α7 nicotinic acetylcholine receptor agonist inhibits the damage of rat hippocampal neurons by TLR4/Myd88/NF-κB signaling pathway during cardiopulmonary bypass

Abstract

The present study aimed to investigate the effect of α7 nicotinic acetylcholine receptor (α7nAChR) agonist on the damage of hippocampal neurons and the expression of toll like receptor 4 (TLR4)/myeloid differentiation primary response 88 (Myd88)/nuclear factor (NF)-κB signal pathway-associated factors in cardiopulmonary bypass (CPB). Sprague Dawley rats were randomly divided into five groups: Sham operation (Sham); CPB; CPB + α7nAChR agonist PHA568487 (PHA); CPB + α7nAChR inhibitor MLA (MLA); and CPB + PHA568487 + TLR4 antagonist (CPT). Blood and brain tissue samples were harvested at 12 h following the withdrawal of CPB. Levels of serum inflammatory factors [interleukin (IL)-1β, IL-6 and tumor necrosis factor (TNF)-α] and brain injury markers [S-100β and neuron-specific enolase (NSE)] were measured using ELISA. In addition, pathological histology and apoptosis changes were observed using hematoxylin and eosin staining, and Tunnel assays. Quantitative polymerase chain reaction and western blot assays were used to determine the expression of TLR4, Myd88 and NF-κB mRNA, and protein in the hippocampus. The morphology of hippocampal pyramidal cells in the Sham group was observed to be normal. Pyramidal cells in the CPB, MLA and CPT groups were loosely arranged, and the baselines had disappeared, with clear nucleus pyknosis and neuronal apoptosis. Furthermore, the cells in the PHA group were slightly damaged. IL-1β, IL-6, TNF-α, S-100β and NSE expression levels in the CPB, MLA, and CPT groups were significantly higher compared with that in the Sham group (P<0.05). Compared with CPB group, the expression of inflammatory cytokines in the PHA group was significantly lower (P<0.05). The expression of TLR4, Myd88 and NF-κB mRNA, and protein in the hippocampus of CPB, MLA and CPT groups were significantly higher compared with that in the Sham group, and the PHA group expression was significantly lower compared with the CPB group (P<0.05). α7nAChRs agonist can inhibit the apoptosis of rat brain neurons induced by CPB, and may protect against brain injury through the TLR4/Myd88/NF-κB signaling pathway.

Neuroinflammation Alters Integrative Properties of Rat Hippocampal Pyramidal Cells

“…Notably, TLR4 expression was undetectable by immunohistochemistry in sham rats [33, 58]. However, basal level of TLR4 expression were measured using RTqPCR [59, 60]. It is likely therefore that immunohistochemistry is not sensitive enough to detect the basal cellular expression of TLR4.…”

A Selective α7 Nicotinic Acetylcholine Receptor Agonist, PNU-282987, Attenuates ILC2s Activation and Alternaria-Induced Airway Inflammation

“…This was not surprising as many α7nAChRs-mediated pathways are involved in the process of inhibiting inflammation. This includes the JAK2-STAT3 signaling pathway, α7nAChR/IKK/NF-κB signaling pathway, and α7nAChR/MyD88/IKK/NF-κB pathway ( 39 , 40 ). STAT3 activated by α7nAChR is a negative regulator of the inflammatory response, and in α7nAChR/IKK/NF-κB signaling axis, α7nAChR further inhibits the nuclear translocation of NF-κB by inhibiting the phosphorylation of upstream signal IKK ( 41 ).…”

κ‑opioid receptor agonists may alleviate intestinal damage in cardiopulmonary bypass rats by inhibiting the NF‑κB/HIF‑1α pathway

“…Nicotine can attenuate the activation of the NF-κB signaling pathway caused by endotoxin (56,57). In addition, the α7 nicotinic acetylcholine receptor (α7nAchR) can inhibit the activity of transcription factor NF-κB, leading to attenuation of inflammatory cytokines (58). Furthermore, vagus nerve stimulation prior to α7nAchR antagonist treatment attenuated the destruction of the intestinal epithelial cells of rats with endotoxemia, which was mediated by the inhibition of NF-κB-p65 and transport of myosin light-chain kinase (59).…”