Department of Pharmacology and Physiology, Oklahoma State University Center for Health Sciences, Tulsa, OK, USA.
Department of Pharmacology and Physiology, Oklahoma State University Center for Health Sciences, Tulsa, OK, USA.
Int J Biochem Cell Biol. 2023 May;158:106405. doi: 10.1016/j.biocel.2023.106405. Epub 2023 Mar 24.
We studied, using a combination of animal and cellular models, the glial mechanisms underlying the anti-neuropathic and anti-inflammatory properties of PAM-2 [(E)-3-furan-2-yl-N-p-tolyl-acrylamide], a positive allosteric modulator of α7 nicotinic acetylcholine receptors (nAChRs). In mice, PAM-2 decreased the inflammatory process induced by the combination of oxaliplatin (OXA), a chemotherapeutic agent, and interleukin-1β (IL-1β), a pro-inflammatory molecule. In the brain and spinal cord of treated animals, PAM-2 reduced pro-inflammatory cytokines/chemokines by mechanisms involving mRNA downregulation of factors in the toll-like receptor 4 (TLR4)/nuclear factor (NF)-κB pathway, and increased the precursor of brain-derived neurotrophic factor (proBDNF). To determine the molecular mechanisms underlying the anti-inflammatory activity of PAM-2, both human C20 microglia and normal human astrocytes (NHA) were used. The results showed that PAM-2-induced potentiation of glial α7 nAChRs decreases OXA/IL-1β-induced overexpression of inflammatory molecules by different mechanisms, including mRNA downregulation of factors in the NF-κB pathway (in microglia and astrocyte) and ERK (only in microglia). The OXA/IL-1β-mediated reduction in proBDNF was prevented by PAM-2 in microglia, but not in astrocytes. Our findings also indicate that OXA/IL-1β-induced organic cation transporter 1 (OCT1) expression is decreased by PAM-2, suggesting that decreased OXA influx may be involved in the protective effects of PAM-2. The α7-selective antagonist methyllycaconitine blocked the most important effects mediated by PAM-2 at both animal and cellular levels, supporting a mechanism involving α7 nAChRs. In conclusion, glial α7 nAChR stimulation/potentiation downregulates neuroinflammatory targets, and thereby remains a promising therapeutic option for cancer chemotherapy-induced neuroinflammation and neuropathic pain.
我们使用动物和细胞模型研究了 PAM-2（（E）-3-呋喃-2-基-N-对甲苯基丙烯酰胺）的神经胶质机制，PAM-2 是一种α7 烟碱型乙酰胆碱受体（nAChR）的正变构调节剂，具有抗神经病和抗炎特性。在小鼠中，PAM-2 降低了奥沙利铂（OXA）与白细胞介素-1β（IL-1β）组合诱导的炎症过程。在治疗动物的大脑和脊髓中，PAM-2 通过下调 Toll 样受体 4（TLR4）/核因子（NF）-κB 途径中因子的 mRNA 来减少促炎细胞因子/趋化因子，并增加脑源性神经营养因子（proBDNF）的前体。为了确定 PAM-2 抗炎活性的分子机制，我们使用了人 C20 小胶质细胞和正常人类星形胶质细胞（NHA）。结果表明，PAM-2 诱导的神经胶质 α7 nAChR 增强作用通过不同的机制降低了 OXA/IL-1β 诱导的炎症分子的过度表达，包括 NF-κB 途径（在小胶质细胞和星形胶质细胞中）和 ERK（仅在小胶质细胞中）因子的 mRNA 下调。PAM-2 防止了 OXA/IL-1β 介导的 proBDNF 减少，而在星形胶质细胞中则没有。我们的研究结果还表明，PAM-2 降低了 OXA/IL-1β 诱导的有机阳离子转运蛋白 1（OCT1）表达，这表明 OXA 内流的减少可能与 PAM-2 的保护作用有关。α7 选择性拮抗剂甲基金刚烷胺阻断了 PAM-2 在动物和细胞水平上介导的最重要的作用，支持涉及α7 nAChR 的机制。总之，神经胶质 α7 nAChR 刺激/增强可下调神经炎症靶标，因此仍然是癌症化疗引起的神经炎症和神经病性疼痛的有前途的治疗选择。
