Carnosine protects against permanent cerebral ischemia in histidine decarboxylase knockout mice by reducing glutamate excitotoxicity.
Recently, we showed 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 in both histidine decarboxylase knockout 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 the glutamate/aspartate transporter in astrocytes exposed to ischemia in vivo and in vitro. It suppressed the dissipation of Delta Psi(m) 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 in 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 antiexcitotoxic agent in ischemic injury.
Shen
Yao
Y
Institute of Molecular and Cellular Medicine, Wenzhou Medical College, Wenzhou 325035, China.
He
Ping
P
Fan
Yan-ying
YY
Zhang
Jian-xiang
JX
Yan
Hai-jing
HJ
Hu
Wei-wei
WW
Ohtsu
Hiroshi
H
Chen
Zhong
Z
D027322:Amino Acid Transport System X-AG / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D002336:Carnosine / Q000008:administration & dosage / Q000494:pharmacology*; D018698:Glutamic Acid / Q000378:metabolism; D006640:Histidine Decarboxylase / Q000235:genetics / Q000378:metabolism; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000187:drug effects; D016202:N-Methylaspartate / Q000378:metabolism; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000494:pharmacology*; D016716:PC12 Cells; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D012402:Rotenone / Q000494:pharmacology
D027322:Amino Acid Transport System X-AG; D018696:Neuroprotective Agents; D017382:Reactive Oxygen Species; D012402:Rotenone; D018698:Glutamic Acid; D016202:N-Methylaspartate; D002336:Carnosine; D006640:Histidine Decarboxylase