title: Yohimbine enhances protection of berberine against LPS-induced mouse lethality through multiple mechanisms.
abstract: Sepsis remains a major cause of mortality in intensive care units, better therapies are urgently needed. Gram-negative bacterial lipopolysaccharide (LPS) is an important trigger of sepsis. We have demonstrated that berberine (Ber) protects against lethality induced by LPS, which is enhanced by yohimbine (Y) pretreatment, and Ber combined with Y also improves survival in septic mice. However, the precise mechanisms by which Y enhances protection of Ber against LPS-induced lethality remain unclear. The present study confirmed that simultaneously administered Y also enhanced protection of Ber against LPS-induced lethality. Ber or/and Y attenuated liver injury, but not renal injury in LPS-challenged mice. Ber or/and Y all inhibited LPS-stimulated IκBα, JNK and ERK phosphorylation, NF-κB activation as well as TNF-α production. Ber also increased IL-10 production in LPS-challenged mice, which was enhanced by Y. Furthermore, Ber or/and Y all suppressed LPS-induced IRF3, TyK2 and STAT1 phosphorylation, as well as IFN-β and IP-10 mRNA expression in spleen of mice at 1 h after LPS challenge. Especially, Y enhanced the inhibitory effect of Ber on LPS-induced IP-10 mRNA expression. In vitro experiments further demonstrated that Y significantly enhanced the inhibitory effect of Ber on TNF-α production in LPS-treated peritoneal macrophages, Ber combined with Y promoted LPS-induced IL-10 production and LPS-stimulated IκBα, JNK, ERK and IRF3 phosphorylation and NF-κB activation were also suppressed by Ber or/and Y pretreatment in peritoneal macrophages. Taken together, these results demonstrate that Y enhances the protection of Ber against LPS-induced lethality in mice via attenuating liver injury, upregulating IL-10 production and suppressing IκBα, JNK, ERK and IRF3 phosphorylation. Ber combined with Y may be an effective immunomodulator agent for the prevention of sepsis.
authors.affiliation: Department of Otolaryngology, Guangzhou Overseas Chinese Hospital, School of Medicine, Jinan University, Guangzhou, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Li
authors.forename: Yiyang
authors.initials: Y
authors.lastname: Wang
authors.forename: Haoqing
authors.initials: H
authors.lastname: Zhang
authors.forename: Baoyin
authors.initials: B
authors.lastname: Jia
authors.forename: Daan
authors.initials: D
authors.lastname: Wang
authors.forename: Hongmei
authors.initials: H
authors.lastname: Li
authors.forename: Daxiang
authors.initials: D
authors.lastname: Lu
authors.forename: Renbin
authors.initials: R
authors.lastname: Qi
authors.forename: Yuxia
authors.initials: Y
authors.lastname: Yan
authors.forename: Huadong
authors.initials: H
authors.lastname: Wang
mesh_terms: D000818:Animals; D001599:Berberine / Q000008:administration & dosage / Q000494:pharmacology*; D002478:Cells, Cultured; D004357:Drug Synergism; D008070:Lipopolysaccharides / Q000633:toxicity; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009184:Mydriatics / Q000008:administration & dosage*; D018805:Sepsis / Q000139:chemically induced / Q000401:mortality / Q000517:prevention & control*; D015398:Signal Transduction / Q000187:drug effects; D015016:Yohimbine / Q000008:administration & dosage*
chemical_list: D008070:Lipopolysaccharides; D009184:Mydriatics; D001599:Berberine; D015016:Yohimbine