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IGF-1 exacerbates the neurotoxicity of the mitochondrial inhibitor 3NP in rats

Carole Escartin 1, 2, * Frédéric Boyer 1, 2 Alexis-Pierre Bemelmans 3 Philippe Hantraye 1, 2 Emmanuel Brouillet 1, 2
* Corresponding author
1 LMN - Laboratoire des Maladies Neurodégénératives - UMR 9199
MIRCEN - Service MIRCEN : DRF/JACOB, CNRS - Centre National de la Recherche Scientifique : UMR 9199
Abstract : 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 $\mu$g/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 $\mu$g/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
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Carole Escartin, Frédéric Boyer, Alexis-Pierre Bemelmans, Philippe Hantraye, Emmanuel Brouillet. IGF-1 exacerbates the neurotoxicity of the mitochondrial inhibitor 3NP in rats. Neuroscience Letters, Elsevier, 2007, 425 (3), pp.167-172. ⟨10.1016/j.neulet.2007.08.031⟩. ⟨cea-02290618⟩

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