Journal
JOURNAL OF NEUROSCIENCE RESEARCH
Volume 82, Issue 5, Pages 665-673Publisher
WILEY
DOI: 10.1002/jnr.20674
Keywords
microdialysis; cerebral ischemia; GABA(A) receptor; GABA(B) receptor; neuroprotection; organotypic hippocampal slice culture
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Funding
- NINDS NIH HHS [NS34773, NS05820, NS45676] Funding Source: Medline
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Excitotoxicity is recognized to play a major role in cerebral ischemia-induced cell death. The main goal of the present study was to define whether our model of ischemic preconditioning (IPC) promotes a shift from excitatory to inhibitory neurotransmission during the test ischemia to diminish metabolic demand during the reperfusion phase. We also determined whether gamma-aminobutyric acid (GABA) played a role in IPC-induced neuroprotection. Ten minutes of cerebral ischemia was produced by tightening the carotid ligatures bilaterally following hypotension. Samples of microdialysis perfusate, representing extracellular fluid, were analyzed for amino acid content by HPLC. IPC promoted a robust release of GABA after lethal ischemia compared with control rats. We also observed that the activity of glutamate decarboxylase (the predominant pathway of GABA synthesis in the brain) was higher in the IPC group compared with control and ischemic groups. Because GABA(A) receptor up-regulation has been shown to occur following IPC, and GABA(A) receptor activation has been implicated in neuroprotection against ischemic insults, we tested the hypothesis that GABA(A) or GABA(B) receptor activation was neuroprotective during ischemia or early reperfusion by using an in vitro model (organotypic hippocampal slice culture). Administration of the GABA(B) agonist baclofen during test ischemia and for 1 hr of reperfusion provided significant neuroprotection. We concluded that increased GABA release in preconditioned animals after ischemia might be one of the factors responsible for IPC neuroprotection. Specific activation of GABA(B) receptor contributes significantly to neuroprotection against ischemia in organotypic hippocampal slices. (c) 2005 Wiley-Liss, Inc.
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