We investigated whether the known neuroprotective effects of two selective glutamate receptor antagonists, the NMDA antagonist MK-801 and the AMPA antagonist NBQX, are reflected in the regional cerebral protein synthesis rates (CPSR) in rats with middle cerebral artery occlusion (MCAO). Rats treated with either saline, MK-801 (5 mg/kg i.p.) or NBQX (30 mg/kg i.p. x 3) were subjected to permanent MCAO. Regional CPSR and volumes of gray matter structures displaying normal CPSR were measured in coronal cryosections of the brain by quantitative autoradiography following an i.v. bolus injection of 35S-labelled L-methionine 2 h after occlusion. MCAO completely inhibited protein synthesis in the lateral part of striatum and part of the adjacent frontoparietal cortex corresponding to the ischemic focus. Surrounding this, a metabolic penumbra with approximately 50% reductions in CPSR was present. Treatment with MK-801 significantly increased the volume of tissue with normal CPSR in the ischemic hemisphere compared to controls, whereas this was not seen with NBQX treatment. The results suggest that MK-801 and NBQX have different effects on peri-infarct protein synthesis after MCAO. Since both compounds reduce infarct size, it is questionable that acute inhibition of protein synthesis in focal ischemia is of significant importance to the final outcome of a stroke lesion.