Neurosci. Res. 89, 955–965, 2011). In the present study, we assessed the effects of DBM 14–26 on microglia using the mouse cell line BV-2 and found that DBM 14–26 inhibited LPS-induced iNOS expression and NO production also in microglia. DBM 14–26 also suppressed LPS-induced IL-1β expression. Conditioned medium of BV-2 cells stimulated by LPS significantly decreased cell viability of neuron (human neuroblastoma SH-SY5Y cells) compared with the absence of LPS. Conditioned medium of BV-2 cells stimulated by LPS in the presence of DBM 14–26 did not significantly decreased cell viability of neuron. These results indicate that microglial activation by LPS causes neuronal cell death and DBM 14–26 protect neuron through the inhibition of microglial activation. Functional regulation of microglia by DBM 14–26 could be a therapeutic candidate for the treatment of neurodegenerative diseases.
Genetic overexpression of glutathione peroxidase-1 attenuates microcystin-leucine-arginine-induced memory impairment in mice Neurochem. Int. (IF 3.603) Pub Date : 2018-06-13 Eun-Joo Shin, Yeong Gwang Hwang, Duc Toan Pham, Ji Won Lee, Yu Jeung Lee, Dongjin Pyo, Xin Gen Lei, Ji Hoon Jeong, Hyoung-Chun Kim
The protective effect of α-lipoic acid against bisphenol A-induced neurobehavioral toxicity Neurochem. Int. (IF 3.603) Pub Date : 2018-06-13 Jasim Khan, Shikha Salhotra, Shahzad Ahmad, Shikha Sharma, Sayed Aliul Hasan Abdi, Basu Dev Banerjee, Suhel Parvez, Sarika Gupta, Sheikh Raisuddin
The neurotoxin diethyl dithiophosphate impairs glutamate transport in cultured Bergmann glia cells Neurochem. Int. (IF 3.603) Pub Date : 2018-06-13 Tatiana N. Olivares-Bañuelos, Isabel Martínez-Hernández, Luisa C. Hernández-Kelly, Donají Chi-Castañeda, Libia Vega, Arturo Ortega
Glutamate, the main excitatory neurotransmitter in the vertebrate Central Nervous System, is involved in almost every aspect of brain physiology, and its signaling properties are severely affected in most neurodegenerative diseases. This neurotransmitter has to be efficiently removed from the synaptic cleft in order to prevent an over-stimulation of glutamate receptors that leads to neuronal death. Specific sodium-dependent membrane transporters, highly enriched in glial cells, elicit the clearance of glutamate. Once internalized, it is metabolized to glutamine by the glia-enriched enzyme Glutamine synthetase. Accumulated glutamine is released into the extracellular space for its uptake into pre-synaptic neurons and its conversion to glutamate that is packed into synaptic vesicles completing the glutamate/glutamine cycle. Diverse chemical compounds, like organophosphates, directly affect brain chemistry by altering levels of neurotransmitters in the synaptic cleft. Organophosphate compounds are widely used as pesticides, and all living organisms are continuously exposed to these substances, either in a direct or indirect manner. Its metabolites, like the diethyl dithiophosphate, are capable of causing brain damage through diverse mechanisms including perturbation of neuronal-glial cell interactions and have been associated with attention-deficit disorders and other mental illness. In order to characterize the neurotoxic mechanisms of diethyl dithiophosphate, we took advantage of the well characterized model of chick cerebellar Bergmann glia cultures. A significant impairment of [3H] d-Aspartate transport was found upon exposure to the metabolite. These results indicate that glia cells are targets of neurotoxic substances such as pesticides and that these cells might be critically involved in the associated neuronal death.
Modulation of GABA and glycine receptors in rat pyramidal hippocampal neurones by 3α5β-pregnanolone derivatives Neurochem. Int. (IF 3.603) Pub Date : 2018-06-07 Julia V. Bukanova, Elena I. Solntseva, Sergey N. Kolbaev, Eva Kudova
The ability of pregnanolone glutamate (PA-Glu), pregnanolone hemisuccinate (PA-hSuc) and pregnanolone hemipimelate (PA-hPim), neuroactive steroids with a negative modulatory effect on excitatory N-methyl-d-aspartate receptors, to influence the functional activity of inhibitory γ-aminobutyric acid and glycine receptors was estimated. The GABA- and glycine-induced chloride currents (IGABA and IGly) were measured in isolated pyramidal neurons of the rat hippocampus using the patch-clamp technique. Compound PA-Glu was found to potentiate IGABA and to inhibit IGly, while PA-hSuc and PA-hPim inhibited both IGABA and IGly. Moreover, PA-Glu, PA-hSuc, and PA-hPim had a greater effect on desensitization than on the peak amplitude of IGly. At a high concentration of glycine (500 μM), the effect of neurosteroids on the peak amplitude of IGly disappeared, and the acceleration of desensitization remained. The conversion of PA-Glu into androstane glutamate (AND-Glu), an analogue that lacks the C-17 acetyl moiety, completely eliminated the effects on these receptors. Our results indicate that the C-17 acetyl moiety is crucial for the action on IGABA and IGly. Our results indicate that the pregnanolone derivatives, in contrast to the androstane analogues, modulate IGABA and IGly at low micromolar concentrations and this family of neurosteroids can be useful for future structure-activity relationship studies of the steroid modulation of other receptor types.
Human dihydrolipoamide dehydrogenase (E3) deficiency: Novel insights into the structural basis and molecular pathomechanism Neurochem. Int. (IF 3.603) Pub Date : 2017-06-02 Attila Ambrus, Vera Adam-Vizi
This review summarizes our present view on the molecular pathogenesis of human (h) E3-deficiency caused by a variety of genetic alterations with a special emphasis on the moonlighting biochemical phenomena related to the affected (dihydro)lipoamide dehydrogenase (LADH, E3, gene: dld), in particular the generation of reactive oxygen species (ROS). E3-deficiency is a rare autosomal recessive genetic disorder frequently presenting with a neonatal onset and premature death; the highest carrier rate of a single pathogenic dld mutation (1:94–1:110) was found among Ashkenazi Jews. Patients usually die during acute episodes that generally involve severe metabolic decompensation and lactic acidosis leading to neurological, cardiological, and/or hepatological manifestations. The disease owes its severity to the fact that LADH is the common E3 subunit of the alpha-ketoglutarate (KGDHc), pyruvate (PDHc), and branched-chain α-keto acid dehydrogenase complexes and is also part of the glycine cleavage system, hence the malfunctioning of LADH simultaneously incapacitates several central metabolic pathways. Nevertheless, the clinical pictures are usually not unequivocally portrayed through the loss of LADH activities and imply auxiliary mechanisms that exacerbate the symptoms and outcomes of this disorder. Enhanced ROS generation by disease-causing hE3 variants as well as by the E1-E2 subcomplex of the hKGDHc likely contributes to selected pathogeneses of E3-deficiency, which could be targeted by specific drugs or antioxidants; lipoic acid was demonstrated to be a potent inhibitor of ROS generation by hE3 in vitro. Flavin supplementation might prove to be beneficial for those mutations triggering FAD loss in the hE3 component. Selected pathogenic hE3 variants lose their affinity for the E2 component of the hPDHc, a mechanism which warrants scrutiny also for other E3-haboring complexes.
Mitochondria/metabolic reprogramming in the formation of neurons from peripheral cells: Cause or consequence and the implications to their utility Neurochem. Int. (IF 3.603) Pub Date : 2017-06-13 Gary E. Gibson, Ankita Thakkar
The induction of pluripotent stem cells (iPSC) from differentiated cells such as fibroblasts and their subsequent conversion to neural progenitor cells (NPC) and finally to neurons is intriguing scientifically, and its potential to medicine is nearly infinite, but unrealized. A better understanding of the changes at each step of the transformation will enable investigators to better model neurological disease. Each step of conversion from a differentiated cell to an iPSC to a NPC to neurons requires large changes in glycolysis including aerobic glycolysis, the pentose shunt, the tricarboxylic acid cycle, the electron transport chain and in the production of reactive oxygen species (ROS). These mitochondrial/metabolic changes are required and their manipulation modifies conversions. These same mitochondrial/metabolic processes are altered in common neurological diseases so that factors related to the disease may alter the cellular transformation at each step including the final phenotype. A lack of understanding of these interactions could compromise the validity of the disease comparisons in iPSC derived neurons. Both the complexity and potential of iPSC derived cells for understanding and treating disease remain great.
PQBP1, an intrinsically disordered/denatured protein at the crossroad of intellectual disability and neurodegenerative diseases Neurochem. Int. (IF 3.603) Pub Date : 2017-06-13 Hitoshi Okazawa
PQBP1 (polyglutamine binding protein-1) is the earliest identified molecule among the group of disease-related intrinsically disordered/denatured proteins. PQBP1 interacts with splicing-related factors via the disordered/denatured domain and regulates post-transcriptional gene expression. The mutations cause intellectual disability due to decreased dendritic spines and abnormal expression of synapse molecules in neurons, and microcephaly due to elongated cell cycle time and abnormal expression of cell cycle proteins in neural stem progenitor cells. Meanwhile, PQBP1 interacts with polyglutamine tract sequences translated from CAG triplet disease genes via their disordered/denatured structures. The second hit on PQBP1 by such neurodegenerative disease proteins is supposed to similarly impair synapse functions in neuron and proliferation of stem cells. The alteration of gene expression profile and consequently induced phenotypes of neuron and stem cells via secondary impairment of the intrinsically disordered/denatured protein PQBP1, which are similar to developmental disorders by PQBP1 gene mutations, could be a part of the main pathologies shared by multiple neurodegenerative diseases.
Mitochondrial permeability transition pore: Back to the drawing board Neurochem. Int. (IF 3.603) Pub Date : 2017-06-21 Christos Chinopoulos
Current models theorizing on what the mitochondrial permeability transition (mPT) pore is made of, implicate the c-subunit rings of ATP synthase complex. However, two very recent studies, one on atomistic simulations and in the other disrupting all genes coding for the c subunit disproved those models. As a consequence of this, the structural elements of the pore remain unknown. The purpose of the present short-review is to (i) briefly review the latest findings, (ii) serve as an index for more comprehensive reviews regarding mPT specifics, (iii) reiterate on the potential pitfalls while investigating mPT in conjunction to bioenergetics, and most importantly (iv) suggest to those in search of mPT pore identity, to also look elsewhere.
The broad spectrum of signaling pathways regulated by unfolded protein response in neuronal homeostasis Neurochem. Int. (IF 3.603) Pub Date : 2017-06-28 Atsushi Saito, Kazunori Imaizumi
The protein folding capabilities in the endoplasmic reticulum (ER) are disturbed by alternations in the cellular homeostasis such as the disruption of calcium ion homeostasis, the expression of mutated proteins and oxidative stress. In response to these ER dysfunctions, eukaryotic cells activate canonical branches of signal transduction cascades to restore the protein folding capacity and avoid irreversible damages, collectively termed the unfolded protein response (UPR). Prolonged ER dysfunctions and the downregulation of UPR signaling pathways have been accepted as a crucial trigger for the pathogenesis of various neurodegenerative diseases. Furthermore, recent studies have revealed that the UPR has a wide spectrum of signaling pathways for unique physiological roles in the diverse developmental, differential and lipidomic processes. A developed and intricate ER network exists in the neurites of neurons. Neuronal ER functions and ER-derived signaling mediate efficient communication between cell soma and distal sites through local protein synthesis, sorting and lipogenesis. However, relevant of ER-derived UPR signaling pathways in the elaborate mechanisms regulating neuronal activities, synaptic functions and protective responses against injury is not fully elucidated. In this review, we summarized our current understanding of how the UPR functions provide the appropriate signals for neuronal capabilities. We also reviewed how UPR dysfunctions lead to the pathogenesis of neurodegenerative diseases, and the possibilities ameliorating their toxic effects by targeting UPR components.
Pathophysiological role of prostaglandin E2-induced up-regulation of the EP2 receptor in motor neuron-like NSC-34 cells and lumbar motor neurons in ALS model mice Neurochem. Int. (IF 3.603) Pub Date : 2017-07-04 Yasuhiro Kosuge, Hiroko Miyagishi, Yuki Yoneoka, Keiko Yoneda, Hiroshi Nango, Kumiko Ishige, Yoshihisa Ito
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by selective degeneration of motor neurons. The primary triggers for motor neuronal death are still unknown, but inflammation is considered to be an important factor contributing to the pathophysiology of ALS both clinically and in ALS models. Prostaglandin E2 (PGE2) and its corresponding four E-prostanoid receptors play a pivotal role in the degeneration of motor neurons in human and transgenic models of ALS. It has also been shown that PGE2-EP2 signaling in glial cells (astrocytes or microglia) promotes motor neuronal death in G93A mice. The present study was designed to investigate the levels of expression of EP receptors in the spinal motor neurons of ALS model mice and to examine whether PGE2 alters the expression of EP receptors in differentiated NSC-34 cells, a motor neuron-like cell line. Immunohistochemical staining demonstrated that EP2 and EP3 immunoreactivity was localized in NeuN-positive large cells showing the typical morphology of motor neurons in mice. Semi-quantitative analysis showed that the immunoreactivity of EP2 in motor neurons was significantly increased in the early symptomatic stage in ALS model mice. In contrast, the level of EP3 expression remained constant, irrespective of age. In differentiated NSC-34 cells, bath application of PGE2 resulted in a concentration-dependent decrease of MTT reduction. Although PGE2 had no effect on cell survival at concentrations of less than 10 μM, pretreatment with 10 μM PGE2 significantly up-regulated EP2 and concomitantly potentiated cell death induced by 30 μM PGE2. These results suggest that PGE2 is an important effector for induction of the EP2 subtype in differentiated NSC-34 cells, and that not only EP2 up-regulation in glial cells but also EP2 up-regulation in motor neurons plays a pivotal role in the vulnerability of motor neurons in ALS model mice.
Traffic jam hypothesis: Relationship between endocytic dysfunction and Alzheimer's disease Neurochem. Int. (IF 3.603) Pub Date : 2017-07-08 Nobuyuki Kimura, Katsuhiko Yanagisawa
Membrane trafficking pathways, like the endocytic pathway, carry out fundamental cellular processes that are essential for normal functioning. One such process is regulation of cell surface receptor signaling. A growing body of evidence suggests that β-amyloid protein (Aβ) plays a key role in Alzheimer's disease (AD) pathogenesis. Cleavage of Aβ from its precursor, β-amyloid precursor protein (APP), occurs through the endocytic pathway in neuronal cells. In early-stage AD, intraneuronal accumulation of abnormally enlarged endosomes is common, indicating that endosome trafficking is disrupted. Strikingly, genome-wide association studies reveal that several endocytosis-related genes are associated with AD onset. Also, recent studies demonstrate that alteration in endocytosis induces not only Aβ pathology but also the propagation of tau protein pathology, another key pathological feature of AD. Endocytic dysfunction can disrupt neuronal physiological functions, such as synaptic vesicle transport and neurotransmitter release. Thus, “traffic jams” in the endocytic pathway may be involved in AD pathogenesis and may serve as a novel target for the development of new therapeutics.
Involvement of endoplasmic reticulum stress and neurite outgrowth in the model mice of autism spectrum disorder Neurochem. Int. (IF 3.603) Pub Date : 2017-07-12 Koichi Kawada, Seisuke Mimori, Yasunobu Okuma, Yasuyuki Nomura
Neurodevelopmental disorders are congenital impairments, impeding the growth and development of the central nervous system. These disorders include autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder in Diagnostic and Statistical Manual of Mental Disorders-5. ASD is caused by a gene defect and chromosomal duplication. Despite numerous reports on ASD, the pathogenic mechanisms are not clear. The optimal methods to prevent ASD and to treat it are also not clear. Other studies have reported that endoplasmic reticulum (ER) stress contributes to the pathogenesis of neurodegenerative diseases. In this study, we have investigated ER stress condition and neuronal maturation in an ASD mice model employing male ICR mice. An ASD mice model was established by injecting with valproic acid (VPA) into pregnant mice. The offspring born from VPA-treated mothers were subjected to the experiments as the ASD model mice. The cerebral cortex and hippocampus of ASD model mice were found to be under high ER stress. The mRNA levels of Hes1 and Pax6 were decreased in the cerebral cortex of the ASD model mice, but not in the hippocampus. In addition, the mRNA level in Math1 was increased in the cerebral cortex. ER stress inhibited dendrite and axon extension in primary culture derived from the cerebral cortex of E14.5 mice. Furthermore, dendrite outgrowth was suppressed in primary culture derived from the cerebral cortex of ASD model mice by the same method. These results indicated the possibility that ER stress induces abnormal neuronal maturation in the embryonal cerebral cortex of ASD model mice employing male ICR mice. Therefore, ER stress may contribute to the pathogenesis of ASD.
Ubiquitination at the mitochondria in neuronal health and disease Neurochem. Int. (IF 3.603) Pub Date : 2017-07-12 Christian Covill-Cooke, Jack H. Howden, Nicol Birsa, Josef T. Kittler
The preservation of mitochondrial function is of particular importance in neurons given the high energy requirements of action potential propagation and synaptic transmission. Indeed, disruptions in mitochondrial dynamics and quality control are linked to cellular pathology in neurodegenerative diseases, such as Alzheimer's and Parkinson's disease. Here, we will discuss the role of ubiquitination by the E3 ligases: Parkin, MARCH5 and Mul1, and how they regulate mitochondrial homeostasis. Furthermore, given the role of Parkin and Mul1 in the formation of mitochondria-derived vesicles we give an overview of this area of mitochondrial homeostasis. We highlight how through the activity of these enzymes and MDV formation, multiple facets of mitochondrial biology can be regulated, ensuring the functionality of the mitochondrial network thus preserving neuronal health.
Pharmacologic modeling of primary mitochondrial respiratory chain dysfunction in zebrafish Neurochem. Int. (IF 3.603) Pub Date : 2017-07-18 James Byrnes, Rebecca Ganetzky, Richard Lightfoot, Michael Tzeng, Eiko Nakamaru-Ogiso, Christoph Seiler, Marni J. Falk
Mitochondrial respiratory chain (RC) disease is a heterogeneous and highly morbid group of energy deficiency disorders for which no proven effective therapies exist. Robust vertebrate animal models of primary RC dysfunction are needed to explore the effects of variation in RC disease subtypes, tissue-specific manifestations, and major pathogenic factors contributing to each disorder, as well as their pre-clinical response to therapeutic candidates. We have developed a series of zebrafish (Danio rerio) models that inhibit, to variable degrees, distinct aspects of RC function, and enable quantification of animal development, survival, behaviors, and organ-level treatment effects as well as effects on mitochondrial biochemistry and physiology. Here, we characterize four pharmacologic inhibitor models of mitochondrial RC dysfunction in early larval zebrafish, including rotenone (complex I inhibitor), azide (complex IV inhibitor), oligomycin (complex V inhibitor), and chloramphenicol (mitochondrial translation inhibitor that leads to multiple RC complex dysfunction). A range of concentrations and exposure times of each RC inhibitor were systematically evaluated on early larval development, animal survival, integrated behaviors (touch and startle responses), organ physiology (brain death, neurologic tone, heart rate), and fluorescence-based analyses of mitochondrial physiology in zebrafish skeletal muscle. Pharmacologic RC inhibitor effects were validated by spectrophotometric analysis of Complex I, II and IV enzyme activities, or relative quantitation of ATP levels in larvae. Outcomes were prioritized that utilize in vivo animal imaging and quantitative behavioral assessments, as may optimally inform the translational potential of pre-clinical drug screens for future clinical study in human mitochondrial disease subjects. The RC complex inhibitors each delayed early embryo development, with short-term exposures of these three agents or chloramphenicol from 5 to 7 days post fertilization also causing reduced larval survival and organ-specific defects ranging from brain death, behavioral and neurologic alterations, reduced mitochondrial membrane potential in skeletal muscle (rotenone), and/or cardiac edema with visible blood pooling (oligomycin). Remarkably, we demonstrate that treating animals with probucol, a nutrient-sensing signaling network modulating drug that has been shown to yield therapeutic effects in a range of other RC disease cellular and animal models, both prevented acute rotenone-induced brain death in zebrafish larvae, and significantly rescued early embryo developmental delay from either rotenone or oligomycin exposure. Overall, these zebrafish pharmacologic RC function inhibition models offer a unique opportunity to gain novel insights into diverse developmental, survival, organ-level, and behavioral defects of varying severity, as well as their individual response to candidate therapies, in a highly tractable and cost-effective vertebrate animal model system.
Oxytocin release via activation of TRPM2 and CD38 in the hypothalamus during hyperthermia in mice: Implication for autism spectrum disorder Neurochem. Int. (IF 3.603) Pub Date : 2017-07-20 Haruhiro Higashida, Teruko Yuhi, Shirin Akther, Sarwat Amina, Jing Zhong, Mingkun Liang, Tomoko Nishimura, Hong-Xiang Liu, Olga Lopatina
Oxytocin (OT) is a critical molecule for social recognition that mediates social and emotional behaviors. OT is released during stress and acts as an anxiolytic factor. To know the precise molecular mechanisms underlying OT release into the brain during stress is important. It has been reported that intracellular concentrations of free calcium in the hypothalamic neurons are elevated by simultaneous stimulation of cyclic ADP-ribose (cADPR) and heat. We have reported in vitro and in vivo data that supports the idea that release of OT in the brain of male mice is regulated by cADPR and fever in relation to stress conditions. 1) Significantly higher levels of OT release were observed in hypothalamus cultures isolated from subordinate mice in group-housed males compared to dominant males after cage-switch stress; 2) OT concentrations in micro-perfusates at the paraventricular nucleus upon perfusion stimulation with cADPR were enhanced in subordinate mice compared to dominant mice; 3) The OT concentration in the cerebrospinal fluid (CSF) was higher in endotoxin-shock mice with fever compared to controls with no body temperature increase; and 4) In mice exposed to new environmental stress, the CSF OT level transiently increased 5 min after exposure, while the rectal temperature increased from 36.6 °C to 37.8 °C from 5 to 15 min after exposure. In this review, we examine whether or not cADPR and hyperthermia co-regulate hypothalamic OT secretion during social stress through the elevation of intracellular free Ca2+ concentrations involved in CD38-dependent Ca2+ mobilization and TRPM2-dependent Ca2+ influx. Finally, we propose that the interaction between CD38 and TRPM2 seems to be a new mechanism for stress-induced release of OT, which may result in anxiolytic effects for temporal recovery from social impairments in children with autism spectrum disorder during hyperthermia.
Spatial organization of genome architecture in neuronal development and disease Neurochem. Int. (IF 3.603) Pub Date : 2017-07-28 Yuki Fujita, Toshihide Yamashita
Although mammalian genomes encode genetic information in their linear sequences, their fundamental function with regard to gene expression depends on the higher-order structure of chromosomes. Current techniques for the evaluation of chromosomal structure have revealed that genomes are arranged at several hierarchical levels in three-dimensional space. The spatial organization of genomes involves the formation of chromatin loops that bypass a wide range of genomic distances, providing a connection between enhancers and chromosomal domains. Furthermore, they form chromatin domains that are arranged into chromosome territories in the three-dimensional space of the cell nucleus. Recent studies have shown that the spatial organization of the genome is essential for normal brain development and function. Activity-dependent alterations in the spatial organization of the genome can regulate transcriptional activity related to neuronal plasticity. Disruptions in the higher-order chromatin architecture have been implicated in neuropsychiatric disorders, such as cognitive dysfunction and anxiety. Here, we discuss the growing interest in the role of genome organization in brain development and neurological disorders.
Mitochondrial dysfunction in the neuro-degenerative and cardio-degenerative disease, Friedreich's ataxia Neurochem. Int. (IF 3.603) Pub Date : 2017-08-04 Shannon Chiang, Danuta S. Kalinowski, Patric J. Jansson, Des R. Richardson, Michael L.-H. Huang
Mitochondrial homeostasis is essential for maintaining healthy cellular function and survival. The detrimental involvement of mitochondrial dysfunction in neuro-degenerative diseases has recently been highlighted in human conditions, such as Parkinson's, Alzheimer's and Huntington's disease. Friedreich's ataxia (FA) is another neuro-degenerative, but also cardio-degenerative condition, where mitochondrial dysfunction plays a crucial role in disease progression. Deficient expression of the mitochondrial protein, frataxin, is the primary cause of FA, which leads to adverse alterations in whole cell and mitochondrial iron metabolism. Dys-regulation of iron metabolism in these compartments, results in the accumulation of inorganic iron deposits in the mitochondrial matrix that is thought to potentiate oxidative damage observed in FA. Therefore, the maintenance of mitochondrial homeostasis is crucial in the progression of neuro-degenerative conditions, particularly in FA. In this review, vital mitochondrial homeostatic processes and their roles in FA pathogenesis will be discussed. These include mitochondrial iron processing, mitochondrial dynamics (fusion and fission processes), mitophagy, mitochondrial biogenesis, mitochondrial energy production and calcium metabolism.
Mitophagy in neurodegenerative diseases Neurochem. Int. (IF 3.603) Pub Date : 2017-08-08 Carlo Rodolfo, Silvia Campello, Francesco Cecconi
Neurodegenerative diseases, such as Parkinson's disease (PD), Alzheimer's disease (AD), Huntington's disease (HD), and Amyotrophic Lateral Sclerosis (ALS), are a complex “family” of pathologies, characterised by the progressive loss of neurons and/or neuronal functions, leading to severe physical and cognitive inabilities in affected patients. These syndromes, despite differences in the causative events, the onset, and the progression of the disease, share as common features the presence of aggregate-prone neuro-toxic proteins, in the form of aggresomes and/or inclusion bodies, perturbing cellular homeostasis and neuronal function (Popovic et al., 2014), and the presence of dysfunctional mitochondria. The removal of protein aggregates and of damaged organelles, through the ubiquitin-proteasome system (UPS) and/or the autophagy/lysosome machinery, is a crucial step for the maintenance of neuronal homeostasis. Indeed, their impairment has been reported as associated with the development of these diseases. In this review, we focus on the role played by mitophagy, a specialised form of autophagy, in the onset and progression of major neurodegenerative diseases, as well as on possible therapeutic approaches involving mitophagy modulation.
Alzheimer's disease as oligomeropathy Neurochem. Int. (IF 3.603) Pub Date : 2017-08-16 Kenjiro Ono
Alzheimer's disease (AD) is the most common age-related neurodegenerative disorder and is characterized by pathological aggregates of amyloid β-protein (Aβ) and tau protein. On the basis of genetic evidence, biochemical data, and animal models, Aβ has been suggested to be responsible for the pathogenesis of AD (the amyloid hypothesis). Aβ molecules tend to aggregate to form oligomers, protofibrils, and mature fibrils. Although mature fibrils in the final stage have been thought to be the cause of AD pathogenesis, recent studies using synthetic Aβ peptides, a cell culture model, Aβ precursor protein transgenic mice models, and human samples, such as cerebrospinal fluids and postmortem brains of AD patients, suggest that pre-fibrillar forms (oligomers of Aβ) are more deleterious than are extracellular fibril forms. Based on this recent evidence showing that oligomers have a central role in the pathogenesis of AD, the term “oligomeropathy” could be used to define AD and other protein-misfolding diseases. In this review, I discuss recent developments in the “oligomer hypothesis” including our research findings regarding the pathogenesis of AD.
Analysis of lipid raft molecules in the living brain slices Neurochem. Int. (IF 3.603) Pub Date : 2017-08-24 Norihiro Kotani, Takanari Nakano, Yui Ida, Rina Ito, Miki Hashizume, Arisa Yamaguchi, Makoto Seo, Tomoyuki Araki, Yasushi Hojo, Koichi Honke, Takayuki Murakoshi
Neuronal plasma membrane has been thought to retain a lot of lipid raft components which play important roles in the neural function. Although the biochemical analyses of lipid raft using brain tissues have been extensively carried out in the past 20 years, many of their experimental conditions do not coincide with those of standard neuroscience researches such as neurophysiology and neuropharmacology. Hence, the physiological methods for lipid raft analysis that can be compatible with general neuroscience have been required. Herein, we developed a system to physiologically analyze ganglioside GM1-enriched lipid rafts in brain tissues using the “Enzyme-Mediated Activation of Radical Sources (EMARS)” method that we reported (Kotani N. et al. Proc. Natl. Acad. Sci. U S A 105, 7405–7409 (2008)). The EMARS method was applied to acute brain slices prepared from mouse brains in aCSF solution using the EMARS probe, HRP-conjugated cholera toxin subunit B, which recognizes ganglioside GM1. The membrane molecules present in the GM1-enriched lipid rafts were then labeled with fluorescein under the physiological condition. The fluorescein-tagged lipid raft molecules called “EMARS products” distributed differentially among various parts of the brain. On the other hand, appreciable differences were not detected among segments along the longitudinal axis of the hippocampus. We further developed a device to label the lipid raft molecules in acute hippocampal slices under two different physiological conditions to detect dynamics of the lipid raft molecules during neural excitation. Using this device, several cell membrane molecules including Thy1, known as a lipid raft resident molecule in neurons, were confirmed by the EMARS method in living hippocampal slices.
Alterations in the E3 ligases Parkin and CHIP result in unique metabolic signaling defects and mitochondrial quality control issues Neurochem. Int. (IF 3.603) Pub Date : 2017-08-26 Britney N. Lizama, Amy M. Palubinsky, BethAnn McLaughlin
E3 ligases are essential scaffold proteins, facilitating the transfer of ubiquitin from E2 enzymes to lysine residues of client proteins via isopeptide bonds. The specificity of substrate binding and the expression and localization of E3 ligases can, however, endow these proteins with unique features with variable effects on mitochondrial, metabolic and CNS function. By comparing and contrasting two E3 ligases, Parkin and C-terminus of HSC70-Interacting protein (CHIP) we seek to highlight the biophysical properties that may promote mitochondrial dysfunction, acute stress signaling and critical developmental periods to cease in response to mutations in these genes. Encoded by over 600 human genes, RING-finger proteins are the largest class of E3 ligases. Parkin contains three RING finger domains, with R1 and R2 separated by an in-between region (IBR) domain. Loss-of-function mutations in Parkin were identified in patients with early onset Parkinson's disease. CHIP is a member of the Ubox family of E3 ligases. It contains an N-terminal TPR domain and forms unique asymmetric homodimers. While CHIP can substitute for mutated Parkin and enhance survival, CHIP also has unique functions. The differences between these proteins are underscored by the observation that unlike Parkin-deficient animals, CHIP-null animals age prematurely and have significantly impaired motor function. These properties make these E3 ligases appealing targets for clinical intervention. In this work, we discuss how biophysical and metabolic properties of these E3 ligases have driven rapid progress in identifying roles for E3 ligases in development, proteostasis, mitochondrial biology, and cell health, as well as new data about how these proteins alter the CNS proteome.
Sex differences in the mitochondrial bioenergetics of astrocytes but not microglia at a physiologically relevant brain oxygen tension Neurochem. Int. (IF 3.603) Pub Date : 2017-09-06 Sausan M. Jaber, Evan A. Bordt, Niraj M. Bhatt, Daniel M. Lewis, Sharon Gerecht, Gary Fiskum, Brian M. Polster
Biological sex is thought to influence mitochondrial bioenergetic function. Previous respiration measurements examining brain mitochondrial sex differences were made at atmospheric oxygen using isolated brain mitochondria. Oxygen is 160 mm Hg (21%) in the atmosphere, while the oxygen tension in the brain generally ranges from ∼5 to 45 mm Hg (∼1–6% O2). This study tested the hypothesis that sex and/or brain physiological oxygen tension influence the mitochondrial bioenergetic properties of primary rat cortical astrocytes and microglia. Oxygen consumption was measured with a Seahorse XF24 cell respirometer in an oxygen-controlled environmental chamber. Strikingly, male astrocytes had a higher maximal respiration than female astrocytes when cultured and assayed at 3% O2. Three percent O2 yielded a low physiological dissolved O2 level of ∼1.2% (9.1 mm Hg) at the cell monolayer during culture and 1.2–3.0% O2 during assays. No differences in bioenergetic parameters were observed between male and female astrocytes at 21% O2 (dissolved O2 of ∼19.7%, 150 mm Hg during culture) or between either of these cell populations and female astrocytes at 3% O2. In contrast to astrocytes, microglia showed no sex differences in mitochondrial bioenergetic parameters at either oxygen level, regardless of whether they were non-stimulated or activated to a proinflammatory state. There were also no O2- or sex-dependent differences in proinflammatory TNF-α or IL-1β cytokine secretion measured at 18 h activation. Overall, results reveal an intriguing sex variance in astrocytic maximal respiration that requires additional investigation. Findings also demonstrate that sex differences can be masked by conducting experiments at non-physiological O2.
Vesicular movements in the growth cone Neurochem. Int. (IF 3.603) Pub Date : 2017-09-27 Motohiro Nozumi, Michihiro Igarashi
Growth cones, which are the highly motile tips of extending neuronal processes in developing neurons, have many vesicles. These vesicles are likely essential for the membrane expansion that is required for nerve growth, and probably coordinate with rearrangement of the cytoskeletons. Such mechanisms are poorly understood from molecular and cell biological aspects. Recently, we used superresolution microscopic approaches and described new mechanisms that are involved in the interaction between the vesicles and F-actin in the leading edge of the peripheral domain. Vesicles mainly accumulate in the central domain of growth cones. However, the dynamics of vesicles in each domain, for example, clathrin dependency, are totally distinct from each other. Here, we discuss the diversity of the dynamics of vesicular and related proteins that play different roles in nerve growth.
Involvement of neuronal and glial activities in control of the extracellular d-serine concentrations by the AMPA glutamate receptor in the mouse medial prefrontal cortex Neurochem. Int. (IF 3.603) Pub Date : 2017-09-28 Sayuri Ishiwata, Asami Umino, Toru Nishikawa
It has been well accepted that d-serine may be an exclusive endogenous coagonist for the N-methyl-d-aspartate (NMDA)-type glutamate receptor in mammalian forebrain regions. We have recently found by using an in vivo dialysis method that an intra-medial prefrontal cortex infusion of S-α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (S-AMPA), a selective AMPA-type glutamate receptor agonist, causes a reduction in the extracellular levels of d-serine in a calcium-permeable AMPA receptor antagonist-sensitive manner. The inhibitory influence by the AMPA receptor on the extracellular d-serine, however, contradicts the data obtained from in vitro experiments that the AMPA receptor stimulation leads to facilitation of the d-serine liberation. This discrepancy appears to be due to the different cell setups between the in vivo and in vitro preparations. From the viewpoints of the previous reports indicating (1) the neuronal presence of d-serine synthesizing enzyme, serine racemase, and d-serine-like immunoreactivity and (2) the same high tissue concentrations of d-serine in the glia-enriched white matter and in the neuron-enriched gray matter of the mammalian neocortex, we have now investigated in the mouse medial prefrontal cortex, the effects of attenuation of neuronal and glial activities, by tetrodotoxin or fluorocitrate, respectively, on the S-AMPA-induced downregulation of the extracellular d-serine contents. In vivo dialysis studies revealed that a local infusion of tetrodotoxin or fluorocitrate eliminated the ability of S-AMPA given intra-cortically to cause a significant decrease in the dialysate concentrations of d-serine without affecting the elevating effects of S-AMPA on those of glycine, another intrinsic coagonist for the NMDA receptor. These findings suggest that the control by the AMPA receptor of the extracellular d-serine levels could be modulated by the neuronal and glial activities in the prefrontal cortex. It cannot be excluded that fluorocitrate would indirectly alter the modulation by changing synaptic neurotransmission via glial activity attenuation as previously reported.
Roles of CSGalNAcT1, a key enzyme in regulation of CS synthesis, in neuronal regeneration and plasticity Neurochem. Int. (IF 3.603) Pub Date : 2017-10-05 Michihiro Igarashi, Kosei Takeuchi, Sayaka Sugiyama
Chondroitin sulfate (CS) is a sulfated glycosaminoglycan composed of a long chain of repeating disaccharide units that are attached to core proteins, resulting in CS proteoglycans (CSPGs). In the mature brain, CS is concentrated in perineuronal nets (PNNs), which are extracellular structures that surround synapses and regulate synaptic plasticity. In addition, CS is rapidly synthesized after CNS injury to create a physical and chemical barrier that inhibits axon growth. Most previous studies used a bacterial CS-degrading enzyme to investigate the physiological roles of CS. Recent studies have shown that CS is synthesized by more than 15 enzymes, all of which have been characterized in vitro. Here we focus on one of those enzymes, CSGalNAcT1 (T1). We produced T1 knockout mice (KO), which show extensive axon regeneration following spinal cord injury, as well as the loss of onset of ocular dominance plasticity. These results from T1KO mice suggest important roles for extracellular CS in the brain regarding neuronal plasticity and axon regeneration.
Quantitative temporal changes in DTI values coupled with histological properties in cuprizone-induced demyelination and remyelination Neurochem. Int. (IF 3.603) Pub Date : 2017-10-10 Ryutaro Yano, Junichi Hata, Yoshifumi Abe, Fumiko Seki, Keitaro Yoshida, Yuji Komaki, Hideyuki Okano, Kenji F. Tanaka
Diffusion tensor imaging (DTI) is widely used to evaluate microstructural variations in brain tissue. In particular, fractional anisotropy (FA), reflecting the magnitude and orientation of anisotropic water diffusion, allows us to detect pathological events in white matter. An ex vivo DTI study coupled with histological assessment is an efficient strategy to evaluate the myelination process, i.e. demyelination and remyelination. The relationship between DTI values and myelin content or the individual cellular components such as oligodendrocytes, microglia, and astrocytes during both processes of demyelination and remyelination are not well-understood. To address this issue, we employed a cuprizone-inducible demyelination mouse model. Demyelination can be induced in this model during cuprizone exposure and termination of cuprizone exposure induces remyelination. We fed the mice cuprizone-containing chow for 4 weeks and then normal chow for an additional 4 weeks. The ex vivo DTI was performed to evaluate the white matter profiles observed by FA, mean diffusivity (MD), and radial diffusivity (RD) at both demyelinating and remyelinating time points, and then we evaluated histological properties at the same time points. The results indicated a gradual FA decrease during the cuprizone treatment (0, 2, 3, 4 weeks). A lower peak was seen at 1 week after the normal chow was resumed, with recovery to baseline at 2 and 4 weeks. MD and RD showed an opposing pattern to that of FA. These DTI values were positively or negatively correlated with myelin content regardless of the status of the white matter. The RD value was more sensitive to myelination status than FA and MD. We have clarified the temporal changes in the DTI values coupled with histological properties over both the demyelination and remyelination processes.
Calcium uptake and cytochrome c release from normal and ischemic brain mitochondria Neurochem. Int. (IF 3.603) Pub Date : 2017-10-16 Alexander Andreyev, Pratistha Tamrakar, Robert E. Rosenthal, Gary Fiskum
At abnormally elevated levels of intracellular Ca2+, mitochondrial Ca2+ uptake may compromise mitochondrial electron transport activities and trigger membrane permeability changes that allow for release of cytochrome c and other mitochondrial apoptotic proteins into the cytosol. In this study, a clinically relevant canine cardiac arrest model was used to assess the effects of global cerebral ischemia and reperfusion on mitochondrial Ca2+ uptake capacity, Ca2+ uptake-mediated inhibition of respiration, and Ca2+-induced cytochrome c release, as measured in vitro in a K+-based medium in the presence of Mg2+, ATP, and NADH-linked oxidizable substrates. Maximum Ca2+ uptake by frontal cortex mitochondria was significantly lower following 10 min cardiac arrest compared to non-ischemic controls. Mitochondria from ischemic brains were also more sensitive to the respiratory inhibition associated with accumulation of large levels of Ca2+. Cytochrome c was released from brain mitochondria in vitro in a Ca2+-dose-dependent manner and was more pronounced following both 10 min of ischemia alone and following 24 h reperfusion, in comparison to mitochondria from non-ischemic Shams. These effects of ischemia and reperfusion on brain mitochondria could compromise intracellular Ca2+ homeostasis, decrease aerobic and increase anaerobic cerebral energy metabolism, and potentiate the cytochrome c-dependent induction of apoptosis, when re-oxygenated mitochondria are exposed to abnormally high levels of intracellular Ca2+.
Motoneuron degeneration in the trigeminal motor nucleus innervating the masseter muscle in Dystonia musculorum mice Neurochem. Int. (IF 3.603) Pub Date : 2017-10-21 M. Ibrahim Hossain, Masao Horie, Nozomu Yoshioka, Masayuki Kurose, Kensuke Yamamura, Hirohide Takebayashi
Dystonia musculorum (dt) mice, which have a mutation in the Dystonin (Dst) gene, are used as animal models to investigate the human disease known as hereditary sensory and autonomic neuropathy type VI. Massive neuronal cell death is observed, mainly in the peripheral nervous system (PNS) of dt mice. We and others have recently reported a histopathological feature of these mice that neurofilament (NF) accumulates in various areas of the central nervous system (CNS), including motor pathways. Although dt mice show motor disorder and growth retardation, the causes for these are still unknown. Here we performed histopathological analyses on motor units of the trigeminal motor nucleus (Mo5 nucleus), because they are a good system to understand neuronal responses in the mutant CNS, and abnormalities in this system may lead to problems in mastication, with subsequent growth retardation. We report that motoneurons with NF accumulation in the Mo5 nuclei of DstGt homozygous mice express the stress-induced genes CHOP, ATF3, and lipocalin 2 (Lcn2). We also show a reduced number of Mo5 motoneurons and a reduced size of Mo5 nuclei in DstGt homozygous mice, possibly due to apoptosis, given the presence of cleaved caspase 3-positive Mo5 motoneurons. In the mandibular (V3) branches of the trigeminal nerve, which contains axons of Mo5 motoneurons and trigeminal sensory neurons, there was infiltration of Iba1-positive macrophages. Finally, we report atrophy of the masseter muscles in DstGt homozygous mice, which showed abnormal nuclear localization of myofibrils and increased expression of atrogin-1 mRNA, a muscle atrophy-related gene and weaker masseter muscle strength with uncontrolled muscle activity by electromyography (EMG). Taken together, our findings strongly suggest that mastication in dt mice is affected due to abnormalities of Mo5 motoneurons and masseter muscles, leading to growth retardation at the post-weaning stages.
Insulin expression in cultured astrocytes and the decrease by amyloid β Neurochem. Int. (IF 3.603) Pub Date : 2017-11-03 Katsura Takano, Keisuke Koarashi, Kenji Kawabe, Masanori Itakura, Hidemitsu Nakajima, Mitsuaki Moriyama, Yoichi Nakamura
Insulin resistance in brain has been reported in Alzheimer's diseases (AD). Insulin signaling is important for homeostasis in brain function and reported to be disturbed in neurons leading to tau phosphorylation and neurofibrillary tangles. Many investigations of insulin in neurons have been reported; however, it has not been reported whether astrocytes also produce insulin. In the present study, we assessed the expression of insulin in astrocytes cultured from rat embryonic brain and the effects of amyloid β1-42 (Aβ) and lipopolysaccharide (LPS) on the expression. We found that astrocytes expressed preproinsulin mRNAs and insulin protein, and that Aβ or LPS decreased these expressions. Antioxidants, glutathione and N-acetylcysteine, restored the decreases in insulin mRNA expression by Aβ and by LPS. Insulin protein was detected in astrocyte conditioned medium. These results suggest that astrocytes express and secrete insulin. Oxidative stress might be involved in the decreased insulin expression by Aβ or LPS. The insulin decrease by Aβ in astrocytes could be a novel disturbing mechanism for brain insulin signaling in AD.
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 3.603) 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.
Trophic modulation of gamma oscillations: The key role of processing protease for Neuregulin-1 and BDNF precursors Neurochem. Int. (IF 3.603) 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.
Neuropathic pain inhibitor, RAP-103, is a potent inhibitor of microglial CCL1/CCR8 Neurochem. Int. (IF 3.603) Pub Date : 2017-12-14 Mami Noda, Daichi Tomonaga, Kota Kitazono, Yusaku Yoshioka, Jiadai Liu, Jean-Philippe Rousseau, Richard Kinkead, Michael R. Ruff, Candace B. Pert
Chemokine signaling 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.
A refined concept: α-synuclein dysregulation disease Neurochem. Int. (IF 3.603) Pub Date : 2018-01-02 Hideki Mochizuki, Chi-Jing Choong, Eliezer Masliah
α-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.
Circadian modification network of a core clock driver BMAL1 to harmonize physiology from brain to peripheral tissues Neurochem. Int. (IF 3.603) 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.
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