title: Neuroprotective effects of SCM198 on 6-hydroxydopamine-induced behavioral deficit in rats and cytotoxicity in neuronal SH-SY5Y cells.
abstract: 6-Hydroxydopamine (6-OHDA), one of the most investigated Parkinson's disease neurotoxins, is widely used to study mechanisms of cell death in dopaminergic neurons. In the present study, we demonstrated that SCM198, a new compound based on the active component of Herba leonuri, significantly reduced 6-OHDA-induced cell death in dopaminergic SH-SY5Y cells and attenuated apomorphine-elicited rotational behavior in 6-OHDA-lesioned rats. Pretreatment with SCM198 (0.001, 0.01, 0.1, 1, and 10 μM) concentration-dependently increased the cell viability as measured in MTT and LDH leakage assays compared with 6-OHDA-injured cells. Tocopherol, an antioxidant used as positive control, had similar effect at 10 μM to SCM198 1 μM. Furthermore, we assessed oxidative stress and subsequent apoptosis, the critical players in dopaminergic neurodegeneration, with 0.1, 1, and 10 μM of SCM198 in SH-SY5Y cells exposed to 6-OHDA. Pretreatment with SCM198 significantly increased antioxidant enzyme superoxide dismutase activity, ameliorated intracellular reactive oxygen species generation, prevented the dissipation of mitochondrial membrane potential, decreased apoptotic cell death in Hoechst 33258 staining, as well as down-regulated Bax and up-regulated Bcl-2 in both mRNA and protein levels compared with 6-OHDA damaged cells. Moreover, intragastrical administration of SCM198 (18 or 60 mg kg⁻¹ day⁻¹) for 4 weeks significantly ameliorates apomorphine-induced contralateral rotations in 6-OHDA-lesioned rats. These results support the neuroprotective effects of SCM198 against 6-OHDA-induced toxicity in vivo and in vitro with the underlying mechanisms of inhibiting oxidative stress and apoptosis. Therefore we suggest that SCM198 might provide a useful therapeutic strategy for neurodegenerative diseases such as Parkinson's disease.
authors.affiliation: Department of Pharmacology, School of Pharmacy and Institute of Biomedical Sciences, Fudan University, No. 826 Zhangheng Road, Shanghai 200032, PR China.
authors.forename: Xue Ru
authors.initials: XR
authors.lastname: Shi
authors.forename: Zhen Yi
authors.initials: ZY
authors.lastname: Hong
authors.forename: Hong Rui
authors.initials: HR
authors.lastname: Liu
authors.forename: Yu Chen
authors.initials: YC
authors.lastname: Zhang
authors.forename: Yi Zhun
authors.initials: YZ
authors.lastname: Zhu
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D005707:Gallic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D031332:Leonurus / Q000737:chemistry; D008297:Male; D009410:Nerve Degeneration / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D016627:Oxidopamine / Q000037:antagonists & inhibitors / Q000633:toxicity*; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D018696:Neuroprotective Agents; D017382:Reactive Oxygen Species; C013587:leonurine; D005707:Gallic Acid; D016627:Oxidopamine; C001945:syringic acid