Endogenous GABA attenuates CNS white matter dysfunction following anoxia.
We studied the effects of GABA on anoxia-induced injury in CNS white matter using optic nerves exposed to 60 min of anoxia. Injury was assessed by recording pre- and postanoxic compound action potentials (CAPs). GABA (1 microM) significantly increased postanoxic CAP recovery when applied 60 min prior to anoxia. This effect was bicuculline (100 microM) insensitive, mimicked by baclofen (1 microM), blocked by GABA-B antagonists, and not mimicked by selective GABA-A agonists. GABA therefore acted at GABA-B receptors. High concentrations of GABA and baclofen did not influence recovery, possibly indicating GABA-B receptor desensitization at high agonist concentrations. Pertussis toxin (PTX) treatment reduced postanoxic CAP recovery in the presence of 1 microM GABA to control levels, indicating the recruitment of a G-protein-linked intracellular pathway. Protein kinase C (PKC) activation with 12-myristate 13-acetate (PMA) mimicked the effects of GABA. Inhibition of PKC with 1-(5-isoquinolinesulfonyl)-2-methylpiperazine dihydrochloride (H7) or staurosporine reduced postanoxic recovery in the presence of GABA to lower levels than under control conditions, confirming the involvement of PKC in the protective effect of GABA and indicating that this GABA-B receptor/G-protein/PKC protective pathway might be active under control conditions. This was confirmed by the observation that GABA-B receptor blockade, in the absence of exogenous GABA, significantly reduced postanoxia recovery. Thus, activation of the protective mechanism under control conditions is due to endogenous GABA release. Increasing the level 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 during anoxia via recruitment of a G-protein/PKC pathway with subsequent phosphorylation of an unknown target protein.
Fern
R
R
Department of Neurology, Yale University School of Medicine, New Haven, Connecticut 06510.
Waxman
S G
SG
Ransom
B R
BR
D000818:Animals; D001369:Axons / Q000502:physiology; D001418:Baclofen / Q000494:pharmacology; D002493:Central Nervous System Diseases / Q000209:etiology* / Q000503:physiopathology*; D004789:Enzyme Activation; D005260:Female; D019204:GTP-Binding Proteins / Q000502:physiology; D000860:Hypoxia / Q000150:complications*; D009431:Neural Conduction; D018696:Neuroprotective Agents / Q000494:pharmacology; D009900:Optic Nerve / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D009994:Osmolar Concentration; D011493:Protein Kinase C / Q000502:physiology; D051381:Rats; D018079:Receptors, GABA / Q000502:physiology; D013997:Time Factors; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology / Q000502:physiology*
D018696:Neuroprotective Agents; D018079:Receptors, GABA; D005680:gamma-Aminobutyric Acid; D011493:Protein Kinase C; D019204:GTP-Binding Proteins; D001418:Baclofen