Ruscogenin reduces cerebral ischemic injury via NF-κB-mediated inflammatory pathway in the mouse model of experimental stroke

• Published in: European journal of pharmacology 2013-08, Vol.714 (1-3), p.303-311
• Main Authors: Guan, Teng, Liu, Qian, Qian, Yisong, Yang, Haopeng, Kong, Jiming, Kou, Junping, Yu, Boyang
• Format: Article
• Language: English
• Subjects: adhesion; adults; animal models; Animals; bioactive properties; brain; brain damage; Brain Ischemia - complications; Brain Ischemia - drug therapy; Brain Ischemia - metabolism; Brain Ischemia - pathology; Cytokines - metabolism; cytosol; Disease Models, Animal; DNA; genes; inducible nitric oxide synthase; infarction; Infarction, Middle Cerebral Artery - complications; Infarction, Middle Cerebral Artery - drug therapy; Infarction, Middle Cerebral Artery - metabolism; Infarction, Middle Cerebral Artery - pathology; Inflammation; Inflammation - metabolism; Inflammation - pathology; interleukin-1beta; ischemia; Male; Mice; Mice, Inbred C57BL; Middle cerebral artery occlusion; Neuroprotective Agents - pharmacology; Neuroprotective Agents - therapeutic use; NF-kappa B - metabolism; NF-κB; Ophiopogon japonicus; pharmacology; phosphorylation; prostaglandin synthase; Ruscogenin; signal transduction; Signal Transduction - drug effects; Spirostans - pharmacology; Spirostans - therapeutic use; Stroke; Stroke - complications; transcription factor NF-kappa B; tumor necrosis factor-alpha; water content
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2013.07.036

Transient cerebral ischemia initiates a complex series of inflammatory events, which has been associated with an increase in behavioral deficits and secondary brain damage. Ruscogenin is a major steroid sapogenin in the traditional Chinese herb Ophiopogon japonicus that have multiple bioactivities. Recent studies have demonstrated that Ruscogenin is involved in down-regulation of intercellular adhesion molecule-1 (ICAM-1) and nuclear factor-κB (NF-κB) activation in anti-inflammatory pathways. We hypothesized that Ruscogenin protects against brain ischemia by inhibiting NF-κB-mediated inflammatory pathway. To test this hypothesis, adult male mice (C57BL/6 strain) were pretreated with Ruscogenin and then subjected to transient middle cerebral artery occlusion (MCAO)/reperfusion. After 1h MCAO and 24h reperfusion, neurological deficit, infarct sizes, and brain water content were measured. Ruscogenin markedly decreased the infarct size, improved neurological deficits and reduced brain water content after MCAO. The activation of NF-κB Signaling pathway was observed after 1h of ischemia and 1h of reperfusion, and Ruscogenin significantly inhibited NF-κB p65 expression, phosphorylation and translocation from cytosol to nucleus at this time point in a dose-dependent manner. NF-κB DNA binding activity, and the expression of NF-κB target genes, including ICAM-1, inducible nitric oxide synthase (iNOS), cyclooxygenase (COX-2), tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), were also suppressed by Ruscogenin pretreatment after 1h MCAO and 24h reperfusion. The results indicated that Ruscogenin protected the brain against ischemic damage caused by MCAO, and this effect may be through downregulation of NF-κB-mediated inflammatory responses.