TY - JOUR
T1 - Neuroprotection against neonatal hypoxia/ischemia-induced cerebral cell death by prevention of calpain-mediated mGluR1α truncation
AU - Zhou, Miou
AU - Xu, Wei
AU - Liao, Guanghong
AU - Bi, Xiaoning
AU - Baudry, Michel
N1 - Funding Information:
This research was supported by NINDS grants NS048521 to MB and NS048423 to XB. The authors wish to thank Anna Knize for her help in preparing cultured hippocampal slices.
PY - 2009/7
Y1 - 2009/7
N2 - Many cellular events are involved in ischemic neuronal death, and it has been difficult to identify those that play a critical role in the cascade triggered by lack of oxygen and glucose, although it has been widely recognized that overactivation of glutamate receptors represents one of the initiating factors. Different glutamate receptor antagonists, especially those for N-methyl-d-aspartate (NMDA) receptors, have achieved significant success in animal models of hypoxia/ischemia; however, these antagonists have failed in clinical trials. We previously reported that calpain-mediated truncation of metabotropic glutamate receptor 1α (mGluR1α) played a critical role in excitotoxicity, and that a TAT-mGluR1 peptide consisting of a peptide surrounding the calpain cleavage site of mGluR1α and the peptide transduction domain of the transactivating regulatory protein (TAT) of HIV was neuroprotective against excitotoxicity. In the present study we tested the effect of this peptide in in vitro and in vivo models of neonatal hypoxia/ischemia. TAT-mGluR1 peptide prevented oxygen/glucose deprivation- (OGD) and hypoxia/ischemia- (H/I) induced neuronal death in cultured hippocampal slices and neonatal rats, respectively. TAT-mGluR1 blocked H/I-induced mGluR1α degradation but had no effect on H/I-induced spectrin degradation, suggesting that neuroprotection was due to prevention of calpain-mediated mGluR1α truncation and not to calpain inhibition. Our results therefore suggest that mGluR1α truncation plays a critical role in neonatal hypoxia/ischemia and that blockade of this event may prevent the activation of many downstream cytotoxic cascades. Compared to glutamate receptor antagonists and general calpain inhibitors, TAT-mGluR1 may have limited side effects.
AB - Many cellular events are involved in ischemic neuronal death, and it has been difficult to identify those that play a critical role in the cascade triggered by lack of oxygen and glucose, although it has been widely recognized that overactivation of glutamate receptors represents one of the initiating factors. Different glutamate receptor antagonists, especially those for N-methyl-d-aspartate (NMDA) receptors, have achieved significant success in animal models of hypoxia/ischemia; however, these antagonists have failed in clinical trials. We previously reported that calpain-mediated truncation of metabotropic glutamate receptor 1α (mGluR1α) played a critical role in excitotoxicity, and that a TAT-mGluR1 peptide consisting of a peptide surrounding the calpain cleavage site of mGluR1α and the peptide transduction domain of the transactivating regulatory protein (TAT) of HIV was neuroprotective against excitotoxicity. In the present study we tested the effect of this peptide in in vitro and in vivo models of neonatal hypoxia/ischemia. TAT-mGluR1 peptide prevented oxygen/glucose deprivation- (OGD) and hypoxia/ischemia- (H/I) induced neuronal death in cultured hippocampal slices and neonatal rats, respectively. TAT-mGluR1 blocked H/I-induced mGluR1α degradation but had no effect on H/I-induced spectrin degradation, suggesting that neuroprotection was due to prevention of calpain-mediated mGluR1α truncation and not to calpain inhibition. Our results therefore suggest that mGluR1α truncation plays a critical role in neonatal hypoxia/ischemia and that blockade of this event may prevent the activation of many downstream cytotoxic cascades. Compared to glutamate receptor antagonists and general calpain inhibitors, TAT-mGluR1 may have limited side effects.
KW - Calpain
KW - Excitotoxicity
KW - Hypoxia/ischemia
KW - Metabotropic glutamate receptors
KW - Oxygen/glucose deprivation
KW - TAT-mGluR1
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UR - http://www.scopus.com/inward/citedby.url?scp=67349277708&partnerID=8YFLogxK
U2 - 10.1016/j.expneurol.2009.04.006
DO - 10.1016/j.expneurol.2009.04.006
M3 - Article
C2 - 19374898
AN - SCOPUS:67349277708
SN - 0014-4886
VL - 218
SP - 75
EP - 82
JO - Experimental Neurology
JF - Experimental Neurology
IS - 1
ER -