The IGF-I amino-terminal tripeptide glycine-proline-glutamate (GPE) is neuroprotective to striatum in the quinolinic acid lesion animal model of Huntington's disease

Huntington's disease is an incurable genetic neurological disorder characte rized by the relatively selective degeneration of the striatum. Lesioning o f the striatum in rodents using the excitatory amino acid agonist, quinolin ic acid (QA), effectively mimics the human neuropathology seen in Huntingto n's disease. Using this animal model of Huntington's disease, we investigat ed the ability of the insulin-like growth factor-I (IGF-I) amino-terminal t ripeptide glycine-proline-glutamate (GPE) to protect striatal neurons from degeneration. Adult rats received a single unilateral intrastriatal injecti on of QA (100 nmol) and then daily injection of either vehicle or GPE (0.3 mu g/mu l/day) into the striatum for 7 days. QA at this dose resulted in a partial lesioning of the striatum after 7 days to approximately 50% of cell s of unlesioned levels in vehicle-treated animals. The major striatal neuro nal phenotype, GABAergic projection neurons, were identified by immunocytoc hemical labeling of either glutamate decarboxylase 67 (GAD(67)) or the calc ium binding protein calbindin in alternate sections. Treatment with GPE for 7 days reversed the loss in projection neurons when assessed by counts of calbindin-stained cells; however, these rescued cells did not regain immuno logically detectable levels of GAD(67) GPE also significantly reversed the phenotypic degeneration of cholinergic interneurons identified by immunolab eling for choline acetyltransferase (ChAT) and NADPH diaphorase interneuron s identified histochemically. GPE treatment failed to rescue the calcium bi nding protein interneuron populations of parvalbumin and calretinin neurons . These findings reveal that exogenous administration of GPE selectively pr events excitotoxin induced phenotypic degeneration of striatal projection n eurons and cholinergic and NADPH diaphorase interneurons in an animal model of Huntington's disease. (C) 1999 Academic Press.