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Brain injury after focal cerebral ischemia develops from a series of pathological processes. However, the results of clinical trials to prevent ischemic brain damage by blocking the detrimental effects are disappointing. We report that suppression of proteolytic degradation of transient receptor potential canonical (TRPC) 6 prevented ischemic neuronal cell death. The TRPC6 protein level in neurons was reduced in ischemia via N-methyl-D-aspartate (NMDA) receptor-dependent calpain proteolysis of N-terminal domain of TRPC6 at Lys16. A fusion peptide derived from the calpain cleavage site in TRPC6 inhibited its degradation, reduced infarct size and improved behavior outcome of ischemic rats. Thus, suppression of TRPC6 degradation prevented ischemic brain damage.