@article{APS10435,
author = {Wen-li Dong and Jia-hong Zhong and Yun-qing Chen and Jin-feng Xie and Yun-yun Qin and Jiang-ping Xu and Ning-bo Cai and Meng-fan Li and Lu Liu and Hai-tao Wang},
title = {Roflupram protects against rotenone-induced neurotoxicity and facilitates α-synuclein degradation in Parkinson’s disease models},
journal = {Acta Pharmacologica Sinica},
volume = {42},
number = {12},
year = {2021},
keywords = {},
abstract = {We have previously shown that roflupram (ROF) protects against MPP+-induced neuronal damage in models of Parkinson’s disease (PD). Since impaired degradation of α-synuclein (α-syn) is one of the key factors that lead to PD, here we investigated whether and how ROF affects the degradation of α-syn in rotenone (ROT)-induced PD models in vivo and in vitro. We showed that pretreatment with ROF (10 μM) significantly attenuated cell apoptosis and reduced the level of α-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 μM) attenuated the neuroprotection of ROF, ROF-reduced expression of α-syn, and ROF-increased expression levels of LAMP1 and mature CTSD. Moreover, inhibition of CTSD by pepstatin A (20 μM) attenuated ROF-reduced expression of α-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 α-syn in the substantia nigra pars compacta. Taken together, these results demonstrate that ROF exerts a neuroprotective action and reduces the α-syn level in PD models. The mechanisms underlying ROF neuroprotective effects appear to be associated with NAD+/SIRT1-dependent activation of lysosomal function.},
issn = {1745-7254}, url = {http://www.chinaphar.com/article/view/10435}
}