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

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 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 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 GABAB receptor contributes significantly to neuroprotection against ischemia in organotypic hippocampal slices.

Pathways for Ischemic Cytoprotection: Role of Sirtuins in Caloric Restriction, Resveratrol, and Ischemic Preconditioning

“…IPC was also shown to increase both the frequency and the amplitude of GABA receptor-mediated miniature postsynaptic currents in hippocampal brain slices . The fact that administration of a GABA agonist led to protection after lethal ischemia (Dave et al, 2005), whereas blockade of GABA receptors abolished IPCmediated protection , confirms the protective role of GABA activity against ischemic injury in the brain. IPC has also been shown to increase inducible NOS in cardiac myocytes (Wang et al, 2002), and the effects of NO on GABA modulation have been linked to the regulation of cardiac properties (Shih and Chuang, 2007).…”

“…We have previously shown that IPC-mediated protection requires NO signaling (Centeno et al, 1999), a pathway that has been linked to modulation of the inhibitory neurotransmitter gaminobutyric acid (GABA) . After lethal ischemia, IPC induced the release of GABA and increased the activity of glutamate decarboxylase (Dave et al, 2005), an enzyme responsible for GABA synthesis. IPC was also shown to increase both the frequency and the amplitude of GABA receptor-mediated miniature postsynaptic currents in hippocampal brain slices .…”

The neuroprotective mechanism of brain ischemic preconditioning

“…Recently, Dave et al found that BIP promoted a robust release of GABA in rats after lethal ischemia [17,18] . They also observed that the activity of glutamate decarboxylase (the rate-limiting enzyme in GABA synthesis in the brain) was higher in the BIP group compared with controls and ischemic groups.…”

Possibilities of Pharmacological Preconditioning

“…При избыточной активации NMDA-рецепторов для ослабления эксайтотоксичности при ИПреК го-ловного мозга происходит усиленное высвобождение γ-аминомасляной кислоты (ГАМК) из нейронов, стиму-ляция ГАМК-А и В рецепторов, снижение поступления ионов кальция в постсинаптический нейрон и высвобож-дения глутамата из пресинаптических окончаний [28].…”