title: Amentoflavone protects dopaminergic neurons in MPTP-induced Parkinson's disease model mice through PI3K/Akt and ERK signaling pathways.
abstract: Parkinson's disease (PD) is characterized by the progressive degeneration of dopaminergic neurons in substantia nigra pars compacta (SNpc). Mitochondrial dysfunction and cell apoptosis are suggested to be actively involved in the pathogenesis of PD. In the present study, the neuroprotective effect of amentoflavone (AF), a naturally occurring biflavonoid from Selaginella tamariscina, was examined in PD models both in vitro and in vivo. On SH-SY5Y cells, AF treatment dose-dependently reduced 1-methyl-4-phenylpyridinium (MPP+)-induced nuclear condensation and loss of cell viability without obvious cytotoxicity. It inhibited the activation of caspase-3 and p21 but increased the Bcl-2/Bax ratio. Further study disclosed that AF enhanced the phosphorylation of PI3K, Akt and ERK1/2 down-regulated by MPP+in SH-SY5Y cells, the effect of which could be blocked by LY294002, the inhibitor of PI3K. Consistently, AF alleviated the behavioral deterioration in pole and traction tests and rescued the loss of dopaminergic neurons in SNpc and fibers in striatum in methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induced mice. It also could enhance the activation of PI3K and Akt as well as Bcl-2/Bax ratio in SN. Moreover, AF alleviated gliosis as well as the gene expression levels of IL-1β and iNOS in SN. Collectively, these results suggested that AF protected dopaminergic neurons against MPTP/MPP+-induced neurotoxicity, which might be mediated through activation of PI3K/Akt and ERK signaling pathways in dopaminergic neurons and attenuation of neuroinflammation.
authors.affiliation: The Ministry of Education (MOE) Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Complex Prescriptions, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai, China.
authors.forename: Qin
authors.initials: Q
authors.lastname: Cao
authors.affiliation: The Ministry of Education (MOE) Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Complex Prescriptions, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai, China.
authors.forename: Liyue
authors.initials: L
authors.lastname: Qin
authors.affiliation: The Ministry of Education (MOE) Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Complex Prescriptions, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai, China. Electronic address: Fei_H@hotmail.com.
authors.forename: Fei
authors.initials: F
authors.lastname: Huang
authors.affiliation: The Ministry of Education (MOE) Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Complex Prescriptions, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai, China.
authors.forename: Xiaoshuang
authors.initials: X
authors.lastname: Wang
authors.affiliation: The Ministry of Education (MOE) Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Complex Prescriptions, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai, China.
authors.forename: Liu
authors.initials: L
authors.lastname: Yang
authors.affiliation: The Ministry of Education (MOE) Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Complex Prescriptions, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai, China.
authors.forename: Hailian
authors.initials: H
authors.lastname: Shi
authors.affiliation: The Ministry of Education (MOE) Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Complex Prescriptions, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Wu
authors.affiliation: The Ministry of Education (MOE) Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Complex Prescriptions, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai, China.
authors.forename: Beibei
authors.initials: B
authors.lastname: Zhang
authors.affiliation: The Ministry of Education (MOE) Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Complex Prescriptions, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai, China.
authors.forename: Ziyu
authors.initials: Z
authors.lastname: Chen
authors.affiliation: The Ministry of Education (MOE) Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Complex Prescriptions, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai, China. Electronic address: xiaojunwu320@126.com.
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Wu
mesh_terms: D000818:Animals; D044946:Biflavonoids / Q000494:pharmacology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D020267:MPTP Poisoning / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use; D051058:Oncogene Protein v-akt / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D011897:Random Allocation
chemical_list: D044946:Biflavonoids; D018696:Neuroprotective Agents; C011164:amentoflavone; D019869:Phosphatidylinositol 3-Kinases; D051058:Oncogene Protein v-akt
keywords: 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP); Amentoflavone; Flavonoids; Neuroinflammation; Parkinson's disease