Disruption of the GluR2/GAPDH complex protects against ischemia-induced neuronal damage.

BACKGROUND

Excitotoxicity and neuronal death following ischemia involve AMPA (α-amino-3hydroxy-5-methylisoxazole-4-propionic acid) glutamate receptors. We have recently reported that the GluR2 subunit of AMPA receptors (AMPARs) forms a protein complex with GAPDH (glyceraldehyde-3-phosphate dehydrogenase). The GluR2/GAPDH complex co-internalizes upon activation of AMPA receptors. Disruption of the GluR2/GAPDH interaction with an interfering peptide protects cells against AMPAR-mediated excitotoxicity and protects against damage induced by oxygen-glucose deprivation (OGD), an in vitro model of brain ischemia.

OBJECTIVE

We sought to test the hypothesis that disruption of the GluR2/GAPDH interaction with an interfering peptide would protect against ischemia-induced neuronal damage in vivo.

METHODS

The rat 4-vessel occlusion (4-VO) model was used to investigate whether the GluR2/GAPDH interaction was enhanced in the hippocampus, and if our newly developed interfering peptide could protect against neuronal death in the ischemic brain area. The transient rat middle cerebral artery occlusion (tMCAo) model was used to determine whether our peptide could reduce infarction volume and improve neurological function. Finally, GAPDH lentiviral shRNA was injected into the brain to reduce GAPDH expression one week prior to tMCAo, to confirm the role of GAPDH in the pathophysiology of brain ischemia.

RESULTS

The GluR2/GAPDH interaction is upregulated in the hippocampus of rats subjected to transient global ischemia. Administration of an interfering peptide that is able to disrupt the GluR2/GAPDH interaction in vivo protects against ischemia-induced cell death in rat models of global ischemia and decreases the infarct volume as well as neurological score in a rat model focal ischemia. Consistent with these observations, decreased GAPDH expression also protects against ischemia-induced cell death in an animal model of focal ischemia.

CONCLUSIONS

Disruption of the GluR2/GAPDH interaction protects against ischemia-induced neuronal damage in vivo. The GluR2/GAPDH interaction may be a novel therapeutic target for development of treatment for ischemic stroke.