Combined administration of anisodamine and neostigmine rescued acute lethal crush syndrome through α7nAChR-dependent JAK2-STAT3 signaling

Abstract

Previously we showed that Ani (anisodamine)/Neo (neostigmine) combination produced anti-shock effect via activating α7 nicotinic acetylcholine receptor (α7nAChR). In this study, we aim to investigate the therapeutic effect and underlying mechanisms of Ani/Neo combination in acute lethal crush syndrome (CS). In rat and rabbit CS models, Ani/Neo combination increased the 24 h survival rates, improved hemodynamics and decreased the levels of creatine kinase, MB isoenzyme of creatine kinase, blood urea nitrogen, creatinine, K+ in serum. It also decreased the levels of H2O2, myeloperoxidase (MPO) and nitric oxide (NO) in serum and compressed muscle in rat CS model. In wild-type (WT) mice with CS, Ani/Neo combination increased 24 h survival rate and decreased the levels of H2O2, MPO, NO, TNFα, IL-6 and IL-10 in compressed muscle. These effects were attenuated by α7nAChR knockout (KO). Moreover, Ani/Neo combination prevented the decrease of phosphorylation of Janus kinase 2 (JAK2) and phosphorylation of signal transducer and activator of transcription 3 (STAT3) induced by CS. These effects of Ani/Neo in CS mice were cancelled by methyllycaconitine (α7nAChR antagonist) and α7nAChR KO. Collectively, our results demonstrate that Ani/Neo combination could produce therapeutic effects in CS. The underlying mechanism involves the activation of α7nAChR-dependent JAK2-STAT3 signaling pathway.

Activating α7 nicotinic acetylcholine receptor inhibits NLRP3 inflammasome through regulation of β‐arrestin‐1

“…Furthermore, Kimura et al reported that central insulin action could regulate the inflammatory response in Kupffer cells through the mediation of α7nAChR‐regulated suppression of IL‐6/STAT3 signaling pathway, thus controlling the pathogenesis of chronic hepatic inflammation in obesity. Several studies from our laboratory also demonstrated the antiinflammatory effects of α7nAChR . For example, Liu et al showed a beneficial effect of anisodamine on arterial pressure and secretion of tumor necrosis factor‐α and IL‐1β in LPS‐induced shock through triggering the α7nAChR‐dependent antiinflammatory pathway.…”

“…For example, Liu et al showed a beneficial effect of anisodamine on arterial pressure and secretion of tumor necrosis factor‐α and IL‐1β in LPS‐induced shock through triggering the α7nAChR‐dependent antiinflammatory pathway. In addition, Xu et al reported that anisodamine/neostigmine combination led to a cholinergic antiinflammatory pathway mediated by α7nAChR, thus contributing to the alleviation of acute lethal crush syndrome. Consistent with those previous studies, here we reported that activating α7nAChR led to an antiinflammatory effect in microglia in vitro and spinal cord from EAE mice in vivo.…”

The importance of the biochemical markers in rapid diagnosis and treatment of crushing syndrome

“…2020;15(1) DOI: 10.37897/RJMP.2020. 1.17 lism becomes anaerobic, with the occurrence of glycolysis, lactic acid and lactic acidosis [1][2][3][4].…”

“…Crush syndrome (CS) is a serious medical condition that can be encountered in patients from emergency departments as a result of accidents occurring in different situations, including vehicle entrapment, falling debris (for example to construction workers), industrial accidents (mine accidents), natural disasters such as earthquakes or by prolonged pressure to a part of the body due to their own body weight in an immobile victim [1][2][3][4].…”

“…The energy absorbed by the affected area represents the difference between the energy of the traumatic agent and the resistance of the structure involved. The muscle is directly affected by the destruction of the muscle fibers, and, indirectly, by affecting the local circulation and disturbing the cellular metabolism, with the release of toxic products at both local and systemic levels (disturbing the membrane pump) [1][2][3][4].…”