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Int. J. Mol. Sci. 2018, 19(11), 3543; https://doi.org/10.3390/ijms19113543

Inhibition of Microglia-Derived Oxidative Stress by Ciliary Neurotrophic Factor Protects Dopamine Neurons In Vivo from MPP+ Neurotoxicity

1
Department of Neuroscience, Graduate School, Kyung Hee University, Seoul 02447, Korea
2
Department of Biochemistry and Signaling Disorder Research Center, College of Medicine, Chungbuk National University, Cheongju 28644, Korea
3
Department of Biochemistry & Molecular Biology, School of Medicine, Kyung Hee University, Seoul 02447, Korea
4
Department of Neurology, School of Medicine, Kyung Hee University, Seoul 02447, Korea
5
Department of Predictive Toxicology, Korea Institute of Toxicology, Daejeon 34114, Korea
These authors contributed equally to this work.
*
Authors to whom correspondence should be addressed.
Received: 17 September 2018 / Revised: 7 November 2018 / Accepted: 8 November 2018 / Published: 10 November 2018
(This article belongs to the Special Issue Neuroprotective Strategies 2018)
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Abstract

We demonstrated that capsaicin (CAP), an agonist of transient receptor potential vanilloid subtype 1 (TRPV1), inhibits microglia activation and microglia-derived oxidative stress in the substantia nigra (SN) of MPP+-lesioned rat. However, the detailed mechanisms how microglia-derived oxidative stress is regulated by CAP remain to be determined. Here we report that ciliary neurotrophic factor (CNTF) endogenously produced by CAP-activated astrocytes through TRPV1, but not microglia, inhibits microglial activation and microglia-derived oxidative stress, as assessed by OX-6 and OX-42 immunostaining and hydroethidine staining, respectively, resulting in neuroprotection. The significant increase in levels of CNTF receptor alpha (CNTFRα) expression was evident on microglia in the MPP+-lesioned rat SN and the observed beneficial effects of CNTF was abolished by treatment with CNTF receptor neutralizing antibody. It is therefore likely that CNTF can exert its effect via CNTFRα on microglia, which rescues dopamine neurons in the SN of MPP+-lesioned rats and ameliorates amphetamine-induced rotations. Immunohistochemical analysis revealed also a significantly increased expression of CNTFRα on microglia in the SN from human Parkinson’s disease patients compared with age-matched controls, indicating that these findings may have relevance to the disease. These data suggest that CNTF originated from TRPV1 activated astrocytes may be beneficial to treat neurodegenerative disease associated with neuro-inflammation such as Parkinson’s disease. View Full-Text
Keywords: Parkinson’s disease; Microglia; Ciliary neurotrophic factor; Ciliary neurotrophic factor receptor; oxidative stress Parkinson’s disease; Microglia; Ciliary neurotrophic factor; Ciliary neurotrophic factor receptor; oxidative stress
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

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Baek, J.Y.; Jeong, J.Y.; Kim, K.I.; Won, S.-Y.; Chung, Y.C.; Nam, J.H.; Cho, E.J.; Ahn, T.-B.; Bok, E.; Shin, W.-H.; Jin, B.K. Inhibition of Microglia-Derived Oxidative Stress by Ciliary Neurotrophic Factor Protects Dopamine Neurons In Vivo from MPP+ Neurotoxicity. Int. J. Mol. Sci. 2018, 19, 3543.

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