SRT1720 as an SIRT1 activator for alleviating paraquat-induced models of Parkinson's disease
Chih-Chang Chao,
Chuen-Lin Huang,
Jing-Jy Cheng,
Chun-Tang Chiou,
I-Jung Lee,
Ying-Chen Yang,
Ting-Huang Hsu,
Chia-En Yei,
Pei-Ying Lin,
Jih-Jung Chen,
Nai-Kuei Huang
Affiliations
Chih-Chang Chao
Institute of Neuroscience, National Chengchi University, Taipei, Taiwan
Chuen-Lin Huang
Medical Research Center, Cardinal Tien Hospital, Hsintien, New Taipei City, Taiwan; Graduate Institute of Physiology & Department of Physiology and Biophysics, National Defense Medical Center, Taipei, 114, Taiwan
Jing-Jy Cheng
National Research Institute of Chinese Medicine, Ministry of Health and Welfare, Taipei, 112, Taiwan; Institute of Biophotonics, National Yang-Ming University, Taipei, 112, Taiwan
Chun-Tang Chiou
National Research Institute of Chinese Medicine, Ministry of Health and Welfare, Taipei, 112, Taiwan
I-Jung Lee
Herbal Medicine Department, Yokohama University of Pharmacy, Yokohama, Japan
Ying-Chen Yang
Department of Biotechnology and Animal Science, National Ilan University, Ilan, Taiwan
Ting-Huang Hsu
Institute of Neuroscience, National Chengchi University, Taipei, Taiwan
Chia-En Yei
National Research Institute of Chinese Medicine, Ministry of Health and Welfare, Taipei, 112, Taiwan
Pei-Ying Lin
National Research Institute of Chinese Medicine, Ministry of Health and Welfare, Taipei, 112, Taiwan
Jih-Jung Chen
Department of Medical Research, China Medical University Hospital, China Medical University, Taichung 404332, Taiwan; Department of Pharmacy, School of Pharmaceutical Sciences, National Yang-Ming Chiao Tung University, Taipei 112304, Taiwan; Corresponding author. National Research Institute of Chinese Medicine, Ministry of Health and Welfare, No.155, Li-Nung St., Sec. 2, Shipai, Peitou, Taipei, 112, Taiwan.
Nai-Kuei Huang
National Research Institute of Chinese Medicine, Ministry of Health and Welfare, Taipei, 112, Taiwan; Ph.D. Program for Neural Regenerative Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei, 11031, Taiwan; Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, 11031, Taiwan; Corresponding author. School of Pharmaceutical Sciences, National Yang-Ming Chiao Tung University, No. 155-1 Li-Nung St., Sec. 2, Shipai, Peitou, Taipei, 112, Taiwan.
Epidemiological studies have linked herbicides and Parkinson's disease (PD), with the strongest associations resulting from long exposure durations. Paraquat (PQ), an herbicide, induces PD-like syndromes and has widely been accepted as a PD mimetic. Currently, there is still no cure to prevent the progression of PD, and the search for effective therapeutic ways is urgent. Recently, the impairing activity of sirtuins (SIRTs), such as SIRT1, may correlate with PD etiology. However, the nonspecificity of SIRT1 agonists has made the protective mechanisms against PD unclear and hampered the therapeutic application of SIRT1. Thus, this study investigated the protective mechanism and therapeutic potential of SRT1720, a more specific agonist for SIRT1 synthesized by Sirtris, in alleviating the toxicity of PQ-induced cellular and animal models of PD. Here we show that SRT1720 alleviates PQ-induced toxicity in cell and animal models. Genetic silencing and pharmacological inhibition of SIRT1 attenuated SRT1720's protection against PQ-induced toxicity. Moreover, SRT1720 not only attenuated PQ-induced increased oxidative stress and mitochondrial free radical formations but also decreased mitochondrial membrane potential. Furthermore, SRT1720 reversed PQ-induced decreased PGC-1α levels and mitochondrial biogenesis. Although PQ and SRT1720 elevated NRF2 and antioxidative enzyme levels, only PQ decreased antioxidative enzyme activity but not SRT1720. NRF2 and PGC-1α silencing attenuated SRT1720 protection against PQ-induced toxicity. SRT1720 targeted SIRT1 and activated downstream PGC-1α and NRF2 signalings to prevent PQ-induced toxicity involving oxidative stress and mitochondrial dysfunction. Thus, SRT1720 might have therapeutic potential in preventing PD.
