The role of Nav 1.7 and methylglyoxal-mediated activation of TRPA1 in itch and hypoalgesia in a murine model of type 1 diabetes
The role of Nav 1.7 and methylglyoxal-mediated activation of TRPA1 in itch and hypoalgesia in a murine model of type 1 diabetes
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Nav1.7 和甲基乙二醛介导的 TRPA1 激活在 1 型糖尿病小鼠模型瘙痒和痛觉减退中的作用
DOI：
10.7150/thno.36077
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发表时间：
2019-01-01
期刊：
影响因子：
12.4
通讯作者：
Liu, Tong
中科院分区：
文献类型：
--
作者：
Cheng, Ruo-Xiao;Feng, Yu;Liu, Tong
丙酮醛（MGO）是一种内源性活性羰基化合物，在糖尿病神经病变的发病机制中起着关键作用。本研究的目的是探讨MGO在糖尿病瘙痒和痛觉减退中的作用，这两种常见的糖尿病神经病变相关症状。方法：皮内（i.d.）在幼稚小鼠中或在通过腹膜内（i. p.）注射链脲佐菌素（STZ）。采用行为学测试、膜片钳记录、转基因小鼠和基因表达分析来研究小鼠糖尿病瘙痒和痛觉减退的机制。结果：ID在正常小鼠中注射MGO诱发剂量依赖性抓挠。添加MGO直接激活瞬时受体电位锚蛋白1（TRPA 1），以诱导背根神经节（DRG）神经元或表达TRPA 1的HEK 293细胞中的内向电流和钙内流。STZ诱导的糖尿病小鼠出现机械性瘙痒，但不出现自发性瘙痒。Trpa 1的基因切除（Trpa 1-/-），TRPA 1和Nav1.7的药理学阻断，抗氧化剂和丝裂原活化蛋白激酶激酶（MEK）抑制剂U 0126消除了由MGO或STZ诱导的糖尿病小鼠引起的瘙痒。通过鞘内（i.t.）注射MGO或STZ诱导的糖尿病小鼠中，其通过MGO清除剂、鞘内注射TRPA 1阻断剂和Trpa 1-/-小鼠消除。结论：这项研究揭示了Nav1.7和MGO介导的TRPA 1激活在1型糖尿病小鼠模型的瘙痒和痛觉减退中起关键作用。因此，我们为治疗糖尿病神经病变引起的瘙痒和痛觉减退提供了一种新的潜在治疗策略。
Methylglyoxal (MGO), an endogenous reactive carbonyl compound, plays a key role in the pathogenesis of diabetic neuropathy. The aim of this study is to investigate the role of MGO in diabetic itch and hypoalgesia, two common symptoms associated with diabetic neuropathy. Methods: Scratching behavior, mechanical itch (alloknesis), and thermal hypoalgesia were quantified after intradermal (i.d.) injection of MGO in naïve mice or in diabetic mice induced by intraperitoneal (i.p.) injection of streptozotocin (STZ). Behavioral testing, patch-clamp recording, transgenic mice, and gene expression analysis were used to investigate the mechanisms underlying diabetic itch and hypoalgesia in mice. Results: I.d. injection of MGO evoked dose-dependent scratching in normal mice. Addition of MGO directly activated transient receptor potential ankyrin 1 (TRPA1) to induce inward currents and calcium influx in dorsal root ganglia (DRG) neurons or in TRPA1-expressing HEK293 cells. Mechanical itch, but not spontaneous itch was developed in STZ-induced diabetic mice. Genetic ablation of Trpa1 (Trpa1-/-), pharmacological blockade of TRPA1 and Nav1.7, antioxidants, and mitogen-activated protein kinase kinase enzyme (MEK) inhibitor U0126 abrogated itch induced by MGO or in STZ-induced diabetic mice. Thermal hypoalgesia was induced by intrathecal (i.t.) injection of MGO or in STZ-induced diabetic mice, which was abolished by MGO scavengers, intrathecal injection of TRPA1 blockers, and in Trpa1-/-mice. Conclusion: This study revealed that Nav1.7 and MGO-mediated activation of TRPA1 play key roles in itch and hypoalgesia in a murine model of type 1 diabetes. Thereby, we provide a novel potential therapeutic strategy for the treatment of itch and hypoalgesia induced by diabetic neuropathy.