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TGF-β1 Neuroprotection via Inhibition of Microglial Activation in a Rat Model of Parkinson’s Disease

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Abstract

Transforming growth factor (TGF)-β1 is a pleiotropic cytokine with immunosuppressive and anti-inflammatory properties. Recently we have shown that TGF-β1 pretreatment in vitro protects against 1-methyl-4-phenylpyridinium (MPP+)-induced dopaminergic neuronal loss that characterizes in Parkinson’s disease (PD). Herein, we aimed to demonstrate that TGF-β1 administration in vivo after MPP+ toxicity has neuroprotection that is achieved by a mediation of microglia. A rat model of PD was prepared by injecting MPP+ unilaterally in the striatum. At 14 days after MPP+ injection, TGF-β1 was administrated in the right lateral cerebral ventricle. Primary ventral mesencephalic (VM) neurons and cerebral cortical microglia were treated by MPP+, respectively, and TGF-β1 was applied to neuronal or microglial cultures at 1 h after MPP+ treatment. As expected, MPP+ resulted in decrease in TGF-β1 production in the substantia nigra and in primary VM neurons and microglia. TGF-β1 intracerebroventricular administration alleviated MPP+-induced PD-like changes in pathology, motor coordination and behavior. Meanwhile, TGF-β1 ameliorated MPP+-induced microglial activation and inflammatory cytokine production in vivo. Interestingly, TGF-β1 treatment was not able to ameliorate MPP+-induced dopaminergic neuronal loss and caspase-3/9 activation in mono-neuron cultures, but TGF-β1 alleviated MPP+-induced microglial activation and inflammatory cytokine production in microglia-enriched cultures. This effect of TGF-β1 inhibiting microglial inflammatory response was blocked by Smad3 inhibitor SIS3. Importantly, neuronal exposure to supernatants of primary microglia that had been treated with TGF-β1 reduced dopaminergic neuronal loss and caspase-3/9 activation induced by MPP+-treated microglial supernatants. These findings establish that TGF-β1 exerts neuroprotective property in PD by inhibiting microglial inflammatory response via Smad3 signaling.

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Acknowledgements

This work was supported by grants 81271323 and 31371182 from the National Natural Science Foundation of China, MS12015104 and MS12015096 from the Nantong Applied Research Program of China, and a project funded by the Priority Academic Program Development (PAPD) of Jiangsu Higher Education Institutions.

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Authors and Affiliations

  1. Department of Physiology, School of Medicine, and Co-innovation Center of Neuroregeneration, Nantong University, 19 Qixiu Road, Nantong, Jiangsu Province, 226001, China

    Xiao Chen, Zhan Liu, Bei-Bei Cao, Yi-Hua Qiu & Yu-Ping Peng

  2. Department of Neurology, Affiliated Hospital, Nantong University, 20 Xisi Road, Nantong, Jiangsu Province, 226001, China

    Xiao Chen

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  1. Xiao Chen
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  2. Zhan Liu
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  3. Bei-Bei Cao
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  4. Yi-Hua Qiu
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Correspondence to Yi-Hua Qiu or Yu-Ping Peng.

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Xiao Chen and Zhan Liu contributed equally to this study.

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Chen, X., Liu, Z., Cao, BB. et al. TGF-β1 Neuroprotection via Inhibition of Microglial Activation in a Rat Model of Parkinson’s Disease. J Neuroimmune Pharmacol 12, 433–446 (2017). https://doi.org/10.1007/s11481-017-9732-y

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