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.
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Acknowledgements
This study was supported by grants from the National Natural Science Foundation of China (No. 81274124, No. 81200982) and Shandong Province Science and Technology Program (No. 2014GSF118038, No.2016GSF201061).
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Ren, M., Han, M., Wei, X. et al. FTY720 Attenuates 6-OHDA-Associated Dopaminergic Degeneration in Cellular and Mouse Parkinsonian Models. Neurochem Res 42, 686–696 (2017). https://doi.org/10.1007/s11064-016-2125-4
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DOI: https://doi.org/10.1007/s11064-016-2125-4