Effect of gamma-aminobutyric acid modulation on neuronal ischemia in rabbits

Antagonists of excitatory neurotransmitters are effective in limiting ischemic damage to the brain and spinal cord, but use in clinical stroke may be limited by side effects. Agonists of inhibitory neurotransmitters, such as gamma-aminobutyric acid (GABA), may provide similar neuroprotection with less severe side effects. This study examines the effect of an agonist and antagonist of the GABA-A receptor on neuronal ischemic damage.

Either muscimol (a GABA-A agonist) or bicuculline (a GABA-A antagonist) was administered intravenously to groups of rabbits exposed to reversible spinal cord ischemia induced by temporary occlusion of the infrarenal aorta. The duration of occlusion for individual animals was varied, providing a range of ischemia for each experimental group. The group P50 represents the duration (in minutes) associated with 50% probability of resultant permanent paraplegia. Neuroprotection was demonstrated if a drug prolonged the P50 compared with the control group.

The P50 of the control group was 26.3 +/- 2.0 minutes. Treatment with intravenous muscimol at 5 mg/kg significantly prolonged the P50 (32.4 +/- 1.3; P = .01). Treatment with intravenous bicuculline at 0.1 mg/kg significantly shortened the P50 (20.6 +/- 1.5; P = .03). The physiological and apparent behavioral effects of the drugs at these doses did not appear substantial.

Pharmacological manipulation of the GABA-A receptor may offer another avenue of therapy for central nervous system ischemia, possibly with less severe associated physiological side effects than other effective drugs.