Inhibition of NF-κB activation is associated with anti-inflammatory and anti-apoptotic effects of Ginkgolide B in a mouse model of cerebral ischemia/reperfusion injury.

Abstract

Ginkgolide B (GB) has potent neuroprotective effects against ischemia-induced brain injury in vivo and in vitro. However, the underlying mechanisms of GB's neuroprotection remain poorly understood. Excessive inflammation and apoptosis contribute to the pathogenesis of ischemic brain damage, and NF-κB is considered to be a key player in these processes. In the present study, we examined the detailed mechanisms underlying the inhibitory effects of GB on inflammatory and apoptotic responses induced by focal cerebral ischemia/reperfusion (I/R). Transient middle cerebral artery occlusion (tMCAO) model was produced by using an intraluminal filament technique in mice. GB (10, 20 and 40 mg/kg) was administered intravenously (i.v.) 2h after MCAO. The results demonstrated that MCAO-induced cerebral injury was associated with an upregulation of p-IKK, p-IκB-α and degradation of IκB-α, indicating of NF-κB activation. Meanwhile activation of microglial and increases in levels of TNF-α, IL-1β and iNOS were observed. Furthermore upregulation of the expression of NF-κB target gene p53 and p53 downstream gene Bax, but downregulation of Bcl-2 and activation of caspase-3 were found. GB treatment showed marked reduction in infarction volume, brain edema and neurological deficits. GB also inhibited I/R induced NF-κB, microglia activation and production of pro-inflammatory cytokines. We also demonstrated that GB reduced Bax protein levels and increased Bcl-2 protein levels in the post-ischemic brains. These results suggest that GB's neuroprotection is attributable to its anti-inflammatory and anti-apoptotic effect through inhibition of NF-κB.

• Authors: Jin-Hua Gu, Jian-Bin Ge, Mei Li, Feng Wu, Wei Zhang, Zheng-Hong Qin
• Journal: European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences (Eur J Pharm Sci) Vol. 47 Issue 4 Pg. 652-60 (Nov 20 2012) ISSN: 1879-0720 [Electronic] Netherlands
• PMID: 22850444 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Elsevier B.V. All rights reserved.

Chemical References

• Anti-Inflammatory Agents
• Ginkgolides
• Lactones
• NF-kappa B
• Neuroprotective Agents
• ginkgolide B

Topics

• Animals
• Anti-Inflammatory Agents (pharmacology)
• Apoptosis (drug effects, genetics)
• Brain (drug effects, metabolism)
• Brain Ischemia (drug therapy, genetics)
• Disease Models, Animal
• Gene Expression Regulation (drug effects, genetics)
• Ginkgolides (pharmacology)
• Infarction, Middle Cerebral Artery (drug therapy, genetics, metabolism)
• Inflammation (drug therapy, genetics, metabolism)
• Lactones (pharmacology)
• Male
• Mice
• Mice, Inbred ICR
• Microglia (drug effects, metabolism)
• NF-kappa B (antagonists & inhibitors, genetics, metabolism)
• Neuroprotective Agents (pharmacology)
• Reperfusion Injury (drug therapy, genetics, metabolism)
• Signal Transduction (drug effects, genetics)