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.