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(+/-) mice 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 MPTP.
Nadjar
Agnès
A
Université Victor Segalen Bordeaux 2, Centre National de la Recherche Scientifique, Bordeaux Institute of Neuroscience, UMR 5227, Bordeaux, France. agnes.nadjar@u-bordeaux2.fr
Berton
Olivier
O
Guo
Shuhong
S
Leneuve
Patricia
P
Dovero
Sandra
S
Diguet
Elsa
E
Tison
François
F
Zhao
Baolu
B
Holzenberger
Martin
M
Bezard
Erwan
E
D000818:Animals; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D004298:Dopamine / Q000378:metabolism; D004578:Electron Spin Resonance Spectroscopy; D005609:Free Radicals / Q000378:metabolism; D020267:MPTP Poisoning / Q000235:genetics / Q000276:immunology / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D015213:Neuroimmunomodulation / Q000502:physiology*; D009474:Neurons / Q000187:drug effects* / Q000276:immunology / Q000502:physiology*; D020411:Oligonucleotide Array Sequence Analysis; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D013378:Substantia Nigra / Q000187:drug effects / Q000276:immunology / Q000502:physiology
D005609:Free Radicals; D017526:Receptor, IGF Type 1; D004298:Dopamine