title: 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.
abstract: Huntington's disease is an incurable genetic neurological disorder characterized by the relatively selective degeneration of the striatum. Lesioning of the striatum in rodents using the excitatory amino acid agonist, quinolinic acid (QA), effectively mimics the human neuropathology seen in Huntington's disease. Using this animal model of Huntington's disease, we investigated the ability of the insulin-like growth factor-I (IGF-I) amino-terminal tripeptide glycine-proline-glutamate (GPE) to protect striatal neurons from degeneration. Adult rats received a single unilateral intrastriatal injection of QA (100 nmol) and then daily injection of either vehicle or GPE (0.3 microgram/microliter/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 cells of unlesioned levels in vehicle-treated animals. The major striatal neuronal phenotype, GABAergic projection neurons, were identified by immunocytochemical labeling of either glutamate decarboxylase 67 (GAD(67)) or the calcium 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 immunologically detectable levels of GAD(67). GPE also significantly reversed the phenotypic degeneration of cholinergic interneurons identified by immunolabeling for choline acetyltransferase (ChAT) and NADPH diaphorase interneurons identified histochemically. GPE treatment failed to rescue the calcium binding protein interneuron populations of parvalbumin and calretinin neurons. These findings reveal that exogenous administration of GPE selectively prevents excitotoxin induced phenotypic degeneration of striatal projection neurons and cholinergic and NADPH diaphorase interneurons in an animal model of Huntington's disease.
authors.affiliation: School of Medicine, University of Auckland, Auckland, New Zealand. t.alexi@auckland.ac.nz
authors.forename: T
authors.initials: T
authors.lastname: Alexi
authors.forename: P E
authors.initials: PE
authors.lastname: Hughes
authors.forename: W M
authors.initials: WM
authors.lastname: van Roon-Mom
authors.forename: R L
authors.initials: RL
authors.lastname: Faull
authors.forename: C E
authors.initials: CE
authors.lastname: Williams
authors.forename: R G
authors.initials: RG
authors.lastname: Clark
authors.forename: P D
authors.initials: PD
authors.lastname: Gluckman
mesh_terms: D000818:Animals; D064032:Calbindin 2; D064026:Calbindins; D002452:Cell Count; D002795:Choline O-Acetyltransferase / Q000032:analysis; D002799:Cholinergic Fibers / Q000737:chemistry / Q000201:enzymology; D003342:Corpus Striatum / Q000737:chemistry* / Q000166:cytology; D003714:Denervation; D004195:Disease Models, Animal; D005968:Glutamate Decarboxylase / Q000032:analysis; D006816:Huntington Disease / Q000188:drug therapy*; D007334:Insulin-Like Growth Factor I / Q000737:chemistry* / Q000502:physiology; D007395:Interneurons / Q000737:chemistry / Q000166:cytology / Q000201:enzymology; D008297:Male; D009252:NADPH Dehydrogenase / Q000032:analysis; D009410:Nerve Degeneration / Q000188:drug therapy / Q000378:metabolism; D018696:Neuroprotective Agents / Q000737:chemistry / Q000494:pharmacology*; D009842:Oligopeptides / Q000494:pharmacology*; D010320:Parvalbumins / Q000032:analysis / Q000235:genetics; D010641:Phenotype; D017378:Quinolinic Acid; D051381:Rats; D017208:Rats, Wistar; D064030:S100 Calcium Binding Protein G / Q000032:analysis / Q000235:genetics; D005680:gamma-Aminobutyric Acid / Q000032:analysis / Q000502:physiology
chemical_list: C576764:CALB2 protein, human; C576512:Calb2 protein, rat; D064032:Calbindin 2; D064026:Calbindins; D018696:Neuroprotective Agents; D009842:Oligopeptides; D010320:Parvalbumins; D064030:S100 Calcium Binding Protein G; D005680:gamma-Aminobutyric Acid; D007334:Insulin-Like Growth Factor I; D009252:NADPH Dehydrogenase; D002795:Choline O-Acetyltransferase; D005968:Glutamate Decarboxylase; D017378:Quinolinic Acid; C062053:glycyl-prolyl-glutamic acid