COMBINATION THERAPY PROTECTS ISCHEMIC BRAIN IN RATS - A GLUTAMATE ANTAGONIST PLUS A GAMMA-AMINOBUTYRIC-ACID AGONIST

Background and Purpose The excitotoxic effects of glutamate can be blo cked almost completely with gamma-aminobutyric acid (GABA), an inhibit ory neurotransmitter, in cell culture, tissue slices, and in some anim al models. After stroke in rats, we showed previously that an agonist of GABA, muscimol, was as neuroprotective as MK-801, an antagonist of glutamate. To obtain further neuroprotection and to avoid the side eff ects associated with high doses of MK-801, we wanted to assess the eff icacy of the two agents in combination. Methods Treatment was administ ered 5 minutes after embolic cerebral ischemia in Sprague-Dawley rats. The subjects were rated using a neurological evaluation 48 hours late r. Visual-spatial learning was measured 8 to 10 weeks after stroke, af ter which we measured the volume of each cerebral hemisphere and sever al large cerebral compartments. Treatment groups included saline (n=27 ), MK-801 1.0 mg/kg (n=23), muscimol 1.0 mg/kg (n=17), and both agents together using a dose of 0.5 mg/kg each (n=25). Results A probit anal ysis of the neurological ratings revealed a protective effect of musci mol used alone (MK-801 potency ratio, 2.0; P=NS; muscimol potency rati o, 4.0; P<.05) and a protective effect of the combination (potency rat io, 5.0; P<.05). Focal ischemia caused a moderate to severe delay in t he acquisition of visual-spatial information, which was completely eli minated by the combination treatment but only partially ameliorated wi th MK-801 or muscimol alone. Ischemia reduced the cerebral hemisphere volume from 0.42 mm3 to 0.34 mm3 (P<.0001), the volume density of cort ex from 22% to 17% of total cerebral volume (P<.01), and that of hippo campus from 4.3% to 3.0% (P<.05). Only the combination was neuroprotec tive, as measured by the ratio of the lesioned to the contralateral he misphere volume (P=.013). The combination treatment and MK-801 protect ed the hemisphere volume, the cortex, and the hippocampus and reduced the size of visible infarction. Conclusions Combination therapy, using a glutamate antagonist and a GABA-A agonist, appeared to protect the brain and ameliorate a defect in learning behavior after stroke. The c ombination may have been more effective than either agent used alone, although further study of higher doses is needed.