Faculdade de Farmácia, Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro, Brazil; Programa de Pós-graduação em Ciências Farmacêuticas, UFRJ, Rio de Janeiro, Brazil.
Faculdade de Farmácia, Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro, Brazil.
Eur J Pharmacol. 2019 Aug 5;856:172408. doi: 10.1016/j.ejphar.2019.172408. Epub 2019 May 24.
Painful diabetic neuropathy (PDN) is a serious symptom that compromises quality of life and remains without effective pharmacological treatment. The transient receptor vanilloid 4 (TRPV4) is a cation-permeable channel implicated in sensory transduction and pain signalling. Therefore, drugs that act on TRPV4 may have therapeutic applications to treat PDN. In the present work, we assessed the effect of the selective TRPV4 channel antagonist HC-067047 on painful neuropathy associated with streptozotocin (STZ)-induced diabetes in mice. STZ-treated animals presented both mechanical and cold allodynia at 6 weeks after diabetes induction. Notably, HC-067047 (1 mg/kg, s.c.) given daily between 2 and 6 weeks after diabetes induction significantly prevented the development of mechanical allodynia. Additionally, both single and repeated treatments with HC-067047 (10 mg/kg, s.c.) significantly reverted established mechanical allodynia induced by STZ. However, HC-067047 was not capable of affecting either thermal cold allodynia or hyperglycemia. Similarly, HC-067047 treatments showed no effect on body weight, temperature, locomotor activity or motor coordination of control mice. Immunohistochemistry assay showed that TRPV4 expression was not different in sciatic nerve, dorsal root ganglia (DRG) or hind paw plantar skin from diabetic and non-diabetic mice, suggesting that HC-067047 acts on constitutive receptors to inhibit mechanical allodynia. Taken together, the data generated in the present study show the potential relevance of using TRPV4 antagonists to treat painful neuropathy associated with diabetes.
痛性糖尿病周围神经病变（PDN）是一种严重的症状，会影响生活质量，目前仍然缺乏有效的药物治疗。瞬时受体电位香草酸亚型 4（TRPV4）是一种阳离子渗透性通道，参与感觉转导和疼痛信号传递。因此，作用于 TRPV4 的药物可能具有治疗 PDN 的应用潜力。在本研究中，我们评估了选择性 TRPV4 通道拮抗剂 HC-067047 对链脲佐菌素（STZ）诱导的糖尿病小鼠痛性神经病变的影响。STZ 处理的动物在糖尿病诱导后 6 周时表现出机械性和冷感觉异常。值得注意的是，HC-067047（1mg/kg，sc）在糖尿病诱导后 2 至 6 周期间每天给药可显著预防机械性痛觉过敏的发展。此外，单次和重复给予 HC-067047（10mg/kg，sc）均可显著逆转 STZ 诱导的已建立的机械性痛觉过敏。然而，HC-067047 不能影响热冷感觉异常或高血糖。同样，HC-067047 治疗对对照小鼠的体重、体温、运动活动或运动协调均无影响。免疫组织化学检测显示，糖尿病和非糖尿病小鼠的坐骨神经、背根神经节（DRG）或后足足底皮肤中的 TRPV4 表达没有差异，这表明 HC-067047 作用于组成型受体以抑制机械性痛觉过敏。综上所述，本研究的数据表明，使用 TRPV4 拮抗剂治疗与糖尿病相关的痛性神经病变具有潜在的相关性。
