Inhibitory effect of carnosine on induction of neuronal autophagy under cerebral ischemia

Abstract

Although ischemic strokeis a major cause of death and disability worldwide, no therapeutic option for neuroprotection is available, urging a development of new drug candidates targeting novel neurotoxic pathways. Recent studies showed that autophagy plays an important role in ischemic neuronal death, suggesting that autophagy can be a primary target for ischemic stroke treatment. It is known that carnosine, an endogenous pleiotropic dipeptide, has a neuroprotective activity against ischemic brain damage. To investigate the underlying mechanism, we examined the effect of carnosine on autophagic processesin NMDA-stimulated primary neurons and in ischemic brain. In isolated primary cortical neurons, which were characterized by morphological and immunofluorescence observation, NMDA induced cytotoxicity as found in PI staining and LDH leakage. NMDA-neuronal toxicity was significantly reduced by carnosine pretreatment, showing neuroprotective effect of carnosine. Autophagic pathways were activated by NMDA stimulation, such as reduction of phosphorylated mTOR and the conversion of LC3-I to LC3-II, while treatment of carnosine attenuated these autophagic signalings in primary neurons. In rat ischemic stroke models, pretreatment of carnosine significantly improved brain infarct. Carnosine reversed autophagic signaling pathways activated in ischemic brain. Taken together, our data suggest that neuroprotection by carnosine is mediated by inhibiting excessive autophagic processes, and that carnosine is a novel drug candidate for the development of anti-ischemic drugs.