Elsevier

Neurobiology of Aging

Volume 30, Issue 12, December 2009, Pages 2021-2030
Neurobiology of Aging

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

https://doi.org/10.1016/j.neurobiolaging.2008.02.009Get rights and content

Abstract

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.

Introduction

Insulin-like growth factor-1 (IGF-1) is a multifunctional peptide essential for normal growth and development (Russo et al., 2005) whose pleiotropic actions are mediated primarily by insulin-like growth factor type 1 receptor (IGF-1R), a transmembrane, ligand-activated tyrosine kinase highly homologous to the insulin receptor. Partial inactivation of the IGF-1R increases lifespan and resistance to oxidative stress in the mouse (Holzenberger et al., 2003). Important reciprocal interactions have also been demonstrated between IGF-1 and the pro-inflammatory cytokines that mediate neuro-inflammation (Venters et al., 1999, Ye et al., 2003, Kenchappa et al., 2004). Recent research revealed an anti-inflammatory action, counteracting pro-inflammatory effects of cytokine tumor necrosis factor alpha (TNF-α) (Bluthe et al., 2006). According to the context, IGF-1 would thus appear capable of antagonistic action, pro-oxidative or anti-inflammatory.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), used for modelling the selective dopaminergic cell injury occurring in Parkinson's disease, has dual inflammatory and oxidative actions, but these are non-antagonistic. 1-Methyl-4-phenyl pyridinium (MPP+), the active metabolite of MPTP induces the formation of reactive oxygen species (ROS), such as superoxide or hydroxyl radicals (Blum et al., 2001, Wang et al., 2001, Ryu et al., 2003, Tunez et al., 2004, Watanabe et al., 2005), suggesting that one of the causes of the neurotoxic action is oxidative stress. MPTP concomitantly activates neuro-inflammatory processes, of which the most important are reactive astrogliosis and microgliosis (Reinhard et al., 1988, Francis et al., 1995, Brouillet et al., 1999, Kurkowska-Jastrzebska et al., 1999) and cytokine synthesis (Rousselet et al., 2002, Hebert et al., 2003, Pera et al., 2004, Pattarini et al., 2007). Finally, during MPTP intoxication in mice, IGF-1R levels are upregulated but AKT phosphorylation remained unchanged (D’Astous et al., 2006), showing that while IGF signalling pathways are active in the brain under this neurotoxic insult, IGF signalling activity is not necessarily further induced by this stress.

To better understand the cellular mechanism underlying the antagonistic pro-oxidant and anti-inflammatory action of IGF-1, we submitted heterozygous IGF-1R+/− mice to acute MPTP intoxication. The lesions induced by MPTP were more severe in these mice than in wild-type control animals. The IGF-1R+/− group also showed lower levels of both nitric oxide (NO) and reactive oxygen species (ROS) than controls, both before and after MPTP treatment, but displayed, on the other hand, a dramatically increased neuro-inflammatory response that could well explain the observed increase in neuronal death.

Section snippets

Animals

We established a targeted IGF-1R gene knockout on 129/Sv genetic background (Holzenberger et al., 2003) and backcrossed the mutants for >15 generations to C57BL/6 mice. IGF-1 receptor levels in IGF-1R+/− mice were half those in WT (IGF-1R+/+) mice. Homozygous IGF-1R−/− knockout mutants invariably die minutes after birth. For this study we used 40 IGF-1R+/− and 38 WT (IGF-1R+/+) littermates, as controls. All mice were males and were used at similar age (10–12 weeks) in the different experiments.

IGF-1R+/− mice show increased loss of mesencephalic dopamine neurons after MPTP treatment

Holzenberger et al. (2003) showed that partial inactivation of IGF-1R increases lifespan and resistance to oxidative stress in the mouse, also raising the possibility that this confers relative protection against neurotoxins involving an oxidative stress response such as MPTP (complex I inhibitor). Under control conditions, both IGF-1R+/− animals and their WT littermates showed similar estimated numbers of TH-ir neurons within the SNc (Fig. 1A). After MPTP treatment, WT mice had 26% less

Discussion

Our main objective is to comprehend and further dissect the cellular mechanism behind the dual and antagonistic pro-oxidant and anti-inflammatory roles of IGF-1. Most inflammatory molecules, such as cytokines for instance, are double-edged molecules, either neuroprotective or neurotoxic, depending on the pathophysiological context. However, IGF-1 seems even more particular in the sense that its duality is expressed simultaneously in the same structure. While previous studies using cultured

Conflict of interest

There is no conflict of interest.

Acknowledgements

The University Victor Segalen, the CNRS, the Bordeaux Institute of Neuroscience (INSERM no. 8; CNRS no. 13) provided the infrastructural support for completion of the study.

References (56)

  • V. Jackson-Lewis et al.

    Time course and morphology of dopaminergic neuronal death caused by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine

    Neurodegeneration

    (1995)
  • I. Kurkowska-Jastrzebska et al.

    The inflammatory reaction following 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine intoxication in mouse

    Exp. Neurol.

    (1999)
  • D. Offen et al.

    Protective effect of insulin-like-growth-factor-1 against dopamine-induced neurotoxicity in human and rodent neuronal cultures: possible implications for Parkinson's disease

    Neurosci. Lett.

    (2001)
  • K. Palin et al.

    TNFalpha-induced sickness behavior in mice with functional 55 kDa TNF receptors is blocked by central IGF-I

    J. Neuroimmunol.

    (2007)
  • R. Pattarini et al.

    Temporal mRNA profiles of inflammatory mediators in the murine 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrimidine model of Parkinson's disease

    Neuroscience

    (2007)
  • J.F. Reinhard et al.

    The neurotoxicant MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) increases glial fibrillary acidic protein and decreases dopamine levels of the mouse striatum: evidence for glial response to injury

    Neurosci. Lett.

    (1988)
  • E. Rousselet et al.

    Role of TNF-alpha receptors in mice intoxicated with the parkinsonian toxin MPTP

    Exp. Neurol.

    (2002)
  • J.K. Ryu et al.

    Microglial activation and cell death induced by the mitochondrial toxin 3-nitropropionic acid: in vitro and in vivo studies

    Neurobiol. Dis.

    (2003)
  • M. Sawada et al.

    Production of tumor necrosis factor-alpha by microglia and astrocytes in culture

    Brain Res.

    (1989)
  • J.G. Shen et al.

    Chinonin, a novel drug against cardiomyocyte apoptosis induced by hypoxia and reoxygenation

    Biochim. Biophys. Acta

    (2000)
  • H. Theoret et al.

    Stereological evaluation of substantia nigra cell number in normal and hemispherectomized monkeys

    Brain Res.

    (1999)
  • L. Zecca et al.

    Neuromelanin of the substantia nigra: a neuronal black hole with protective and toxic characteristics

    Trends Neurosci.

    (2003)
  • M. Abercrombie

    Estimation of nuclear population from microtome sections

    Anat. Rec.

    (1946)
  • O. Berton et al.

    Essential role of BDNF in the mesolimbic dopamine pathway in social defeat stress

    Science

    (2006)
  • E. Bezard et al.

    Enriched environment confers resistance to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and cocaine: involvement of dopamine transporter and trophic factors

    J. Neurosci.

    (2003)
  • E. Bezard et al.

    Spontaneous long-term compensatory dopaminergic sprouting in MPTP-treated mice

    Synapse

    (2000)
  • M.L. Block et al.

    Microglia-mediated neurotoxicity: uncovering the molecular mechanisms

    Nat. Rev. Neurosci.

    (2007)
  • M. D’Astous et al.

    Implication of the phosphatidylinositol-3 kinase/protein kinase B signaling pathway in the neuroprotective effect of estradiol in the striatum of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mice

    Mol. Pharmacol.

    (2006)
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    Present address: CNRS UMR 5226, INRA UMR1286, Université Bordeaux 2, Bordeaux, France.

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