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Calpain Cleavage of Brain Glutamic Acid Decarboxylase 65 Is Pathological and Impairs GABA Neurotransmission  [PDF]
Chandana Buddhala, Marjorie Suarez, Jigar Modi, Howard Prentice, Zhiyuan Ma, Rui Tao, Jang Yen Wu
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0033002
Abstract: Previously, we have shown that the GABA synthesizing enzyme, L-glutamic acid decarboxylase 65 (GAD65) is cleaved to form its truncated form (tGAD65) which is 2–3 times more active than the full length form (fGAD65). The enzyme responsible for cleavage was later identified as calpain. Calpain is known to cleave its substrates either under a transient physiological stimulus or upon a sustained pathological insult. However, the precise role of calpain cleavage of fGAD65 is poorly understood. In this communication, we examined the cleavage of fGAD65 under diverse pathological conditions including rats under ischemia/reperfusion insult as well as rat brain synaptosomes and primary neuronal cultures subjected to excessive stimulation with high concentration of KCl. We have shown that the formation of tGAD65 progressively increases with increasing stimulus concentration both in rat brain synaptosomes and primary rat embryo cultures. More importantly, direct cleavage of synaptic vesicle - associated fGAD65 by calpain was demonstrated and the resulting tGAD65 bearing the active site of the enzyme was detached from the synaptic vesicles. Vesicular GABA transport of the newly synthesized GABA was found to be reduced in calpain treated SVs. Furthermore, we also observed that the levels of tGAD65 in the focal cerebral ischemic rat brain tissue increased corresponding to the elevation of local glutamate as indicated by microdialysis. Moreover, the levels of tGAD65 was also proportional to the degree of cell death when the primary neuronal cultures were exposed to high KCl. Based on these observations, we conclude that calpain-mediated cleavage of fGAD65 is pathological, presumably due to decrease in the activity of synaptic vesicle - associated fGAD65 resulting in a decrease in the GABA synthesis - packaging coupling process leading to reduced GABA neurotransmission.
Modulation of Anxiolytic-Like and Antidepressant-Like Effects of Melatonin by Imipramine in Wistar Rats: Possible Interaction with Central Monoaminergic Systems  [PDF]
Sihame Ouakki, Oussama Zghari, Aboubaker El Hessni, Abdelhalem Mesfioui, Ali Ouichou
Neuroscience & Medicine (NM) , 2019, DOI: 10.4236/nm.2019.102008
Abstract: Our current study aims to explore the interaction of melatonin (MEL) with the monoaminergic system on the pathophysiology of affective disorders in Wistar rats. We mention here that, the role of monoaminergic transmission in the pathophysiology of affective disorders in humans is demonstrated in most recent reports. In this sense, our current work aims to explore the effect of melatonin (MEL) with or without imipramine (IMP) on levels of depression and anxiety in Wistar rats and would determine the role of MEL in modulating serotonin, noradrenaline and dopamine neurotransmission. From this point, twenty-four female Wister rats were divided into 4 groups of 6 animals and received subcutaneously during 4 weeks different doses of MEL (4 mg/kg), IMP (2 mg/kg) or MEL (4 mg/kg) + IMP (2 mg/kg). Behavioral performance especially anxiety and depression is measured in the open field (OFT), elevated plus maze (EPM) and forced swim test (FST). The anxiety-like and antidepressant-like effects were observed with MEL at 4 mg/Kg and IMP at 2 mg/Kg but the potentiating effect was more observed with the two combined molecules (MEL and IMP), since locomotors activity assessed by the OFT and EPM was not affected. These effects suggest that psychopharmacological actions of MEL are due, at least in part, to its ability to potentiate the central monoaminergic transmitter effects.
Traumatic brain injury and the effects of diazepam, diltiazem, and MK-801 on GABA-A receptor subunit expression in rat hippocampus
Cynthia J Gibson, Rebecca C Meyer, Robert J Hamm
Journal of Biomedical Science , 2010, DOI: 10.1186/1423-0127-17-38
Abstract: We used Western blot procedures to test whether in vivo TBI in rat altered the protein expression of hippocampal GABA-A receptor subunits α1, α2, α3, α5, β3, and γ2 at 3 h, 6 h, 24 h, and 7 days post-injuy. We then used pre-injury injections of MK-801 to block calcium influx through the NMDA receptor, diltiazem to block L-type voltage-gated calcium influx, or diazepam to enhance chloride conductance, and re-examined the protein expressions of α1, α2, α3, and γ2, all of which were altered by TBI in the first study and all of which are important constituents in benzodiazepine-sensitive GABA-A receptors.Western blot analysis revealed no injury-induced alterations in protein expression for GABA-A receptor α2 or α5 subunits at any time point post-injury. Significant time-dependent changes in α1, α3, β3, and γ2 protein expression. The pattern of alterations to GABA-A subunits was nearly identical after diltiazem and diazepam treatment, and MK-801 normalized expression of all subunits 24 hours post-TBI.These studies are the first to demonstrate that GABA-A receptor subunit expression is altered by TBI in vivo, and these alterations may be driven by calcium-mediated cascades in hippocampal neurons. Changes in GABA-A receptors in the hippocampus after TBI may have far-reaching consequences considering their essential importance in maintaining inhibitory balance and their extensive impact on neuronal function.Traumatic brain injury (TBI) disrupts neuronal ionic balance and is known to produce glutamate-mediated neurotoxicity [1-3]. Glutamate related activation of N-methyl-D-aspartate (NMDA) receptors and the resulting elevations in intracellular calcium concentration ([Ca2+]i) are important components in synaptic and cellular degeneration and dysfunction after both in vivo [1,4,5] and in vitro neuronal injury [6-8]. Disruption of calcium (Ca2+) homeostasis after TBI has been implicated in a wide range of intracellular changes in gene expression, signaling pathways, enzymatic
Epoxy Fatty Acids and Inhibition of the Soluble Epoxide Hydrolase Selectively Modulate GABA Mediated Neurotransmission to Delay Onset of Seizures  [PDF]
Bora Inceoglu, Dorota Zolkowska, Hyun Ju Yoo, Karen M. Wagner, Jun Yang, Edward Hackett, Sung Hee Hwang, Kin Sing Stephen Lee, Michael A. Rogawski, Christophe Morisseau, Bruce D. Hammock
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0080922
Abstract: In the brain, seizures lead to release of large amounts of polyunsaturated fatty acids including arachidonic acid (ARA). ARA is a substrate for three major enzymatic routes of metabolism by cyclooxygenase, lipoxygenase and cytochrome P450 enzymes. These enzymes convert ARA to potent lipid mediators including prostanoids, leukotrienes and epoxyeicosatrienoic acids (EETs). The prostanoids and leukotrienes are largely pro-inflammatory molecules that sensitize neurons whereas EETs are anti-inflammatory and reduce the excitability of neurons. Recent evidence suggests a GABA-related mode of action potentially mediated by neurosteroids. Here we tested this hypothesis using models of chemically induced seizures. The level of EETs in the brain was modulated by inhibiting the soluble epoxide hydrolase (sEH), the major enzyme that metabolizes EETs to inactive molecules, by genetic deletion of sEH and by direct administration of EETs into the brain. All three approaches delayed onset of seizures instigated by GABA antagonists but not seizures through other mechanisms. Inhibition of neurosteroid synthesis by finasteride partially blocked the anticonvulsant effects of sEH inhibitors while the efficacy of an inactive dose of neurosteroid allopregnanolone was enhanced by sEH inhibition. Consistent with earlier findings, levels of prostanoids in the brain were elevated. In contrast, levels of bioactive EpFAs were decreased following seizures. Overall these results demonstrate that EETs are natural molecules which suppress the tonic component of seizure related excitability through modulating the GABA activity and that exploration of the EET mediated signaling in the brain could yield alternative approaches to treat convulsive disorders.
High- and Low-Rearing Rats Differ in the Brain Excitability Controlled by the Allosteric Benzodiazepine Site in the GABAA Receptor  [PDF]
Rosana Alves, José Gilberto Barbosa de Carvalho, Marco Antonio Campana Venditti
Journal of Behavioral and Brain Science (JBBS) , 2012, DOI: 10.4236/jbbs.2012.23036
Abstract: Rearing is an exploratory behavior induced by novelty, such as exposure to an open field. Stimulation of certain brain regions, including the hippocampus, induces both rearing and clonic convulsions. Brain excitability is controlled by gamma-aminobutyric acid (GABA) inhibitory neurotransmission through its ionotropic GABAA/allosteric benzodiazepine site. Drugs that decrease GABAA receptor fast inhibitory neurotransmission induce clonic convulsions and rearing when injected into the hippocampus. Therefore, individual differences in rearing behavior may be related to the susceptibility to clonic convulsions, which could involve differences in brain excitability controlled by GABAA/allosteric benzodiazepine site receptors. Adult, male Wistar rats were divided into high- (HR) and low-rearing (LR) groups based on the number of rearings in the open field test. Groups of HR and LR rats were challenged with convulsant drugs that antagonize GABA neurotransmission via different mechanisms of action (3-mercaptopropionic acid, a glutamate decarboxilase inhibitor; bicuculline, a GABAA receptor antagonist; pentylenetetrazol and picrotoxin, both GABAA receptor chloride channel blockers and DMCM, a benzodiazepine inverse agonist). The convulsant doses that induced 50% of clonic convulsions were determined for each drug. The LR rats had a higher susceptibility (a lower convulsant dose 50%) to clonic convulsions induced by DMCM than the HR rats, but there were no differences between the groups in the susceptibility to tonic convulsions induced by the same drug. There were no significant differences in the convulsant dose 50% for clonic convulsions between the groups for all other drugs injected. In another experiment, additional HR and LR rats were injected with a sedative-hypnotic dose of diazepam, which caused a significantly higher hypnotic effect (sleeping-time) in the LR rats than in the HR rats. The LR group was also shown to have a significantly lower density of [3H]-Flunitrazepam bound to the GABAA receptor in hippocampal membranes. Our data suggest that inter-individual differences in rearing are related, at least in part, to the GABA inhibitory neurotransmission controlled by the benzodiazepine allosteric site in the GABAA receptor.
A Gut Feeling about GABA: Focus on GABAB Receptors  [PDF]
Niall P. Hyland,John F. Cryan
Frontiers in Pharmacology , 2010, DOI: 10.3389/fphar.2010.00124
Abstract: γ-Aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the body and hence GABA-mediated neurotransmission regulates many physiological functions, including those in the gastrointestinal (GI) tract. GABA is located throughout the GI tract and is found in enteric nerves as well as in endocrine-like cells, implicating GABA as both a neurotransmitter and an endocrine mediator influencing GI function. GABA mediates its effects via GABA receptors which are either ionotropic GABAA or metabotropic GABAB. The latter which respond to the agonist baclofen have been least characterized, however accumulating data suggest that they play a key role in GI function in health and disease. Like GABA, GABAB receptors have been detected throughout the gut of several species in the enteric nervous system, muscle, epithelial layers as well as on endocrine-like cells. Such widespread distribution of this metabotropic GABA receptor is consistent with its significant modulatory role over intestinal motility, gastric emptying, gastric acid secretion, transient lower esophageal sphincter relaxation and visceral sensation of painful colonic stimuli. More intriguing findings, the mechanisms underlying which have yet to be determined, suggest GABAB receptors inhibit GI carcinogenesis and tumor growth. Therefore, the diversity of GI functions regulated by GABAB receptors makes it a potentially useful target in the treatment of several GI disorders. In light of the development of novel compounds such as peripherally acting GABAB receptor agonists, positive allosteric modulators of the GABAB receptor and GABA producing enteric bacteria, we review and summarize current knowledge on the function of GABAB receptors within the GI tract.
A linear relationship between lamotrigine and GABA in cerebrospinal fluid  [cached]
Berna Terzio?lu,Atilla Karaalp,M. Zafer G?ren
Marmara Pharmaceutical Journal , 2011,
Abstract: ABSTRACT: Theγ-amino butyric acid (GABA)-mediated neurotransmission is useful in treat-ing conditions like anxiety, sleep disturbances, depression and bipolar disorders. The aim ofthe present study is to supply evidence about neurochemical effects of acute lamotriginetreatment on GABA and L-glutamic acid levels in the cerebrospinal fluid of Wistar Albino ratsand the involvement of cholinergic system. The day after the placement of concentric micro-dialysis probes into the lateral ventricles of rats, microdialysis experiments were performedin conscious rat model. The rats either received intraperitoneal injections of physiologicalsaline or 20 mg/kg lamotrigine. For assessing the cholinergic involvement 0.5 mg/kg phys-ostigmine or 2 mg/kg atropine sulfate pre-treatments were given prior to lamotrigine injec-tion. GABA, L-glutamic acid and lamotrigine concentrations in the dialysates were analyzedusing High Performance Liquid Chromatography. Saline produced no change in GABA orL-glutamic acid levels, but lamotrigine treatment significantly elevated GABA concentrations(p<0.05). Pre-treatment with physostigmine or atropine sulfate did not affect either GABA or L-glutamic acid levels siginificantly. Physostigmine or atropine sulfate pre-treatments did not affect the lamotrigine-induced GABA levels. The results may imply that lamotrigine-induced GABA plays a role in the pharmacological effects of lamotrigine where a linear relationship exists between lamotrigine and GABA. However, central cholinergic system fails to affect lamotrigine-induced GABA release.
GABA Transporter-1 Deficiency Confers Schizophrenia-Like Behavioral Phenotypes  [PDF]
Zhe Yu, Qi Fang, Xian Xiao, Yi-Zhi Wang, You-Qing Cai, Hui Cao, Gang Hu, Zhong Chen, Jian Fei, Neng Gong, Tian-Le Xu
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0069883
Abstract: The mechanism underlying the pathogenesis of schizophrenia remains poorly understood. The hyper-dopamine and hypo-NMDA receptor hypotheses have been the most enduring ideas. Recently, emerging evidence implicates alterations of the major inhibitory system, GABAergic neurotransmission in the schizophrenic patients. However, the pathophysiological role of GABAergic system in schizophrenia still remains dubious. In this study, we took advantage of GABA transporter 1 (GAT1) knockout (KO) mouse, a unique animal model with elevated ambient GABA, to study the schizophrenia-related behavioral abnormalities. We found that GAT1 KO mice displayed multiple behavioral abnormalities related to schizophrenic positive, negative and cognitive symptoms. Moreover, GAT1 deficiency did not change the striatal dopamine levels, but significantly enhanced the tonic GABA currents in prefrontal cortex. The GABAA receptor antagonist picrotoxin could effectively ameliorate several behavioral defects of GAT1 KO mice. These results identified a novel function of GAT1, and indicated that the elevated ambient GABA contributed critically to the pathogenesis of schizophrenia. Furthermore, several commonly used antipsychotic drugs were effective in treating the locomotor hyperactivity in GAT1 KO mice, suggesting the utility of GAT1 KO mice as an alternative animal model for studying schizophrenia pathogenesis and developing new antipsychotic drugs.
Fast Neurotransmission Related Genes Are Expressed in Non Nervous Endoderm in the Sea Anemone Nematostella vectensis  [PDF]
Matan Oren, Itzchak Brikner, Lior Appelbaum, Oren Levy
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0093832
Abstract: Cnidarian nervous systems utilize chemical transmission to transfer signals through synapses and neurons. To date, ample evidence has been accumulated for the participation of neuropeptides, primarily RFamides, in neurotransmission. Yet, it is still not clear if this is the case for the classical fast neurotransmitters such as GABA, Glutamate, Acetylcholine and Monoamines. A large repertoire of cnidarian Fast Neurotransmitter related Genes (FNGs) has been recently identified in the genome of the sea anemone, Nematostella vectensis. In order to test whether FNGs are localized in cnidarian neurons, we characterized the expression patterns of eight Nematostella genes that are closely or distantly related to human central and peripheral nervous systems genes, in adult Nematostella and compared them to the RFamide localization. Our results show common expression patterns for all tested genes, in a single endodermal cell layer. These expressions did not correspond with the RFamide expressing nerve cell network. Following these results we suggest that the tested Nematostella genes may not be directly involved in vertebrate-like fast neurotransmission.
Modulation of Neurotransmission by a Specified Oregano Extract Alters Brain Electrical Potentials Indicative of Antidepressant-Like and Neuroprotective Activities  [PDF]
M. Hasan Mohajeri, Regina Goralczyk, Wilfried Dimpfel
Neuroscience & Medicine (NM) , 2012, DOI: 10.4236/nm.2012.31006
Abstract: Different behavioral states are characterized by distinct patterns of global brain activity. Therefore, the biological effects of herbal extracts on brain functions can be assessed by analyzing the local field potentials, the so-called electropharmacogram analysis. Inspired by our recent findings that a specified oregano extract (OE) exhibited a triple-reuptake activity in vitro, this extract was tested in model of Tele-Stereo-electroencephalogram (EEG) to elucidate how OE affects the electrical brain activity in freely moving rats. Furthermore, discriminant analysis was performed to compare the electric brain activity of four standardized brain regions with those produced by several reference compounds, representing a whole variety of clinical indications. Oral intake of OE produced fast and robust dose and time dependent EEG alterations consisting of significant changes of spectral power in comparison to controls. Strongest effects were seen with respect to alpha1, alpha2 and beta1 waves representing an activation of serotonergic, dopaminergic and glutamatergic neurotransmission, respectively. Moreover, the discriminant analysis revealed that OE’s pattern of activity locates in close vicinity to antidepressant and neuroprotective compound. The presented data support the hypothesis suggesting the use of OE as a neuroprotective dietary supplement to promote mood, motivation and mental wellbeing.
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