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 1alpha (mGluR1alpha) played a critical role in excitotoxicity, and that a
TAT-mGluR1 peptide consisting of a
peptide surrounding the
calpain cleavage site of mGluR1alpha 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 mGluR1alpha degradation but had no effect on H/I-induced
spectrin degradation, suggesting that neuroprotection was due to prevention of
calpain-mediated mGluR1alpha truncation and not to
calpain inhibition. Our results therefore suggest that mGluR1alpha 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.