title: A Potent Multi-functional Neuroprotective Derivative of Tetramethylpyrazine.
abstract: Neurodegenerative disorders are one of the leading causes of death among the elderly. Therapeutic approaches with a single target have proven unsuccessful in treating these diseases. Structural combination of multi-functional compounds may lead to a molecule with multiple properties. In this study, we designed and synthesized T-006, a novel analog derived from two multi-functional neuroprotective chemicals, tetramethylpyrazine and J147. The methoxyphenyl group of J147 was replaced by tetramethylpyrazine. Bioactivity evaluation showed that T-006 at very low concentrations had multi-functional neuroprotective effects including rescuing iodoacetic acid-induced neuronal loss, preventing oxidative stress-induced neurotoxicity and reducing glutamate-induced excitotoxicity in vitro. Most importantly, T-006 significantly ameliorated memory impairments in APP/PS1 transgenic mice. These multiple functions of a single molecule suggest that T-006 is a promising novel neuroprotective agent for treating various neurodegenerative disorders, including and in particular Alzheimer's disease.
authors.affiliation: Institute of New Drug Research and Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine, Jinan University College of Pharmacy, Huangpu Road, Guangzhou, 510632, China.
authors.forename: Hai-Yun
authors.initials: HY
authors.lastname: Chen
authors.affiliation: Department of Applied Biology and Chemical Technology, Institute of Modern Chinese Medicine, Hong Kong Polytechnic University, Hong Kong, China.
authors.forename: Da-Ping
authors.initials: DP
authors.lastname: Xu
authors.affiliation: Institute of New Drug Research and Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine, Jinan University College of Pharmacy, Huangpu Road, Guangzhou, 510632, China.
authors.forename: Guo-Lian
authors.initials: GL
authors.lastname: Tan
authors.affiliation: Institute of New Drug Research and Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine, Jinan University College of Pharmacy, Huangpu Road, Guangzhou, 510632, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Cai
authors.affiliation: Institute of New Drug Research and Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine, Jinan University College of Pharmacy, Huangpu Road, Guangzhou, 510632, China.
authors.forename: Gao-Xiao
authors.initials: GX
authors.lastname: Zhang
authors.affiliation: Department of Applied Biology and Chemical Technology, Institute of Modern Chinese Medicine, Hong Kong Polytechnic University, Hong Kong, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Cui
authors.affiliation: School of Life Sciences, South China Normal University, Guangzhou, 510631, China.
authors.forename: Jin-Zhao
authors.initials: JZ
authors.lastname: Wang
authors.affiliation: School of Life Sciences, South China Normal University, Guangzhou, 510631, China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Long
authors.affiliation: Institute of New Drug Research and Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine, Jinan University College of Pharmacy, Huangpu Road, Guangzhou, 510632, China.
authors.forename: Ye-Wei
authors.initials: YW
authors.lastname: Sun
authors.affiliation: Institute of New Drug Research and Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine, Jinan University College of Pharmacy, Huangpu Road, Guangzhou, 510632, China.
authors.forename: Pei
authors.initials: P
authors.lastname: Yu
authors.affiliation: Division of Life Science, Center for Chinese Medicine and State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science and Technology, Hong Kong, China.
authors.forename: Karl Wahkeung
authors.initials: KW
authors.lastname: Tsim
authors.affiliation: Institute of New Drug Research and Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine, Jinan University College of Pharmacy, Huangpu Road, Guangzhou, 510632, China. zaijunzhang@163.com.|Department of Applied Biology and Chemical Technology, Institute of Modern Chinese Medicine, Hong Kong Polytechnic University, Hong Kong, China. zaijunzhang@163.com.
authors.forename: Zai-Jun
authors.initials: ZJ
authors.lastname: Zhang
authors.affiliation: Department of Applied Biology and Chemical Technology, Institute of Modern Chinese Medicine, Hong Kong Polytechnic University, Hong Kong, China. bcyfhan@polyu.edu.hk.|State Key Laboratory of Chinese Medicine and Molecular Pharmacology (Incubation), The Hong Kong Polytechnic University, Hung Hom, Hong Kong, China. bcyfhan@polyu.edu.hk.
authors.forename: Yi-Fan
authors.initials: YF
authors.lastname: Han
authors.affiliation: Institute of New Drug Research and Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine, Jinan University College of Pharmacy, Huangpu Road, Guangzhou, 510632, China.
authors.forename: Yu-Qiang
authors.initials: YQ
authors.lastname: Wang
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy*; D000818:Animals; D000975:Antioxidants / Q000138:chemical synthesis / Q000494:pharmacology* / Q000627:therapeutic use; D002478:Cells, Cultured; D006835:Hydrazones / Q000138:chemical synthesis / Q000494:pharmacology*; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000138:chemical synthesis / Q000494:pharmacology* / Q000627:therapeutic use; D016716:PC12 Cells; D011719:Pyrazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000975:Antioxidants; D006835:Hydrazones; D018696:Neuroprotective Agents; D011719:Pyrazines; C000608515:T-006 compound; C017953:tetramethylpyrazine