Neuroprotective effects of fingolimod in mouse models of Parkinson's disease.
Parkinson's disease (PD) is characterized by a progressive loss of dopaminergic neurons with limited treatment options. Emerging evidence shows that FTY720 protects against neural injury via modulation of the sphingosine-1-phosphate 1 receptor (S1PR1). However, it remains unclear whether FTY720 could influence neurodegeneration in PD. Therefore, the present study was designed to determine the impact of fingolimod (FTY720), a sphingosine-1-phosphate receptor (S1PR) agonist, on 2 mouse models of PD. We found that FTY720 significantly reduced the deficit of motor function, diminished the loss of tyrosine hydroxylase-positive neurons in the substantia nigra, and attenuated the decrease of striatal dopamine and metabolite levels in mice receiving 6-hydroxydopamine (6-OHDA) or rotenone to simulate PD. An S1PR1-selective antagonist, W146, blocked the neuroprotective effects of FTY720. Of note, FTY720 retained the phosphorylation of ERK, together with a decreased expression of cleaved caspase-3 in mice treated with 6-OHDA or rotenone. In vitro studies revealed that FTY720 also attenuated 6-OHDA- or rotenone-induced toxicity in SH-SY5Y cells. These findings suggest the potential of S1PR modulation as a treatment for PD.-Zhao, P., Yang, X., Yang, L., Li, M., Wood, K., Liu, Q., Zhu, X. Neuroprotective effects of fingolimod in mouse models of Parkinson's disease.
Department of Neurology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, China; and.
Peng
P
Zhao
Department of Neurology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, China; and.
Xiaoxia
X
Yang
Department of Neurology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, China; and.
Liu
L
Yang
Department of Neurology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, China; and.|Division of Neurology, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, Arizona, USA.
Minshu
M
Li
Division of Neurology, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, Arizona, USA.
Kristofer
K
Wood
Department of Neurology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, China; and qliu@tmu.edu.cn.|Division of Neurology, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, Arizona, USA.
Qiang
Q
Liu
Department of Neurology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, China; and zxd3516@163.com.|Division of Neurology, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, Arizona, USA.
Xiaodong
X
Zhu
D000818:Animals; D045744:Cell Line, Tumor; D000068876:Fingolimod Hydrochloride / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D008297:Male; D051379:Mice; D009447:Neuroblastoma / Q000188:drug therapy; D018696:Neuroprotective Agents / Q000494:pharmacology*; D016627:Oxidopamine / Q000494:pharmacology; D010300:Parkinson Disease / Q000188:drug therapy*; D049349:Receptors, Lysosphingolipid / Q000235:genetics / Q000378:metabolism; D012402:Rotenone / Q000633:toxicity; D000081025:Sphingosine-1-Phosphate Receptors
D018696:Neuroprotective Agents; D049349:Receptors, Lysosphingolipid; C477362:S1PR1 protein, human; D000081025:Sphingosine-1-Phosphate Receptors; D012402:Rotenone; D016627:Oxidopamine; D000068876:Fingolimod Hydrochloride
S1PR; neuroprotection; neurotoxicity