Journal
CNS & NEUROLOGICAL DISORDERS-DRUG TARGETS
Volume 13, Issue 5, Pages 874-884Publisher
BENTHAM SCIENCE PUBL LTD
DOI: 10.2174/18715273113129990104
Keywords
Total bakkenolides; cerebral ischemia; neuroprotection; mechanism; nuclear factor-kappa B
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Funding
- Chinese Ministry of Science and Technology [2009ZX09103-420]
- Science and Technology Commission Research Projects of Shanghai Municipality [08DZ19715]
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Total bakkenolides is the major component of the rhizome of Petasites trichinous Franch.. In this study, we investigated its neuroprotective effects in a rat transient focal cerebral ischemia-reperfusion model, and in an in vitro cerebral ischemia model, oxygen-glucose deprivation of cultured nerve cells. Oral administration of total bakkenolides immediately after reperfusion at doses of 5, 10 and 20 mg/kg markedly reduced brain infarct volume and neurological deficits. Total bakkenolides significantly attenuated cell death and apoptosis in primarily cultured neurons subject to 1-h hypoxia followed by 24-h reoxygenation. Morphologic observations directly confirmed its protective effect on neurons. We also demonstrated that total bakkenolides could inhibit nuclear factor-kappa B (NF-kappa B) activation by blocking the classic activation pathway through suppression of phosphorylation of I kappa B-kinase complex, NF-kappa B/p65 and inhibitor protein I kappa B, inducing nuclear translocation of NF-kappa B/p65 and degradation of I kappa B. Further, total bakkenolides inhibited the activation of Akt and the extracellular signal-regulated kinase 1/2, two important upstream activators of NF-kappa B. In conclusion, our results provide a strong pharmacological basis for further understanding the potential therapeutic role of total bakkenolides in cerebral ischemic disease and shed new light on its neuroprotective mechanism.
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