Therapeutic effect of ACS84 on Parkinson's disease in 6-OHDA-induced rat model

Parkinson's disease (PD), characterized by loss of dopaminergic neurons in the substantia nigra, is a neurodegenerative disorder of the central nervous system. The present study was designed to investigate the effect of ACS84, an H2S-releasing compound, on 6-hydroxydopamine (6-OHDA)-induced PD model. Cell viability in SH-SY5Y cells was measured using MTT and LDH assays. Reactive oxygen species (ROS) measurement was carried out using DCF-Fluorescent method. Glutathione, malondialdehyde levels and monoamine oxidase B activity were measured with commercial kits. Rotation behaviour was tested to evaluate the movement disorder in 6-OHDA-induced PD rat model. Dopamine concentration was determined by HPLC method. Pre-treatment of SH-SY5Y cells with ACS84 (10 μM) for 1 h significantly protected the cells against 6-OHDA (50 μM) -induced cell injury. ACS84 conferred better protection as compared to NaHS and L-Dopa at the same concentration range. Furthermore, pre-treatment with ACS84 for 1 h decreased 6-OHDA-induced reactive oxygen species release. We also found that ACS84 reduced oxidative stress via induction of glutathione (GSH) synthesis in SH-SY5Y cells. Moreover, treatment with ACS84 (10 μM) for 1-8 h significantly reduced the activity of monoamine oxidase B (MAO B) in the primary cultured striatum astroglial cells. In 6-OHDA-induced PD model, administration of ACS84 (i.g. 10 mg/kg) significantly relieved the movement dysfunction. Immunohistochemistry and biochemistry analysis showed that ACS84 reversed the loss of tyrosine-hydroxylase positive neurons in the SN, the elevation of malondialdehyde (MDA) level and the decline of dopamine concentration in injured striatums of the 6-OHDA-induced PD model. In addition, ASC84 was also found to upregulate the GSH level and to reduce MAO B activity in vivo. ACS84 may prevent neurodegeneration via an anti-oxidative mechanism and has potential therapeutic values for Parkinson's disease.