Neuroprotective effects of ebselen are associated with the regulation of Bcl-2 and Bax proteins in cultured mouse cortical neurons.
There is little information available on the mechanisms underlying the neuroprotective actions of the organoselenium compound ebselen. In this study, we sought to determine the relationship between alterations in the expression of Bcl-2 and Bax proteins and intracellular levels of calcium and the protective effects of ebselen with a concentration range of 0.01-20 microM against glutamate toxicity in cultured mouse cortical neurons. Pretreatment with ebselen at moderate doses (4-12 microM), but not at lower or higher doses, significantly improved glutamate-induced suppression of cell viability. Pretreatment with ebselen (8 microM) also prevented apoptotic alterations, completely reversed the suppression of Bcl-2 expression, and significantly inhibited Bax overexpression, but did not alter elevated intracellular concentrations of calcium induced by glutamate. Pre-, co-, and post-treatment with ebselen (8 microM) had similar potency in improving the decreased viability of glutamate-exposed cells. These results indicate that the neuroprotective effects of ebselen at low doses are associated with the regulation of Bcl-2 and Bax proteins but appear to be independent of glutamate-mediated elevation of intracellular calcium, suggesting that different mechanisms are involved in the actions of low and high dose regimens. Ebselen may be an effective agent used for early treatment of acute brain injuries.
Xu
Jie-Hua
JH
Department of Human Anatomy and Histoembryology, College of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China.
Hu
Hai-Tao
HT
Liu
Yong
Y
Qian
Yi-Hua
YH
Liu
Zhao-Hui
ZH
Tan
Qing-Rong
QR
Zhang
Zhang-Jin
ZJ
D000704:Analysis of Variance; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001393:Azoles / Q000494:pharmacology*; D002452:Cell Count / Q000379:methods; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004622:Embryo, Mammalian; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D018698:Glutamic Acid / Q000009:adverse effects; D054833:Isoindoles; D051379:Mice; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D016566:Organoselenium Compounds / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D013997:Time Factors; D051028:bcl-2-Associated X Protein / Q000378:metabolism*
D001393:Azoles; D054833:Isoindoles; D018696:Neuroprotective Agents; D016566:Organoselenium Compounds; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D018698:Glutamic Acid; C042986:ebselen