GABA Agonist "Muscimol" Is Neuroprotective in Repetitive Transient Forebrain Ischemia in Gerbils

Shuaib, Ashfaq; Mazagri, Rida; Ijaz, Sadiq

doi:10.1006/exnr.1993.1160

Cited by 86 publications

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“…Activated GABA A receptors play a neuroprotective role in ischemia (25)(26)(27). Our data show that activation of GABA A receptors and GluR5-containing KA receptors could lead to similar results.…”

Section: Discussionsupporting

confidence: 66%

Neuroprotection of GluR5-containing Kainate Receptor Activation against Ischemic Brain Injury through Decreasing Tyrosine Phosphorylation of N-Methyl-d-aspartate Receptors Mediated by Src Kinase

Xu¹,

Liu²,

Zhang

2008

Journal of Biological Chemistry

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Previous studies indicate that cerebral ischemia breaks the dynamic balance between excitatory and inhibitory inputs. The neural excitotoxicity induced by ionotropic glutamate receptors gain the upper hand during ischemia-reperfusion. In this paper, we investigate whether GluR5 (glutamate receptor 5)-containing kainate receptor activation could lead to a neuroprotective effect against ischemic brain injury and the related mechanism. The results showed that (RS)-2-amino-3-(3-hydroxy-5-tert-butylisoxazol-4-yl) propanoic acid (ATPA), a selective GluR5 agonist, could suppress Src tyrosine phosphorylation and interactions among N-methyl-D-aspartate (NMDA) receptor subunit 2A (NR2A), postsynaptic density protein 95 (PSD-95), and Src and then decrease NMDA receptor activation through attenuating tyrosine phosphorylation of NR2A and NR2B. More importantly, ATPA had a neuroprotective effect against ischemiareperfusion-induced neuronal cell death in vivo. However, four separate drugs were found to abolish the effects of ATPA. These were selective GluR5 antagonist NS3763; GluR5 antisense oligodeoxynucleotides; CdCl 2 , a broad spectrum blocker of voltage-gated calcium channels; and bicuculline, an antagonist of ␥-aminobutyric acid A (GABA A ) receptor. GABA A receptor agonist muscimol could attenuate Src activation and interactions among NR2A, PSD-95 and Src, resulting the suppression of NMDA receptor tyrosine phosphorylation. Moreover, patch clamp recording proved that the activated GABA A receptor could inhibit NMDA receptor-mediated whole-cell currents. Taken together, the results suggest that during ischemia-reperfusion, activated GluR5 may facilitate Ca 2؉ -dependent GABA release from interneurons. The released GABA can activate postsynaptic GABA A receptors, which then attenuates NMDA receptor tyrosine phosphorylation through inhibiting Src activation and disassembling the signaling module NR2A-PSD-95-Src. The final result of this process is that the pyramidal neurons are rescued from hyperexcitability.Brain functions are based on the dynamic balance between excitatory and inhibitory inputs. Cerebral ischemia breaks this balance, and the neural excitotoxicity takes over, which induces delayed neuronal cell death. Glutamate, as the primary excitatory neurotransmitter in the central nervous system, has been given widespread attention in previous studies. Ionotropic glutamate receptors, which play an important part in ischemic excitotoxicity, are divided into N-methyl-D-aspartate (NMDA), 3 ␣-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA), and kainate (KA) receptors (1, 2). The NMDA receptor, as a type of ligand-gated ion channel, attracts the most attention in research of cerebral ischemia. It is composed of three types of subunits: NR1, NR2 (NR2A to -D), and NR3 (NR3A and -B) (3-5). Among these subunits, transient global ischemia increases tyrosine phosphorylation of NR2A and NR2B (6). During ischemia-reperfusion, excessive glutamate release induces the influx of Na ϩ and Ca 2ϩ ions through NMDA receptors (7), ...

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Section: Discussionsupporting

confidence: 66%

Neuroprotection of GluR5-containing Kainate Receptor Activation against Ischemic Brain Injury through Decreasing Tyrosine Phosphorylation of N-Methyl-d-aspartate Receptors Mediated by Src Kinase

Xu¹,

Liu²,

Zhang

2008

Journal of Biological Chemistry

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“…This proposal was initiated by the suggestion of Meldrum (1990) that the excitotoxic process depended on a balance between excitatory and inhibitory mechanisms. These speculations were supported by the observations that the GABA-mimetics muscimol and clomethiazole are neuroprotective (Cross et al, 1991;Shuaib et al, 1993;Lyden, 1997;Green, 1998) and the current data. In con®rmation of earlier reports (e.g.…”

Section: Discussionsupporting

confidence: 78%

On the regulation of ischaemia‐induced glutamate efflux from rat cortex by GABA; in vitro studies with GABA, clomethiazole and pentobarbitone

Nelson

Green

Lambert

et al. 2000

British J Pharmacology

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1 Prisms of adult rat cortex were maintained in vitro in either aerobic conditions (control) or conditions simulating an acute ischaemic challenge (hypoxia with no added glucose). 2 Endogenous glutamate e ux increased with time in ischaemic conditions, being 2.7 fold higher than control e ux at 45 min. Returning prisms to control solution after 20 min of simulated ischaemia resulted in glutamate e ux returning to near-control values. Endogenous GABA e ux in ischaemic conditions also increased, being 4.5 fold higher than control e ux at 45 min. 3 Ischaemia-induced glutamate e ux was not accompanied by increased lactate dehydrogenase e ux and was unaltered by omitting calcium from the extra-cellular solution and adding EGTA (0.1 mM). 4 Both GABA and the GABA-mimetic clomethiazole inhibited ischaemia-induced glutamate e ux, with IC 50 values of 26 and 24 mM respectively. The maximum inhibition by either drug was 60 ± 70%. Bicuculline (10 mM) abolished the inhibitory e ect of GABA (100 mM) but not clomethiazole (100 mM). Picrotoxin (100 mM) abolished the action of both GABA and clomethiazole. 5 Pentobarbitone inhibited glutamate e ux at 100 ± 300 mM (maximal inhibition: 39%). Bicuculline (10 mM) abolished this e ect. 6 These data suggest that ischaemia-induced glutamate e ux from rat cerebral cortex is calciumindependent and not due to cell damage up to 45 min. The inhibitory e ect of GABA, clomethiazole and pentobarbitone on ischaemia-induced glutamate e ux appears to be mediated by GABA A receptors. The results suggest that clomethiazole, unlike pentobarbitone, is able to activate the GABA A receptor-linked chloride channel directly and not merely potentiate the e ect of endogenous GABA.

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“…11) And drugs that potentiate GABA have been shown to provide significant neuronal protection when used before or after the ischemic insult in global or focal ischemia. 12,13) The present study aims to assess the effects of gastrodin on extracellular glutamate and GABA in the hippocampus of rats during transient focal cerebral ischemia, when administrated before ischemic injury.…”

mentioning

confidence: 99%

A Microdialysis Study of Effects of Gastrodin on Neurochemical Changes in the Ischemic/Reperfused Rat Cerebral Hippocampus

Zeng

Zhang

et al. 2007

Biological & Pharmaceutical Bulletin

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Gastrodin is a component extracted from the rhizome of Gastrodia elata, and has been shown to possess protective effects against neuron damage induced by simulated cerebral ischemia in previous studies. But its neurochemical effects on the ischemic brain had not been well studied. The present study aimed at evaluating the effects of gastrodin on the changes of transmitter amino acids in rat hippocampus during cerebral ischemia/reperfusion. Microdialysis sampling was performed during ischemia and early reperfusion periods in rats, and the glutamate and gamma-aminobutyric acid (GABA) in the dialysate were measured using high-performance liquid chromatography (HPLC). Administration of gastrodin (100 mg/kg) before ischemia significantly reduced the ischemia-induced elevation of glutamate levels during the postischemic period, increased the rise of extracellular GABA during the reperfusion periods, thus decreased the glutamate/GABA ratios during ischemia and reperfusion. These results provide insights to explain the neurochemical effects of gastrodin when applied prior to an ischemic event.

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GABA Agonist "Muscimol" Is Neuroprotective in Repetitive Transient Forebrain Ischemia in Gerbils

Cited by 86 publications

References 0 publications

Neuroprotection of GluR5-containing Kainate Receptor Activation against Ischemic Brain Injury through Decreasing Tyrosine Phosphorylation of N-Methyl-d-aspartate Receptors Mediated by Src Kinase

Neuroprotection of GluR5-containing Kainate Receptor Activation against Ischemic Brain Injury through Decreasing Tyrosine Phosphorylation of N-Methyl-d-aspartate Receptors Mediated by Src Kinase

On the regulation of ischaemia‐induced glutamate efflux from rat cortex by GABA; in vitro studies with GABA, clomethiazole and pentobarbitone

A Microdialysis Study of Effects of Gastrodin on Neurochemical Changes in the Ischemic/Reperfused Rat Cerebral Hippocampus

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