Roflupram protects against rotenone-induced neurotoxicity and facilitates α-synuclein degradation in Parkinson's disease models

作者：Dong, Wen-li; Zhong, Jia-hong; Chen, Yun-qing; Xie, Jin-feng; Qin, Yun-yun; Xu, Jiang-ping^*; Cai, Ning-bo; Li, Meng-fan; Liu, Lu; Wang, Hai-tao^*

来源：Acta Pharmacologica Sinica, 2021, 42(12): 1991-2003.

DOI：10.1038/s41401-021-00768-4

• Parkinson's disease
• alpha-synuclein
• SIRT1
• rotenone
• roflupram
• lysosome
• Sirtuin 1
• pepstatin A

We have previously shown that roflupram (ROF) protects against MPP+-induced neuronal damage in models of Parkinson's disease (PD). Since impaired degradation of alpha-synuclein (alpha-syn) is one of the key factors that lead to PD, here we investigated whether and how ROF affects the degradation of alpha-syn in rotenone (ROT)-induced PD models in vivo and in vitro. We showed that pretreatment with ROF (10 mu M) significantly attenuated cell apoptosis and reduced the level of alpha-syn in ROT-treated SH-SY5Y cells. Furthermore, ROF significantly enhanced the lysosomal function, as evidenced by the increased levels of mature cathepsin D (CTSD) and lysosomal-associated membrane protein 1 (LAMP1) through increasing NAD(+)/NADH and the expression of sirtuin 1 (SIRT1). Pretreatment with an SIRT1 inhibitor selisistat (SELI, 10 mu M) attenuated the neuroprotection of ROF, ROF-reduced expression of alpha-syn, and ROF-increased expression levels of LAMP1 and mature CTSD. Moreover, inhibition of CTSD by pepstatin A (20 mu M) attenuated ROF-reduced expression of alpha-syn. In vivo study was conducted in mice exposed to ROT (10 mg.kg(-1).d(-1), i.g.) for 6 weeks; then, ROT-treated mice received ROF (0.5, 1, or 2 mg.kg(-1).d(-1); i.g.) for four weeks. ROF significantly ameliorated motor deficits, which was accompanied by increased expression levels of tyrosine hydroxylase, SIRT1, mature CTSD, and LAMP1, and a reduced level of alpha-syn in the substantia nigra pars compacta. Taken together, these results demonstrate that ROF exerts a neuroprotective action and reduces the alpha-syn level in PD models. The mechanisms underlying ROF neuroprotective effects appear to be associated with NAD(+)/SIRT1-dependent activation of lysosomal function.

• 单位
  南方医科大学