title: FTY720 Attenuates 6-OHDA-Associated Dopaminergic Degeneration in Cellular and Mouse Parkinsonian Models.
abstract: FTY720 (fingolimod) is the first oral drug approved for treating relapsing-remitting forms of multiple sclerosis. It is also protective in other neurological models including ischemia, Alzheimer's disease, Huntington disease and Rett syndrome. However, whether it might protect in a 6-hydroxydopamine (6-OHDA) mouse model associated with the dopaminergic pathology of Parkinson's disease (PD), has not been explored. Therefore, in the present study, we investigated the effects of FTY720 on 6-OHDA-induced neurotoxicity in cell cultures and mice. Here we show that FTY720 protected against 6-OHDA cytotoxicity and apoptosis in SH-SY5Y cells. We also show that prior administration of FTY720 to 6-OHDA lesioned mice ameliorated both motor deficits and nigral dopaminergic neurotoxicity, while also reducing 6-OHDA-associated inflammation. The protective effects of FTY720 were associated with activation of AKT and ERK1/2 pro-survival pathways and an increase in brain derived neurotrophic factor (BDNF) expression in vitro and in vivo. These findings suggest that FTY720 holds promise as a PD therapeutic acting, at least in part, through AKT/ERK1/2/P-CREB-associated BDNF expression.
authors.affiliation: Department of Pharmacology, School of Medicine, Shandong University, No. 44 Wenhua Xi Road, Jinan, 250012, Shandong, China.
authors.forename: Manru
authors.initials: M
authors.lastname: Ren
authors.affiliation: Department of Pharmacology, School of Medicine, Shandong University, No. 44 Wenhua Xi Road, Jinan, 250012, Shandong, China.
authors.forename: Minxing
authors.initials: M
authors.lastname: Han
authors.affiliation: Department of Pharmacology, School of Medicine, Shandong University, No. 44 Wenhua Xi Road, Jinan, 250012, Shandong, China.
authors.forename: Xinbing
authors.initials: X
authors.lastname: Wei
authors.affiliation: Department of Pharmacology, School of Medicine, Shandong University, No. 44 Wenhua Xi Road, Jinan, 250012, Shandong, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Guo
authors.affiliation: Department of Pharmacology, School of Medicine, Shandong University, No. 44 Wenhua Xi Road, Jinan, 250012, Shandong, China.
authors.forename: Huanying
authors.initials: H
authors.lastname: Shi
authors.affiliation: Department of Pharmacology, School of Medicine, Shandong University, No. 44 Wenhua Xi Road, Jinan, 250012, Shandong, China.
authors.forename: Xiumei
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Paul L. Foster School of Medicine, Graduate School of Biomedical Sciences, Texas Tech University Health Science Center El Paso, El Paso, TX, 79905, USA. ruth.g.perez@ttuhsc.edu.
authors.forename: Ruth G
authors.initials: RG
authors.lastname: Perez
authors.affiliation: Department of Pharmacology, School of Medicine, Shandong University, No. 44 Wenhua Xi Road, Jinan, 250012, Shandong, China. louhaiyan@sdu.edu.cn.
authors.forename: Haiyan
authors.initials: H
authors.lastname: Lou
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D000068876:Fingolimod Hydrochloride / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009410:Nerve Degeneration / Q000378:metabolism* / Q000517:prevention & control*; D016627:Oxidopamine / Q000633:toxicity; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000378:metabolism* / Q000517:prevention & control*
chemical_list: D016627:Oxidopamine; D000068876:Fingolimod Hydrochloride
keywords: 6-OHDA; Apoptosis; BDNF; FTY720; Parkinson’s disease