Abstract
Parkinson’s disease (PD) is a multifactorial disorder characterized by progressive loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc) and the presence of Lewy bodies (LBs) consisting of misfolded α-synuclein protein. The etiology of PD is still not clear but systemic inflammation is proved to trigger and exacerbate DA neurons degeneration. Toll-like receptor 4 (TLR4) is a pattern-recognition receptor (PRR) and plays a major role in promoting the host immune. TLR4-mediated signal pathways induce the release of many inflammatory cytokines. It is reasonable to hypothesize that TLR4 is the mediator in microglia contributing to the damage of DA neurons in the SNpc. In this study, we evaluated the role of TLR4 in the chronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)/probenecid mouse model. Both TLR4-deficient and wild-type (WT) mice were injected with probenecid (250 mg/kg, i.p.) followed by injection of MPTP (25 mg/kg, s.c.) every 4 days for 10 times. From D43 to D47, the behavioral performance in pole test and wire hang test was assessed. Then the mice were euthanized, and SN and striatum were dissected out for biochemical tests. We showed that compared with MPTP-treated WT mice, TLR4 deficiency significantly attenuated MPTP-induced motor deficits and TH-protein expression reduction in SNpc and striatum, suppressed MPTP-induced α-synuclein abnormality and neuroinflammation mediated through oxidative stress, glial activation, NF-κB and the NLRP3 inflammasome signaling pathways. These findings highlight the neuroprotective effect of TLR4-pathways in the chronic MPTP-induced PD mouse model.
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Acknowledgements
This work was supported by the National Natural Science Foundation of China (81573640 and 81773925), the Beijing Natural Science Foundation (7161011), and the Drug Innovation Major Project 2018ZX09711-001-001 and 2018ZX09711-001-001-003.
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YHY and NHC designed research; QHS performed research; FFL, SW and XLZ contributed new analytical tools and reagents; YC analyzed data; QHS wrote the paper. All authors reviewed the manuscript.
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Shao, Qh., Chen, Y., Li, Ff. et al. TLR4 deficiency has a protective effect in the MPTP/probenecid mouse model of Parkinson’s disease. Acta Pharmacol Sin 40, 1503–1512 (2019). https://doi.org/10.1038/s41401-019-0280-2
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DOI: https://doi.org/10.1038/s41401-019-0280-2
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