title: Protection against MPP(+)-induced neurotoxicity in SH-SY5Y cells by tormentic acid via the activation of PI3-K/Akt/GSK3β pathway.
abstract: The cause of Parkinson's disease (PD) could be ascribed to the progressive and selective loss of dopaminergic neurons in the substantia nigra pars compacta, and thus molecules with neuroprotective ability may have therapeutic value against PD. In the current study, the neuroprotective effects and underlying mechanisms of tormentic acid (TA), a naturally occurring triterpene extracted from medicinal plants such as Rosa rugosa and Potentilla chinensis, were evaluated in a widely used cellular PD model in which neurotoxicity was induced by MPP(+) in cultured SH-SY5Y cells. We found that TA at 1-30 μM substantially protected against MPP(+)-induced neurotoxicity, as evidenced by the increase in cell viability, decrease in lactate dehydrogenase release and the reduction in apoptotic nuclei. Moreover, TA effectively inhibited the elevated intracellular accumulation of reactive oxygen species as well as Bax/Bcl-2 ratio caused by MPP(+). Most importantly, TA markedly reversed the inhibition of protein expression of phosphorylated Akt (Ser 473) and phosphorylated GSK3β (Ser 9) caused by MPP(+). LY294002, the specific inhibitor of PI3-K, significantly abrogated the up-regulated phosphorylated Akt and phosphorylated GSK3β offered by TA, suggesting that the neuroprotection of TA was mainly dependent on the activation of PI3-K/Akt/GSK3β signaling pathway. The results taken together indicate that TA may be a potential candidate for further preclinical study aimed at the prevention and treatment of PD.
authors.affiliation: Department of Neurology, Linzi Maternal & Child Health Hospital of Zibo, Zibo, Shandong, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Zhao
authors.affiliation: Department of Pathophysiology, Medical College, Qingdao University, Qingdao, Shandong, China.
authors.forename: Junli
authors.initials: J
authors.lastname: Ye
authors.affiliation: Department of Neurology, Linzi Maternal & Child Health Hospital of Zibo, Zibo, Shandong, China.
authors.forename: Na
authors.initials: N
authors.lastname: Wei
authors.affiliation: Department of Biomedical Sciences, City University of Hong Kong, Hong Kong, China.
authors.forename: Chichun
authors.initials: C
authors.lastname: Fong
authors.affiliation: Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong, China; Shenzhen Research Institute of the Hong Kong Polytechnic University, State Key Laboratory of Chinese Medicine and Molecular Pharmacology (Incubation), Shenzhen, Guangdong, China. Electronic address: xiaoli.dong@polyu.edu.hk.
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Dong
mesh_terms: D015655:1-Methyl-4-phenylpyridinium / Q000633:toxicity*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D000071679:Glycogen Synthase Kinase 3 beta / Q000378:metabolism*; D006540:Herbicides / Q000633:toxicity; D006801:Humans; D018696:Neuroprotective Agents / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D014315:Triterpenes / Q000494:pharmacology*
chemical_list: D006540:Herbicides; D018696:Neuroprotective Agents; D014315:Triterpenes; C007695:euscaphic acid; D019869:Phosphatidylinositol 3-Kinases; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt; D015655:1-Methyl-4-phenylpyridinium
keywords: MPP(+); Neuroprotection; PI3-K/Akt/GSK3; Parkinson's disease; SH-SY5Y cells; Tormentic acid