Disruption of GluR2/GAPDH Complex Interaction by TAT-GluR2 NT1-3-2 Peptide Protects against Neuronal Death Induced by Epilepsy.

OBJECTIVE: Excitotoxic neuronal death induced by epilepsy is associated with α-amino-3-hydroxyl-5-methylisoxazole-4-propionate acid (AMPA) receptors. The GluR2 subunit of AMPA receptors (AMPARs) may bind with glyceraldehyde-3-phosphate dehydrogenase (GAPDH). The GluR2/GAPDH complex co-internalizes upon stimulation of AMPARs, which might be involved in the development of epilepsy. In this research, we hypothesized that disruption of the GluR2/GAPDH interaction with an interfering peptide would protect against neuronal damage in vivo .

METHODS: Rat models of epilepsy were induced by pilocarpine hydrochloride. TAT-GluR2NT1-3-2 peptide was synthesized to block interaction between GluR2 and GAPDH. Fluoro-Jade B and TUNEL staining were used to detect degeneration and apoptosis of neurons after interference by the peptide. Co-immunoprecipitation assay and western-blot was performed to confirm that the peptide disturbed interactions between GluR2 and GAPDH.

RESULTS: The time of epileptic seizure was found to be delayed after peptide interference. It was concluded that administration of an interfering peptide is able to significantly reduce degeneration and apoptosis of neurons. The GluR2/GAPDH interaction and GAPDH nuclear expression were upregulated in the hippocampus of rats subjected to pilocarpine-induced seizures.

CONCLUSION: Disruption of the GluR2/GAPDH interaction by administration of an interfering peptide protects against seizure-induced neuronal damage that is dose dependent. Thus, the GluR2/GAPDH interaction may be a novel therapeutic target for development of treatment for epilepsy.