Targeting of CaV3.2 T-type calcium channels in peripheral sensory neurons for the treatment of painful diabetic neuropathy
Targeting of CaV3.2 T-type calcium channels in peripheral sensory neurons for the treatment of painful diabetic neuropathy
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DOI：
10.1007/s00424-014-1452-z
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发表时间：
2014-01
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影响因子：
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通讯作者：
S. Todorovic;V. Jevtovic-Todorovic
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文献类型：
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作者：
S. Todorovic;V. Jevtovic-Todorovic
背根神经节 (DRG) 的疼痛感觉神经元（伤害感受器）可能会因糖尿病等病理状况而变得敏感（过度兴奋），这反过来可能导致疼痛性周围糖尿病神经病变 (PDN) 的发展。由于对这种超敏反应机制的了解不足，目前对疼痛性 PDN 的治疗仅限于具有显着副作用或滥用可能性的非特异性全身药物。最近的研究表明，T 通道的 CaV3.2 亚型通过增强 1 型和 2 型 PDN 动物模型中伤害感受器的兴奋性，对疼痛反应的敏化做出了以前未被认识到的贡献。此外，据报道，糖基化抑制剂神经氨酸酶可以在体外抑制天然和重组CaV3.2 T电流，并在体内完全逆转患有PDN的糖尿病动物的机械和热痛觉过敏。了解通过糖基化对伤害性通道活性进行翻译后调节的细节可能有助于开发治疗疼痛性 PDN 的新疗法。针对特定致病机制而不是通道本身的药理学可能会减少糖尿病患者的副作用并降低药物滥用的可能性。
Pain-sensing sensory neurons (nociceptors) of the dorsal root ganglion (DRG) can become sensitized (hyperexcitable) in response to pathological conditions such as diabetes, which in turn may lead to the development of painful peripheral diabetic neuropathy (PDN). Because of insufficient knowledge about the mechanisms for this hypersensitization, current treatment for painful PDN has been limited to somewhat nonspecific systemic drugs having significant side effects or potential for abuse. Recent studies have established that the CaV3.2 isoform of T-channels makes a previously unrecognized contribution to sensitization of pain responses by enhancing excitability of nociceptors in animal models of type 1 and type 2 PDN. Furthermore, it has been reported that the glycosylation inhibitor neuraminidase can inhibit the native and recombinant CaV3.2 T-currents in vitro and completely reverse mechanical and thermal hyperalgesia in diabetic animals with PDN in vivo. Understanding details of posttranslational regulation of nociceptive channel activity via glycosylation may facilitate development of novel therapies for treatment of painful PDN. Pharmacological targeting the specific pathogenic mechanism rather than the channel per se may cause fewer side effects and reduce the potential for drug abuse in patients with diabetes.