TGF-β1 Neuroprotection via Inhibition of Microglial Activation in a Rat Model of Parkinson’s Disease
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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.
KeywordsTransforming growth factor-β1 Parkinson’s disease Microglia 1-methyl-4-phenylpyridinium Smad3
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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Conflict of Interest
The authors declare that they have no conflict of interest.
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