PKC and CaMK-II inhibitions coordinately rescue ischemia-induced GABAergic neuron dysfunction.

Li Huang,Jin-Hui Wang,Sudong Guan,Chun Wang,Shidi Zhao,Rongjing Ge

doi:10.18632/oncotarget.16947

Abstract

Cerebral ischemia leads to neuronal death for stroke, in which the imbalance between glutamatergic neurons and GABAergic neurons toward neural excitotoxicity is presumably involved. GABAergic neurons are vulnerable to pathological factors and impaired in an early stage of ischemia. The rescue of GABAergic neurons is expected to be the strategy to reserve ischemic neuronal impairment. As protein kinase C (PKC) and calmodulin-dependent protein kinase II (CaMK-II) are activated during ischemia, we have investigated whether the inhibitions of these kinases rescue the ischemic impairment of cortical GABAergic neurons. The functions of GABAergic neurons were analyzed by whole-cell recording in the cortical slices during ischemia and in presence of 1-[N,O-bis(5-isoquinolinesulfonyl)-N-methyl-L-tyrosyl]-4-phenylpiperazine (CaMK-II inhibitor) and chelerythrine chloride (PKC inhibitor). Our results indicate that PKC inhibitor or CaMK-II inhibitor partially prevents ischemia-induced functional deficits of cortical GABAergic neurons. Moreover, the combination of PKC and CaMK-II inhibitors synergistically reverses this ischemia-induced deficit of GABAergic neurons. One of potential therapeutic strategies for ischemic stroke may be to rescue the ischemia-induced deficit of cortical GABAergic neurons by inhibiting PKC and CaMK-II.

Highlights

Ischemic neuron death is presumably initiated by neural excitotoxicity, in which glutamate elevation [1,2,3,4,5,6,7] and GABAergic neuron impairment [8,9,10,11,12] have been found to be involved
As protein kinase C (PKC) and calmodulin-dependent protein kinase II (CaMK-II) are activated during ischemia, we have investigated whether the inhibitions of these kinases rescue the ischemic impairment of cortical GABAergic neurons
Our study demonstrates that the ischemia induces the overexcited impairment of cortical GABAergic neurons (Figures 1-2), consistent to previous studies [8,9,10, 12], which may lead to the excitotoxicity of GABAergic neurons in the early stage of ischemia and subsequently ischemic death of all neurons for cerebral stroke

Summary

Introduction

Ischemic neuron death is presumably initiated by neural excitotoxicity, in which glutamate elevation [1,2,3,4,5,6,7] and GABAergic neuron impairment [8,9,10,11,12] have been found to be involved. GABAergic neurons are vulnerable to various pathogenic factors and functionally impaired in the early stage of ischemia [9, 12, 19,20,21,22,23,24] Their ischemic impairment shifts the balance between excitation and inhibition toward neuronal over-excitation [25], leading to the elevated glutamate release and subsequently neuronal excitotoxicity for ischemic neuronal death. The enhancement of GABAergic synapse transmission reduces loss of hippocampal CA1 pyramidal neurons [26] In this regard, the elucidation of mechanisms underlying the functional impairment of cerebral GABAergic neurons as well as their protection will provide the clues for developing therapeutic strategies of ischemic neuron death

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