Ischemic preconditioning ameliorates excitotoxicity by shifting glutamate/γ-aminobutyric acid release and biosynthesis

Kunjan R. Dave, Christian Lange-Asschenfeldt, Ami P. Raval, Ricardo Prado, Raul Busto, Isabel Saul, Miguel A. Pérez-Pinzón

Research output: Contribution to journalArticle

79 Scopus citations

Abstract

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 γ-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 GABAA receptor up-regulation has been shown to occur following IPC, and GABAA receptor activation has been implicated in neuroprotection against ischemic insults, we tested the hypothesis that GABAA or GABAB receptor activation was neuroprotective during ischemia or early reperfusion by using an in vitro model (organotypic hippocampal slice culture). Administration of the GABAB 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.

Original languageEnglish (US)
Pages (from-to)665-673
Number of pages9
JournalJournal of Neuroscience Research
Volume82
Issue number5
DOIs
StatePublished - Dec 1 2005

Keywords

  • Cerebral ischemia
  • GABA receptor
  • GABA receptor
  • Microdialysis
  • Neuroprotection
  • Organotypic hippocampal slice culture

ASJC Scopus subject areas

  • Neuroscience(all)

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