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

• 作者: Wen-li Dong Jia-hong Zhong Yun-qing Chen Jin-feng Xie Yun-yun Qin Jiang-ping Xu Ning-bo Cai Meng-fan Li Lu Liu Hai-tao Wang
• 来源期刊: 中国药理学报（英文版）
• 年，卷（期）: 2021,（12）
• 所属期刊栏目: Article Neuropharmacology
• 页码范围: 1991-2003
• 页数: 13页
• 语种: 英文

摘要

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-SYSY 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 (SELl,10 μM) attenuated the neuroprotection of ROF,ROF-reduced expression of cα-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.