Abstract
Neuroprotection targeting mitochondrial dysfunction has been proposed as an important therapeutic strategy for Parkinson’s disease. Ganoderma lucidum (GL) has emerged as a novel agent that protects neurons from oxidative stress. However, the detailed mechanisms underlying GL-induced neuroprotection have not been documented. In this study, we investigated the neuroprotective effects of GL extract (GLE) and the underlying mechanisms in the classic MPTP(1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-induced mouse model of PD. Mice were injected with MPTP to induce parkinsonism. Then the mice were administered GLE (400 mg kg−1 d−1, ig) for 4 weeks. We observed that GLE administration significantly improved locomotor performance and increased tyrosine hydroxylase expression in the substantia nigra pars compact (SNpc) of MPTP-treated mice. In in vitro study, treatment of neuroblastoma neuro-2a cells with 1-methyl-4-phenylpyridinium (MPP+, 1 mmol/L) caused mitochondrial membrane potential collapse, radical oxygen species accumulation, and ATP depletion. Application of GLE (800 μg/mL) protected neuroblastoma neuro-2a cells against MPP+ insult. Application of GLE also improved mitochondrial movement dysfunction in cultured primary mesencephalic neurons. In addition, GLE counteracted the decline in NIX (also called BNIP3L) expression and increase in the LC3-II/LC3-I ratio evoked by MPP+. Moreover, GLE reactivated MPP+-inhibited AMPK, mTOR, and ULK1. Similarly, GLE was sufficient to counteract MPP+-induced inhibition of PINK1 and Parkin expression. GLE suppressed MPP+-induced cytochrome C release and activation of caspase-3 and caspase-9. In summary, our results provide evidence that GLE ameliorates parkinsonism pathology via regulating mitochondrial function, autophagy, and apoptosis, which may involve the activation of both the AMPK/mTOR and PINK1/Parkin signaling pathway.
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Acknowledgements
This study was supported by grants from the China Postdoctoral Science Foundation (2015M581133) and Beijing Postdoctoral Research Foundation (2015ZZ-63); from Beijing Municipal Administration of Hospitals’ Mission Plan, Code: SML20150803 and Beijing Municipal Science & Technology Commission No. Z171100000117013 to Dr. Piu Chan; and from The National Key R&D Program of China (2016YFC1306000) to Dr. Chao-dong Wang.
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Ren, Zl., Wang, Cd., Wang, T. et al. Ganoderma lucidum extract ameliorates MPTP-induced parkinsonism and protects dopaminergic neurons from oxidative stress via regulating mitochondrial function, autophagy, and apoptosis. Acta Pharmacol Sin 40, 441–450 (2019). https://doi.org/10.1038/s41401-018-0077-8
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DOI: https://doi.org/10.1038/s41401-018-0077-8
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