Effects of RGH-2202 on behavioral deficits after focal cerebral ischemia in rats

We investigated the effects of RGH-2202 (posatirelin, (-)-(2S)-N-[(1S)-1-[[(2S)-2-carbamoyl-1-pyrrolidinyl[carbonyl]-3- methylbutyl]-6-oxopipecolamide), a thyrotropin-releasing hormone (TRH) analog, on behavioral changes during a chronic phase of focal ischemia in rats in comparison with the parent peptide. The left middle cerebral artery (MCA) was occluded under halothane anesthesia, and the subsequent behavioral changes were observed for 35 days. RGH-2202 (1, 3, and 10 mg/kg) and TRH (10 mg/kg) were given IP just after the operation and afterward once a day for 14 days. MCA-occluded rats exhibited neurologic symptoms including hemiplegia and abnormal posture and disturbance of passive avoidance learning during the entire 35-day observation period. The repeated treatment with either peptides improved the neurologic and cognitive deficits. In addition, a recovery from deficits was still advanced after discontinuation of the drug treatment. In these effects, RGH-2202 was about three times more potent than TRH. Neural tissue damage in drug-treated groups, measured by omega 3 binding site densities 35 days after MCA occlusion, was included to be less than that in the vehicle-treated group. These results suggest that appropriate treatment with RGH-2202 may be useful in the treatment of functional disturbances after focal cerebral ischemia.