title: Discovery of a benzofuran derivative (MBPTA) as a novel ROCK inhibitor that protects against MPP⁺-induced oxidative stress and cell death in SH-SY5Y cells.
abstract: Parkinson disease (PD) is a neurodegenerative disease with multifactorial etiopathogenesis. The discovery of drug candidates that act on new targets of PD is required to address the varied pathological aspects and modify the disease process. In this study, a small compound, 2-(5-methyl-1-benzofuran-3-yl)-N-(5-propylsulfanyl-1,3,4-thiadiazol-2-yl) acetamide (MBPTA) was identified as a novel Rho-associated protein kinase inhibitor with significant protective effects against 1-methyl-4-phenylpyridinium ion (MPP(+))-induced damage in SH-SY5Y neuroblastoma cells. Further investigation showed that pretreatment of SH-SY5Y cells with MBPTA significantly suppressed MPP(+)-induced cell death by restoring abnormal changes in nuclear morphology, mitochondrial membrane potential, and numerous apoptotic regulators. MBPTA was able to inhibit MPP(+)-induced reactive oxygen species (ROS)/NO generation, overexpression of inducible NO synthase, and activation of NF-κB, indicating the critical role of MBPTA in regulating ROS/NO-mediated cell death. Furthermore, MBPTA was shown to activate PI3K/Akt survival signaling, and its cytoprotective effect was abolished by PI3K and Akt inhibitors. The structural comparison of a series of MBPTA analogs revealed that the benzofuran moiety probably plays a crucial role in the anti-oxidative stress action. Taken together, these results suggest that MBPTA protects against MPP(+)-induced apoptosis in a neuronal cell line through inhibition of ROS/NO generation and activation of PI3K/Akt signaling.
authors: State Key Laboratory of Quality Research in Chinese Medicine and Institute of Chinese Medical Sciences, University of Macau, Macao, China.
authors: Cheong-Meng
authors: CM
authors: Chong
authors: Institute of Functional Nano & Soft Materials and Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Soochow University, Suzhou, Jiangsu 215123, China.
authors: Mingyun
authors: M
authors: Shen
authors: State Key Laboratory of Quality Research in Chinese Medicine and Institute of Chinese Medical Sciences, University of Macau, Macao, China.
authors: Zhong-Yan
authors: ZY
authors: Zhou
authors: Institute of Functional Nano & Soft Materials and Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Soochow University, Suzhou, Jiangsu 215123, China.
authors: Peichen
authors: P
authors: Pan
authors: State Key Laboratory of Quality Research in Chinese Medicine and Institute of Chinese Medical Sciences, University of Macau, Macao, China.
authors: Pui-Man
authors: PM
authors: Hoi
authors: State Key Laboratory of Quality Research in Chinese Medicine and Institute of Chinese Medical Sciences, University of Macau, Macao, China.
authors: Shang
authors: S
authors: Li
authors: State Key Laboratory of Quality Research in Chinese Medicine and Institute of Chinese Medical Sciences, University of Macau, Macao, China.
authors: Wang
authors: W
authors: Liang
authors: State Key Laboratory of Quality Research in Chinese Medicine and Institute of Chinese Medical Sciences, University of Macau, Macao, China.
authors: Nana
authors: N
authors: Ai
authors: State Key Laboratory of Quality Research in Chinese Medicine and Institute of Chinese Medical Sciences, University of Macau, Macao, China.
authors: Lun-Qing
authors: LQ
authors: Zhang
authors: State Key Laboratory of Quality Research in Chinese Medicine and Institute of Chinese Medical Sciences, University of Macau, Macao, China.
authors: Cheuk-Wing
authors: CW
authors: Li
authors: Rongene Pharma Co., Ltd., International Business Incubator, Guangzhou Science Town, Guangdong 510663, China.
authors: Huidong
authors: H
authors: Yu
authors: Institute of Functional Nano & Soft Materials and Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Soochow University, Suzhou, Jiangsu 215123, China; College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, China. Electronic address: tingjunhou@zju.edu.cn.
authors: Tingjun
authors: T
authors: Hou
authors: State Key Laboratory of Quality Research in Chinese Medicine and Institute of Chinese Medical Sciences, University of Macau, Macao, China. Electronic address: simonlee@umac.mo.
authors: Simon Ming-Yuen
authors: SM
authors: Lee
mesh_terms: D000081:Acetamides / Q000737:chemistry; D017738:Alkanesulfonic Acids / Q000737:chemistry; D000975:Antioxidants / Q000737:chemistry / Q000494:pharmacology*; D001572:Benzofurans / Q000737:chemistry / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D019610:Cytoprotection / Q000187:drug effects; D055808:Drug Discovery; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D058990:Molecular Targeted Therapy; D051058:Oncogene Protein v-akt / Q000378:metabolism; D016877:Oxidants / Q000633:toxicity; D018384:Oxidative Stress / Q000187:drug effects; D010300:Parkinson Disease / Q000188:drug therapy*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011726:Pyridinium Compounds / Q000633:toxicity; D015398:Signal Transduction / Q000187:drug effects; D013830:Thiadiazoles / Q000737:chemistry / Q000494:pharmacology*; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors*
chemical_list: C000598114:2-(5-methyl-1-benzofuran-3-yl)-N-(5-propylsulfanyl-1,3,4-thiadiazol-2-yl)acetamide; D000081:Acetamides; D017738:Alkanesulfonic Acids; D000975:Antioxidants; D001572:Benzofurans; D016877:Oxidants; D011726:Pyridinium Compounds; D013830:Thiadiazoles; C068559:propylsulfonic acid; C030686:acetamide; D019869:Phosphatidylinositol 3-Kinases; D051058:Oncogene Protein v-akt; D054460:rho-Associated Kinases; C105430:benzofuran
keywords: Benzofuran; Free radicals; MPP(+); NO; Parkinson disease; ROCK; ROS