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Study Title:

Carnosine and Excitotoxicity

Study Abstract

Recently, we have shown that carnosine protects against NMDA-induced excitotoxicity in differentiated PC12 cells through a histaminergic pathway. However, whether the protective effect of the carnosine metabolic pathway also occurs in ischemic brain is unknown. Utilizing the model of permanent middle cerebral artery occlusion (pMCAO) in mice, we found that carnosine significantly improved neurological function and decreased infarct size both in histidine decarboxylase knock-out and the corresponding wild type mice, to the same extent. Carnosine decreased the glutamate levels, and preserved the expression of glutamate transporter-1 (GLT-1) but not glutamate/aspartate transporter in astrocytes exposed to ischemia in vivo and in vitro. It suppressed the dissipation of DeltaPsim and generation of mitochondrial reactive oxygen species (ROS) induced by oxygen-glucose deprivation in astrocytes. Furthermore, carnosine also decreased the mitochondrial ROS and reversed the decrease of GLT-1 induced by rotenone. These findings are the first to demonstrate that the mechanism of carnosine action in pMCAO may not be mediated by the histaminergic pathway, but by reducing glutamate excitotoxicity through the effective regulation of the expression of GLT-1 in astrocytes due to improved mitochondrial function. Thus, our study reveals a novel anti-excitotoxic agent in ischemic injury.

Study Information

Shen Y, He P, Fan YY, Zhang JX, Yan HJ, Hu WW, Ohtsu H, Chen Z.
Carnosine protects against permanent cerebral ischemia in histidine decarboxylase knock-out mice through reducing glutamate excitotoxicity.
Free Radic Biol Med.
2009 December
Institute of Molecular and Cellular Medicine, Wenzhou Medical College, Wenzhou, 325035, China; Department of Pharmacology, Institute of Neuroscience, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China.