Abstract

Recent studies have suggested that α₂-adrenergic agonists prevent neuronal cell death in a number of animal models, although the mechanism of α₂-neuroprotection remains unclear. In a retinal ischemia model, the α₂-specific agonist brimonidine (1 mg/kg i.p.) preserves approximately 80% of the electroretinogram (ERG) b-wave. The protective effect of brimonidine is completely blocked by coadministration of the α₂- antagonist rauwolscine. Brimonidine treatment preserves the ERG b-wave if animals are treated 1 or 3 h before ischemia, but has no effect if it is injected during ischemia. The 3-h pretreatment effect is blocked by i.v. injection of rauwolscine 2 h later (1 h before ischemia). A comparison of vitreous humor glutamate levels between untreated and brimonidine-treated eyes shows that 1) after ischemia, glutamate levels rise 2- to 3-fold in the untreated animals, and 2) glutamate levels in the brimonidine-treated animals are comparable to the nonischemic controls. Hence, the mechanism for brimonidine-mediated protection in the retinal ischemia model requires activation of the α₂-adrenergic receptors immediately before and during ischemia. These data suggest that activation of the α₂-adrenergic receptor may reduce ischemic retinal injury by preventing the accumulation of extracellular glutamate and aspartate.