瞬时受体电位经典型 5（TRPC5）通道激活剂，BTD [N-（3-（金刚烷-2-氧基）丙基）-3-（6-甲基-1,1-二氧代-2H-1λ，2,4-苯并噻二嗪-3-基）-丙酰胺）] 改善大鼠糖尿病心脏自主神经病变。
Transient Receptor Potential Canonical 5 (TRPC5) Channels Activator, BTD [N-{3-(adamantan-2-yloxy)-propyl}-3-(6-methyl-1,1-dioxo-2H-1λ,2,4- benzothiadiazin-3-yl)-propanamide)] Ameliorates Diabetic Cardiac Autonomic Neuropathy in Rats.
机构信息
Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Nagar (Mohali), 160 062, Punjab, India.
出版信息
Curr Neurovasc Res. 2023;20(1):112-123. doi: 10.2174/1567202620666230403134627.
BACKGROUND
Diabetic cardiac autonomic neuropathy (DCAN) is a serious diabetic complication with no approved pharmacological agents for its treatment. Parasympathetic system dysfunction characterized by vagal nerve damage is one of the major drivers of DCAN. The TRPC5 or transient receptor potential canonical 5 channel is a promising target in autonomic dysfunction; however, its role in vagal nerve damage and subsequent DCAN has not yet been elucidated. The present study investigated the role of the TRPC5 channel in DCAN using [N-{3-(adamantan-2-yloxy)-propyl}-3-(6-methyl-1,1-dioxo-2H-1λ,2,4-benzothiadiazin-3-yl) propanamide)] or BTD, which is a potent TRPC5 activator.
OBJECTIVES
The role of the TRPC5 channel and its activator, BTD, was investigated in the treatment of parasympathetic dysfunction associated with DCAN.
METHODS
Type 1 diabetes was induced in male Sprague-Dawley rats using streptozotocin. The alterations in cardiac autonomic parameters in diabetic animals were assessed by heart rate variability, hemodynamic parameters, and baroreflex sensitivity. TRPC5's role in DCAN was investigated by treating diseased rats with BTD (1 and 3 mg/kg, i.p. for 14 days). BTD's beneficial effects in parasympathetic dysfunction were assessed by western blotting, estimating oxidative stress and inflammatory markers in the vagus nerve.
RESULTS
BTD treatment (3 mg/kg, i.p.) once daily for 14 days ameliorated heart rate variability, hemodynamic dysfunction, and baroreflex sensitivity in diseased rats. BTD treatment down regulated TRPC5 expression by increasing the activity of protein kinase C in the vagus nerve. It also down-regulated the apoptotic marker CASPASE-3 and also exerted potent anti-inflammatory action on pro-inflammatory cytokines levels in the vagus.
CONCLUSION
BTD ameliorated parasympathetic dysfunction associated with DCAN by virtue of its TRPC5 modulatory, anti-inflammatory, and anti-apoptotic properties.
背景
糖尿病心脏自主神经病变（DCAN）是一种严重的糖尿病并发症，目前尚无批准的药物可用于治疗。自主神经功能障碍的主要驱动因素之一是副交感神经系统功能障碍，其特征是迷走神经损伤。瞬时受体电位经典型 5 通道（TRPC5）是自主神经功能障碍的一个有前途的靶点；然而，其在迷走神经损伤和随后的 DCAN 中的作用尚未阐明。本研究使用[ N -{3-（金刚烷-2-基氧基）-丙基}-3-（6-甲基-1,1-二氧代-2H-1λ,2,4-苯并噻二嗪-3-基）丙酰胺）]或 BTD 研究 TRPC5 通道在 DCAN 中的作用，BTD 是一种有效的 TRPC5 激活剂。
目的
研究 TRPC5 通道及其激活剂 BTD 在治疗与 DCAN 相关的副交感神经功能障碍中的作用。
方法
使用链脲佐菌素诱导雄性 Sprague-Dawley 大鼠 1 型糖尿病。通过心率变异性、血流动力学参数和压力反射敏感性评估糖尿病动物心脏自主神经参数的变化。通过用 BTD（1 和 3 mg/kg，腹腔注射，14 天）治疗患病大鼠来研究 TRPC5 在 DCAN 中的作用。通过 Western blot 评估 BTD 在迷走神经中对氧化应激和炎症标志物的影响，来评估 BTD 在副交感神经功能障碍中的有益作用。
结果
BTD（3 mg/kg，腹腔注射）每天一次，连续 14 天治疗可改善患病大鼠的心率变异性、血流动力学功能障碍和压力反射敏感性。BTD 治疗通过增加迷走神经中蛋白激酶 C 的活性而下调 TRPC5 表达。它还下调凋亡标志物 CASPASE-3，并对迷走神经中的促炎细胞因子水平发挥强大的抗炎作用。
结论
BTD 通过其对 TRPC5 的调节、抗炎和抗凋亡作用改善了与 DCAN 相关的副交感神经功能障碍。
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