Growth hormone releasing peptide-6 acts as a survival factor in glutamate-induced excitotoxicity

Chronic systemic treatment given to adult male rats with growth hormone releasing peptide-6, an agonist of the ghrelin receptor, increases insulin-like growth factor I levels in various brain regions, including the hypothalamus and cerebellum. Furthermore, intracellular signalling cascades normally associated with anti-apoptotic actions are activated in the same areas and are coincident with decreased basal cell death. Because abnormally high concentrations of glutamate can lead to overexcitation of neurones leading to cell damage and/or death, we investigated whether administration of growth hormone releasing peptide-6 attenuates monosodium glutamate-induced apoptosis in the rat hypothalamus and cerebellum. Glutamate increased activation of caspase 9 followed by cleavage of caspase 7, which in turn fragmented poly(ADP-ribose) polymerase, terminating in cell death in both the hypothalamus and cerebellum. Growth hormone releasing peptide-6 reversed glutamate-induced cell death by decreasing activation of caspases 9 and 7 and poly(ADP-ribose) polymerase fragmentation. These results provide a better understanding of the neuroprotective role of growth hormone secretagogues and the mechanisms involved.