Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia; Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, 23298, USA.
Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, 23298, USA.
Eur J Pharmacol. 2020 Sep 15;883:173320. doi: 10.1016/j.ejphar.2020.173320. Epub 2020 Jul 7.
Nicotinic acetylcholine receptors can regulate inflammation primarily through the vagus nerve via the cholinergic anti-inflammatory pathway. α9α10 nicotinic receptors (nAChRs) are a new promising target for chronic pain and inflammation. Recently, α9α10 selective α-conotoxin antagonists were shown to have antinociception effect in neuropathic and tonic inflammatory pain animal models. However, limited data available on the role of α9α10 nAChRs in experimental colitis. In this study, we report for the first time, the role of α9α10 nAChRs in the dextran sodium sulfate (DSS) experimental animal colitis model. We determined the effect of the α9α10 nAChRs antagonist, α-conotoxin RgIA (α-RgIA) in DSS-induced colitis model in adult male and female C57BL/6 J mice. DSS solution was freely given in the drinking water for seven consecutive days, and tap water was given on the 8th day. We then sacrificed mice on day 8 to examine the entire colon. Disease severity, colon tissue histology, and tumor necrosis factor-α (TNF-α) were evaluated. The lower doses (0.02 and 0.1 nmol/mouse, s.c.) of α-RgIA treatment in DSS-treated mice were inactive, whereas the higher dose (0.2 nmol/mouse, s.c.) reversed the disease activity index (DAI) score, loss of body weight, total histological damage score, as well as the colonic level of TNF-α compared to the DSS-control group. Moreover, the highest dose of α-RgIA (0.2 nmol/mouse, s.c.) significantly rescued the colon length shortening in DSS-treated mice compared to the DSS-control mice. The availability of α9*-selective conotoxins has opened new avenues in pharmacology research and potential targets in inflammatory disorders.
烟碱型乙酰胆碱受体主要通过迷走神经通过胆碱能抗炎途径来调节炎症。α9α10 型烟碱受体 (nAChRs) 是慢性疼痛和炎症的一个新的有前途的靶点。最近，α9α10 选择性α-芋螺毒素拮抗剂在神经病理性和紧张性炎症性疼痛动物模型中显示出镇痛作用。然而，关于 α9α10 nAChRs 在实验性结肠炎中的作用的可用数据有限。在这项研究中，我们首次报告了 α9α10 nAChRs 在葡聚糖硫酸钠 (DSS) 实验性动物结肠炎模型中的作用。我们确定了 α9α10 nAChRs 拮抗剂α-芋螺毒素 RgIA (α-RgIA) 在成年雄性和雌性 C57BL/6J 小鼠 DSS 诱导的结肠炎模型中的作用。DSS 溶液连续 7 天自由饮用，第 8 天给予自来水。然后，我们在第 8 天处死小鼠，检查整个结肠。评估疾病严重程度、结肠组织学和肿瘤坏死因子-α (TNF-α)。DSS 处理小鼠中较低剂量 (0.02 和 0.1 nmol/只，皮下) 的 α-RgIA 治疗无效，而较高剂量 (0.2 nmol/只，皮下) 逆转了疾病活动指数 (DAI) 评分、体重减轻、总组织损伤评分以及与 DSS 对照组相比的结肠 TNF-α 水平。此外，与 DSS 对照组相比，α-RgIA 的最高剂量 (0.2 nmol/只，皮下) 显著挽救了 DSS 处理小鼠的结肠长度缩短。α9*-选择性芋螺毒素的可用性为药理学研究开辟了新途径，并为炎症性疾病提供了潜在靶点。
