ENDOGENOUS GABA ATTENUATES CNS WHITE-MATTER DYSFUNCTION FOLLOWING ANOXIA

We studied the effects of GABA on anoxia-induced injury in CNS white m atter using optic nerves exposed to 60 min of anoxia. Injury was asses sed by recording pre- and postanoxic compound action potentials (CAPs) . GABA (1 mu M) significantly increased postanoxic CAP recovery when a pplied 60 min prior to anoxia. This effect was bicuculline (100 mu M) insensitive, mimicked by baclofen (1 mu M), blocked by GABA-B antagoni sts, and not mimicked by selective GABA-A agonists. GABA therefore act ed at GABA-B receptors. High concentrations of GABA and baclofen did n ot influence recovery, possibly indicating GABA-B receptor desensitiza tion at high agonist concentrations. Pertussis toxin (PTX) treatment r educed postanoxic CAP recovery in the presence of 1 mu M GABA to contr ol levels, indicating the recruitment of a G-protein-linked intracellu lar pathway. Protein kinase C (PKC) activation with 12-myristate 13-ac etate (PMA) mimicked the effects of GABA. Inhibition of PKC with 1-(5- isoquinolinesulfonyl)-2-methylpiperazine dihydrochloride (H7) or staur osporine reduced postanoxic recovery in the presence of GABA to lower levels than under control conditions, confirming the involvement of PK C in the protective effect of GABA and indicating that this GABA-B rec eptor/G-protein/PKC protective pathway might be active under control c onditions. This was confirmed by the observation that GABA-B receptor blockade, in the-absence of exogenous GABA, significantly reduced post anoxia recovery. Thus, activation of the protective mechanism under co ntrol conditions is due to endogenous GABA release. Increasing the lev el of endogenous extracellular GABA by blocking GABA uptake with 1 mM nipecotic acid also protected against anoxia. We propose a model where release of GABA in white matter helps to limit nerve fiber injury dur ing anoxia via recruitment of a G-protein/PKC pathway with subsequent phosphorylation of an unknown target protein.