IGF-1 signaling reduces neuro-inflammatory response and sensitivity of neurons to MPTP

Reduced expression of IGF-1R increases lifespan and resistance to oxidative stress in the mouse, raising the possibility that this also confers relative protection against the pro-parkinsonian neurotoxin MPTP, known to involve an oxidative stress component We used heterozygous IGF-1R(+/-) mice and challenged them with MPTP Interestingly, MPTP induced more severe lesions of dopaminergic neurons of the substantia nigra, in IGF-1R(+/-) mice than in wild-type animals Using electron spin resonance, we found that free radicals were decreased in IGF-1R(+/-) mice in comparison with controls, both before and after MPTP exposure, Suggesting that the increased vulnerability of dopamine neurons is not caused by oxidative stress Importantly, we showed that IGF-1R(+/-) truce display a dramatically increased neuro-inflammatory response to MPTP that may ground the observed increase in neuronal death. Microarray analysis revealed that oxidative stress-associated genes, but also several anti-inflammatory signaling pathways were downregulated under control conditions in IGF-1R(+/-) mice compared to WT Collectively, these data indicate that IGF signaling can reduce neuro-inflammation dependent sensitivity of neurons to WIT (C) 2008 Elsevier Inc. All rights reserved.