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.

Adenosine 5′-monophosphate-induced hypothermia inhibits the activation of ERK1/2, JNK, p38 and NF-κB in endotoxemic rats

“…In LPS-stimulated inflammatory pathways, JNK signaling is key for cytokine production [37]. In other previous studies, the JNK pathway could be inhibited by hypothermia [38][39][40]; our work verified these results.…”

β1-adrenoceptor stimulation promotes LPS-induced cardiomyocyte apoptosis through activating PKA and enhancing CaMKII and IκBα phosphorylation

“…On the other hand, it was reported that sustained (24-hour) β 1 -AR stimulation activates the PKA-independent Ca 2+ / CaMKII signaling pathway and subsequently induces cardiomyocyte apoptosis [ 24 , 33 , 38 ]. β 1 -AR stimulation increases cytosolic Ca 2+ concentration and activates CaMKII in cardiomyocytes, blockade of L-type calcium channel with NIF or inhibition of CaMKII activity fully attenuates cardiomyocyte apoptosis induced by β 1 -AR stimulation, and overexpression of active CaMKII leads to cardiomyocyte apoptosis through increased cytochrome c release [ 24 , 33 , 39 ]. Accordingly, we observed the effects of NIF on cytosolic Ca 2+ concentration, CaMKII, caspase-3/7 and caspase-9 activation in DOB- and LPS-treated cardiomyocytes, and found that LPS not only increased cytosolic Ca 2+ concentration, but also elevated CaMKII phosphorylation in cardiomyocytes, both of which were enhanced by DOB treatment.…”

“…Cardiac and serum TNF-α was detected using a mouse TNF-α enzyme-linked immunosorbent assay (ELISA) kit (R&D Systems, Inc, Minneapolis, MN, USA) according to the manufacturer’s instructions. Cardiomyocyte nuclear NF-κB activity was measured using a NF-kB (p65) Transcription Factor Assay kit (Cayman Chemical, Ann Arbor, MI, USA) as previously described [ 24 ].…”

Berberine Prevents Cognitive Disorders Induced by Sepsis by Regulating the Inflammatory Cytokines, Oxidative Stress and Neuronal Apoptosis in Rat Brain

“…Many signalling pathways, including CCR2 expression in neutrophils [15], Toll-like receptors [14], NF-ΚB [28], and PPARγ [29], were targets of BBR in vitro or vivo. In addition, some effects of BBR were significantly enhanced by combination with Yohimbine treatment [30]. Whether BBR combination treatment with Yohimbine before CLP surgery will show an increasing beneficial effect towards sepsis induced cognitive impairment and precise mechanisms underlying this effect still remain to be further explored.…”