期刊
NEUROMOLECULAR MEDICINE
卷 20, 期 1, 页码 97-111出版社
HUMANA PRESS INC
DOI: 10.1007/s12017-018-8478-x
关键词
Ischemic stroke; Free radicals; Calcium overload; Mitochondrial dysfunction; Neuroprotection
资金
- Scientific Projects of Guangdong Province [2013A022100030, 2015A020211019, 2015B020232011, 2016A030313107]
- National Science Foundation of China [81502908]
- Science and Technology Program of Guangzhou [201704020181]
- Fundamental Research Funds for the Central Universities [21617469]
Our previous studies demonstrated that the multifunctional agent TBN, a derivative of tetramethylpyrazine armed with a nitrone moiety, displayed high therapeutic efficacy in experimental ischemic stroke models. However, its molecular mechanisms of action underlying the neuroprotective effect need further exploration. In the present study, we found that TBN had significant activities scavenging free radicals such as (OH)-O-center dot, O-2(center dot-) and ONOO-, inhibiting Ca2+ overload, maintaining mitochondrial function and preventing neuronal damage in primary cortical cultures. Further, TBN was effective in reducing brain infarction and ameliorating impairment of behavioral functions in the permanent middle cerebral artery occlusion (p-MCAo) rat model. TBN down-regulated the expression of pro-apoptotic factors Bax, while up-regulated the expression of anti-apoptotic factor Bcl-2 and increased the expression of pro-survival factors including p-Akt and p-GSK3 beta in the peri-infarct cortex of p-MCAo rats. In addition, LY-294002 (a PI3K inhibitor) and MK2206 (an Akt inhibitor) significantly blocked the protective effect of TBN against OGD-induced death of cortical neurons. Taken together, the multifunctional mechanisms including scavenging free radicals, blocking calcium overload, maintaining mitochondrial function and activating the PI3K/Akt/p-GSK3 beta cell survival pathway were possibly involved in the neuroprotective effects of TBN, making it a promising clinical candidate for the treatment of ischemic stroke.
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