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Discovery of a novel neuroprotectant, BHDPC, that protects against MPP+/MPTP-induced neuronal death in multiple experimental models
Cheong-Meng Chong5; Dan Ma2; Chao Zhao2; Robin J.M. Franklin2; Zhong-Yan Zhou5; Nana Ai5; Chuwen Li5; Huidong Yu1; Tingjun Hou3,4; Tingjun Hou5; Simon Ming-Yuen Lee5
2015-12-01
Source PublicationFree Radical Biology and Medicine
ISSN18734596 08915849
Volume89Pages:1057-1066
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.

KeywordMpp++++ Neurodegeneration Rat Organotypiccerebellarcultures Zebrafish
DOI10.1016/j.freeradbiomed.2015.08.013
URLView the original
Indexed BySCIE
Language英语
WOS Research AreaBiochemistry & Molecular Biology ; Endocrinology & Metabolism
WOS SubjectBiochemistry & Molecular Biology ; Endocrinology & Metabolism
WOS IDWOS:000366355800099
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Cited Times [WOS]:13   [WOS Record]     [Related Records in WOS]
Document TypeJournal article
CollectionInstitute of Chinese Medical Sciences
Corresponding AuthorSimon Ming-Yuen Lee
Affiliation1.Rongene Pharma Co., Ltd. 3 Juquan Rd, International Business Incubator, Guangzhou Science Town, Guangdong, 510663, China
2.Wellcome Trust - Medical Research Council Cambridge Stem Cell Institute and Department of Clinical Neuroscience, University of Cambridge, UK
3.College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, China
4.Institute of Functional Nano & Soft Materials (FUNSOM) and Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Soochow University, Suzhou, Jiangsu 215123, China
5.State Key Laboratory of Quality Research in Chinese Medicine and Institute of Chinese Medical Sciences, University of Macau, Macao, China
First Author AffilicationInstitute of Chinese Medical Sciences
Corresponding Author AffilicationInstitute of Chinese Medical Sciences
Recommended Citation
GB/T 7714
Cheong-Meng Chong,Dan Ma,Chao Zhao,et al. Discovery of a novel neuroprotectant, BHDPC, that protects against MPP+/MPTP-induced neuronal death in multiple experimental models[J]. Free Radical Biology and Medicine,2015,89:1057-1066.
APA Cheong-Meng Chong,Dan Ma,Chao Zhao,Robin J.M. Franklin,Zhong-Yan Zhou,Nana Ai,Chuwen Li,Huidong Yu,Tingjun Hou,Tingjun Hou,&Simon Ming-Yuen Lee.(2015).Discovery of a novel neuroprotectant, BHDPC, that protects against MPP+/MPTP-induced neuronal death in multiple experimental models.Free Radical Biology and Medicine,89,1057-1066.
MLA Cheong-Meng Chong,et al."Discovery of a novel neuroprotectant, BHDPC, that protects against MPP+/MPTP-induced neuronal death in multiple experimental models".Free Radical Biology and Medicine 89(2015):1057-1066.
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