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

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.