IGF-1 exacerbates the neurotoxicity of the mitochondrial inhibitor 3NP in rats.
Insulin-like Growth Factor 1 (IGF-1) has broad-range neuroprotective effects and is a therapeutic candidate for Huntington's disease (HD). IGF-1 protects striatal neurons from the toxicity of mutated huntingtin in vitro and improves neuronal survival in vivo in a phenotypic model of HD involving excitotoxic cell death. Because HD is a multifactorial disease, it is important to evaluate the neuroprotective role of IGF-1 in other pathological situations involved in HD progression. We have evaluated the neuroprotective effects of IGF-1 in vivo, using the 3-nitropropionic acid (3NP) rat model which replicates the mitochondrial dysfunction observed in HD. Continuous intracerebroventricular infusion of recombinant IGF-1 at a low dose (0.025 microg/h for 5 days) did not alleviate motor impairment and weight loss induced by 3NP treatment. In addition, histological evaluation and quantification of DNA fragmentation evidenced no improvement in neuronal survival. Of interest, we found that a higher concentration of IGF-1 (0.25 microg/h) resulted in an exacerbation of 3NP toxicity on striatal neurons. These results suggest that intracerebral delivery of IGF-1 may not provide a fully effective therapeutic strategy for HD or other disorders involving mitochondrial impairment.
Escartin
Carole
C
CEA-DSV, I2BM, Service Hospitalier Frédéric Joliot, CNRS URA 2210, 4 place du Général Leclerc, 91401 Orsay, France. carolescartin@yahoo.fr
Boyer
Frédéric
F
Bemelmans
Alexis-Pierre
AP
Hantraye
Philippe
P
Brouillet
Emmanuel
E
D000818:Animals; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D003292:Convulsants / Q000633:toxicity; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D006816:Huntington Disease / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D007276:Injections, Intraventricular; D007334:Insulin-Like Growth Factor I / Q000627:therapeutic use / Q000633:toxicity*; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D028361:Mitochondrial Diseases / Q000139:chemically induced* / Q000188:drug therapy* / Q000503:physiopathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009498:Neurotoxins / Q000633:toxicity; D009574:Nitro Compounds / Q000633:toxicity*; D011422:Propionates / Q000633:toxicity*; D051381:Rats; D011917:Rats, Inbred Lew; D016896:Treatment Outcome
D003292:Convulsants; D009498:Neurotoxins; D009574:Nitro Compounds; D011422:Propionates; D007334:Insulin-Like Growth Factor I; C015392:3-nitropropionic acid