PROTECTIVE EFFECT OF SYNAPTIC INHIBITION DURING CEREBRAL-ISCHEMIA IN RATS AND RABBITS

Background: Excitatory neurotransmitters appear to cause cell death during ischemia by inducing depolarization, influx of ions, and metabolic failure in the postsynaptic neuron. If this hypothesis is correct, then postsynaptic membrane hyperpolarization and inhibition of metabolism may be protective. Antagonists of the excitotoxic amino acid glutamate protect neurons in culture and in animal models of stroke but appear to cause unacceptable side effects in humans. We propose an alternative strategy of protection using agonists of the inhibitory neurotransmitter gamma-aminobutyric acid. Methods: We caused multifocal cerebral ischemia in rats and rabbits by injecting microspheres into the carotid circulation. We administered saline, muscimol, or MK-801 within 5 minutes of stroke onset. We used a bioassay to measure outcome. In rats, we also used learning to assess cortical function, and we performed detailed quantitative brain morphometry 3 months after infarction. Results: Using the bioassay, we found that muscimol exerted a protective effect in rats (p<0.01). There was a dose-response effect seen in muscimol-treated rabbits. Rats treated with muscimol or MK-801 exhibited significantly better visual-spatial learning compared with saline-treated subjects (p<0.001). Hemisphere volume after ischemia was comparable in all groups. Conclusions: Agonists of gamma-aminobutyric acid and antagonists of glutamate appear to protect brain during ischemia. Since agonists of gamma-aminobutyric acid are known to have fewer side effects in humans, they may prove more useful in the clinical setting as neuroprotective agents.