机械性异常性疼痛是疼痛性糖尿病神经病变 (PDN) 的一种严重并发症，治疗选择有限。瞬时受体电位规范 5 (TRPC5) 通道是治疗疼痛的一个有希望的靶点；然而，其在疼痛性糖尿病神经病变中的作用尚未阐明。在本研究中，我们使用 BTD [N-{3-(金刚烷-2-基氧基)-丙基}-3-(6-甲基-1,1-dioxo-2H-1λ 6 ,2) 研究了 TRPC5 通道的作用,4-苯并噻二嗪-3-基)-丙酰胺)]，一种有效的 TRPC5 激活剂和 HC070，作为 PDN 大鼠模型中的 TRPC5 通道抑制剂。在这项研究中，链脲佐菌素被用来诱导雄性斯普拉格-道利大鼠患糖尿病。通过各种行为和功能参数评估糖尿病动物的机械和热痛阈值的变化、神经功能缺陷。通过用 BTD、TRPC5 通道激活剂（1 和 3 mg/kg，腹膜内注射 14 天）治疗神经病大鼠来研究 TRPC5 参与情况）和 HC070，一种 TRPC5 通道抑制剂（1 和 3 mg/kg）。通过蛋白质印迹法评估 BTD 和 HC070 减轻疼痛的效果，评估腰脊髓中的氧化应激和炎症标志物。BTD 治疗（3 mg/kg，腹腔注射）每天一次，持续 14 天，可改善糖尿病神经病变大鼠的机械异常性疼痛，但不能改善热感觉减退或神经功能缺陷。BTD 治疗通过增加蛋白激酶 C 的活性来下调 TRPC5 的表达。它随后还下调了脊髓中的下游疼痛标记物（CAMKII、ERK）。此外，炎症细胞因子（TNF-α、IL-6）的减少也证明了 BTD 在减少机械异常性疼痛方面具有有效的抗炎特性。另一方面，HC070对行为和神经功能参数没有产生任何有益的影响。该研究得出的结论是，BTD 不仅通过调节 TRPC5-CAMKII-ERK 通路，而且还通过其抗炎和抗凋亡特性，改善了疼痛性糖尿病神经病变大鼠模型的机械异常性疼痛。总体而言，BTD 是一种有前途的治疗分子，用于治疗疼痛性糖尿病神经病变的机械性异常性疼痛。
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BTD: A TRPC5 activator ameliorates mechanical allodynia in diabetic peripheral neuropathic rats by modulating TRPC5-CAMKII-ERK pathway
Mechanical allodynia is a serious complication of painful diabetic neuropathy (PDN) with limited treatment options. The transient receptor potential canonical 5 (TRPC5) channel is a promising target in pain; however, its role in painful diabetic neuropathy has not yet been elucidated. In this study, we have investigated the role of TRPC5 channels using BTD [N-{3-(adamantan-2-yloxy)-propyl}-3-(6-methyl-1,1-dioxo-2H-1λ6,2,4-benzothiadiazin-3-yl)-propanamide)],a potent TRPC5 activator and HC070, as TRPC5 channel inhibitor in rat model of PDN. In this study, streptozotocin was used to induce diabetes in male Sprague-Dawley rats. The alterations in mechanical and thermal pain thresholds, nerve functional deficits in diabetic animals were assessed by various behavioral and functional parameters.TRPC5 involvement was investigated by treating neuropathic rats with BTD, TRPC5 channel activator (1 and 3 mg/kg, i.p. for 14 days) and HC070, a TRPC5 channel inhibitor (1 and 3 mg/kg). BTD and HC070 effects in pain reduction were assessed by western blotting, estimating oxidative stress and inflammatory markers in the lumbar spinal cord. BTD treatment (3 mg/kg, i.p.) once daily for 14 days ameliorated mechanical allodynia but not thermal hyposensation or nerve functional deficit in diabetic neuropathic rats. BTD treatment down-regulated TRPC5 expression by increasing the activity of protein kinase C. It also subsequently down-regulated the downstream pain markers (CAMKII, ERK) in the spinal cord. Additionally, a decrease in inflammatory cytokines (TNF-α, IL-6) also demonstrated BTD's potent anti-inflammatory properties in reducing mechanical allodynia. On the other hand, HC070 did not exert any beneficial effects on behavioural and nerve functional parameters. The study concludes that BTD ameliorated mechanical allodynia in a rat model of painful diabetic neuropathy not only through modulation of the TRPC5-CAMKII-ERK pathway but also through its anti-inflammatory and anti-apoptotic properties. Overall, BTD is a promising therapeutic molecule in the treatment of mechanical allodynia in painful diabetic neuropathy.
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