title: Discovery of a novel neuroprotectant, BHDPC, that protects against MPP+/MPTP-induced neuronal death in multiple experimental models.
abstract: Progressive degeneration and death of neurons are main causes of neurodegenerative disorders such as Parkinson's disease and Alzheimer's disease. Although some current medicines may temporarily improve their symptoms, no treatments can slow or halt the progression of neuronal death. In this study, a pyrimidine derivative, benzyl 7-(4-hydroxy-3-methoxyphenyl)-5-methyl-4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-carboxylate (BHDPC), was found to attenuate dramatically the MPTP-induced death of dopaminergic neurons and improve behavior movement deficiency in zebrafish, supporting its potential neuroprotective activity in vivo. Further study in rat organotypic cerebellar cultures indicated that BHDPC was able to suppress MPP(+)-induced cell death of brain tissue slices ex vivo. The protective effect of BHDPC against MPP(+) toxicity was also effective in human neuroblastoma SH-SY5Y cells through restoring abnormal changes in mitochondrial membrane potential and numerous apoptotic regulators. Western blotting analysis indicated that BHDPC was able to activate PKA/CREB survival signaling and further up-regulate Bcl2 expression. However, BHDPC failed to suppress MPP(+)-induced cytotoxicity and the increase of caspase 3 activity in the presence of the PKA inhibitor H89. Taken together, these results suggest that BHDPC is a potential neuroprotectant with prosurvival effects in multiple models of neurodegenerative disease in vitro, ex vivo, and in vivo.
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine and Institute of Chinese Medical Sciences, University of Macau, Macao, China.
authors.forename: Cheong-Meng
authors.initials: CM
authors.lastname: Chong
authors.affiliation: Wellcome Trust - Medical Research Council Cambridge Stem Cell Institute and Department of Clinical Neuroscience, University of Cambridge, UK.
authors.forename: Dan
authors.initials: D
authors.lastname: Ma
authors.affiliation: Wellcome Trust - Medical Research Council Cambridge Stem Cell Institute and Department of Clinical Neuroscience, University of Cambridge, UK.
authors.forename: Chao
authors.initials: C
authors.lastname: Zhao
authors.affiliation: Wellcome Trust - Medical Research Council Cambridge Stem Cell Institute and Department of Clinical Neuroscience, University of Cambridge, UK.
authors.forename: Robin J M
authors.initials: RJ
authors.lastname: Franklin
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine and Institute of Chinese Medical Sciences, University of Macau, Macao, China.
authors.forename: Zhong-Yan
authors.initials: ZY
authors.lastname: Zhou
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine and Institute of Chinese Medical Sciences, University of Macau, Macao, China.
authors.forename: Nana
authors.initials: N
authors.lastname: Ai
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine and Institute of Chinese Medical Sciences, University of Macau, Macao, China.
authors.forename: Chuwen
authors.initials: C
authors.lastname: Li
authors.affiliation: Rongene Pharma Co., Ltd. 3 Juquan Rd, International Business Incubator, Guangzhou Science Town, Guangdong, 510663, China.
authors.forename: Huidong
authors.initials: H
authors.lastname: Yu
authors.affiliation: College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, China; Institute of Functional Nano & Soft Materials (FUNSOM) and Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Soochow University, Suzhou, Jiangsu 215123, China.
authors.forename: Tingjun
authors.initials: T
authors.lastname: Hou
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine and Institute of Chinese Medical Sciences, University of Macau, Macao, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Sa
authors.affiliation: 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.forename: Simon Ming-Yuen
authors.initials: SM
authors.lastname: Lee
mesh_terms: D015655:1-Methyl-4-phenylpyridinium / Q000633:toxicity; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002478:Cells, Cultured; D002531:Cerebellum / Q000187:drug effects / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006540:Herbicides / Q000633:toxicity; D006801:Humans; D008124:Locomotion / Q000187:drug effects; D020267:MPTP Poisoning / Q000517:prevention & control*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D008962:Models, Theoretical; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009498:Neurotoxins / Q000633:toxicity*; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D012249:Rhombencephalon / Q000187:drug effects / Q000378:metabolism; D013777:Tetrazoles / Q000494:pharmacology*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D015027:Zebrafish / Q000254:growth & development / Q000378:metabolism
chemical_list: C000611568:BHDPC compound; D006540:Herbicides; D018696:Neuroprotective Agents; D009498:Neurotoxins; D011743:Pyrimidines; D017382:Reactive Oxygen Species; D013777:Tetrazoles; D014446:Tyrosine 3-Monooxygenase; D015655:1-Methyl-4-phenylpyridinium
keywords: MPP(+); Neurodegeneration; Rat organotypic cerebellar cultures; Zebrafish