Global cerebral ischemia leads to long lasting hyperexcitability and a reduced protein synthesis in non-infarcted tissue surrounding the lesion. In this study we investigated whether protein synthesis inhibition by pharmacological means itself changes neocortical excitability. Two hours after the last of three i.p. injections with the protein synthesis inhibitor cycloheximide (12 h interval, 1.5 mg/kg body weight) we observed a widespread reduction of neocortical inhibition. The study indicates that inhibition of protein synthesis may contribute to the altered brain excitability following ischemia.