α7 Nicotinic acetylcholine receptor-mediated anti-inflammatory effect in a chronic migraine rat model via the attenuation of glial cell activation

Abstract

BackgroundEvidence suggests that the activation of α7 nicotinic acetylcholine receptor (α7nAChR) can greatly decrease the neuroinflammation response. Neuroinflammation plays a pivotal role in the pathogenesis of chronic migraine (CM). Clinical observations also show that nicotine gum induces analgesic effects in migraine patients. However, whether α7nAChR is involved in CM is unclear.ObjectiveTo investigate the role of α7nAChR in CM and provide a new therapeutic target for CM.Materials and methodsThirty-six male Sprague–Dawley rats were distributed randomly into control, CM, PNU-282987, and α-bungarotoxin groups (n=9 rats in each group). The CM model was established by the recurrent daily administration of inflammatory soup on the dura over the course of 1 week. The hind paw threshold and facial allodynia were assessed by the von Frey test. The expression levels of α7nAChR, tumor necrosis factor-alpha, and interleukin-1 beta were analyzed by Western blot and real-time fluorescence quantitative polymerase chain reaction. The location of α7nAChR in the hippocampus was quantified by immunofluorescence, as well as the microglial and astrocyte alterations. Changes in the calcitonin gene-related peptide and the phosphorylated JNK protein among different groups were measured by Western blot.ResultsWe found that the expression of α7nAChR was reduced after repeated inflammatory soup administration. The increased expression of tumor necrosis factor-alpha, interleukin-1 beta, and calcitonin gene-related peptide in CM group were significantly decreased by PNU-282987 and aggravated by α-bungarotoxin. Moreover, PNU-282987 decreased the numbers of astrocytes and microglia compared with the numbers in the CM group in both hippocampal CA1 and CA3 regions. In contrast, α-bungarotoxin activated the astrocytes and microglia, but the differences with respect to the CM group were not significant. Activated c-Jun N-terminal kinase signaling was observed in CM rats and was also blocked by PNU-282987.ConclusionThe activation of α7nAChR increased the mechanical threshold and alleviated pain in the CM rat model. α7nAChR activation also decreased the upregulation of astrocytes and microglia through the p-c-Jun N-terminal kinase–mitogen-activated protein kinase signaling pathway.

The spinal microglial IL-10/β-endorphin pathway accounts for cinobufagin-induced mechanical antiallodynia in bone cancer pain following activation of α7-nicotinic acetylcholine receptors

“…The notion that agonism of microglial α7-nAChR triggers IL-10/β-endorphin pathway is further supported by the facts that the specific inhibitors of MAPK activation attenuated cinobufagin-stimulated IL-10/β-endorphin expression in microglial cells. MAPKs are a family of evolutionally conserved molecules including p38, JNK, and ERK1/2 [75] and have been suggested to be involved in the antiinflammatory properties of α7-nAChRs possibly through modulation of inflammatory cytokine release [23,49,60,69,85]. Our study demonstrated that the specific JNK activation inhibitor SP600125, ERK1/2 activation inhibitor UO126 and p38 activation inhibitor SB203580 significantly blocked the gene expression of IL-10 and POMC in cultured microglia.…”

“…Activation of mitogen-activated protein kinases (MAPKs), including p38, extracellular signal-related kinases 1/2 (ERK1/2) and c-Jun N-terminal kinases (JNK) [75], was involved in α7-nAChR-induced inhibition of neuroinflammation [23,49,85]. To illustrate which subtype(s) of MAPKs were involved in cinobufagin-induced IL-10/β-endorphin expression, the specific p38 inhibitor SB203580, JNK inhibitor SP600125, and ERK1/2 inhibitor UO126 were used.…”

Cholinergic Modulation of Glial Function During Aging and Chronic Neuroinflammation

“…Also, activation of α7nAChR by a pre-treatment with a positive allosteric modulator (PAM) reduced LPS-induced expression of the pro-inflammatory markers IL-1β, TNF-α, and the microglial activation marker cluster of differentiation 11b (CD11b) in the hippocampus and prefrontal cortex (PFC) of mice, and even blocked LPS-induced anxiety-like behaviors (Abbas et al, 2017;Alzarea and Rahman, 2019). On the other hand, neuroinflammation induced by the intra-cerebroventricular injection of an inflammatory soup containing prostaglandin E2 (0.2 mM), serotonin (2 mM), bradykinin (2 mM), and histamine (2 mM), in a rat model can also be linked with a decrease in the expression level of α7nAChR in the hippocampus, which can be reversed by the treatment with an α7nAChR agonist (Liu et al, 2018).…”

Inflammation has synergistic effect with nicotine in periodontitis by up‐regulating the expression of α7 nAChR via phosphorylated GSK‐3β

“…It has been confirmed that there might be a bidirectional regulation between α7 nAChR and certain inflammatory factors like interleukin‐1β (IL‐1β) and tumour necrosis factor‐α (TNF‐α) . Moreover, the inflammatory response of PDLSCs could activate multiple signalling pathways, such as those involving glycogen synthase kinase‐3β (GSK‐3β) .…”

“…It has been confirmed that there might be a bidirectional regulation between α7 nAChR and certain inflammatory factors like interleukin-1β (IL-1β) and tumour necrosis factor-α (TNF-α). 16,17 Moreover, the inflammatory response of PDLSCs could activate multiple signalling pathways, such as those involving glycogen synthase kinase-3β (GSK-3β). 18 Furthermore, in the central nervous system, increased expression of phosphorylated GSK-3β can up-regulate the expression and promote the function of α7 nAChR, thus suppressing the progression of degenerative diseases.…”