Armstrong David G, Bley Keith, Simpson David M, Staats Peter, Allen Samuel, Carnevale Audrey, Marcondes Lizandra
Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
Pyrotech Therapeutics, Inc., Beijing, People's Republic of China.
J Exp Pharmacol. 2025 Sep 9;17:651-665. doi: 10.2147/JEP.S526968. eCollection 2025.
Diabetic peripheral neuropathy (DPN) is a chronic, progressive complication of diabetes. Pain in DPN can be severe and detrimental to the patient's quality of life. In this review, we provide an update on the mechanism of action (MOA) of high-concentration capsaicin topical system (HCCTS) for treatment of painful DPN, with an emphasis on neuroregeneration. In diabetes, hyperglycemia and other metabolic imbalances lead to oxidative stress and inflammation, which result in degeneration of the axons of afferent neurons (particularly C and Aδ fibers) within the peripheral nervous system. Dysfunction of the microvasculature supporting the nerves further exacerbates neural damage. As a result, epidermal nerve fiber density (ENFD) diminishes, and physical and chemical changes to the remaining afferent fibers render them hypersensitive to painful stimuli and hyposensitive to normal stimuli. As the longest axons are usually damaged first, DPN normally begins in the feet, then legs, and finally the hands. HCCTS incorporates a matrix technology that forcibly diffuses a high concentration of capsaicin (a TRPV1 agonist) to the dermis and epidermis, targeting TRPV1 receptors that are upregulated in DPN and play a key role in pain generation. HCCTS activates TRPV1 receptors expressed on the neuron cell membrane and endoplasmic reticulum, leading to cytoplasmic calcium ion overload, and then a cascade of cellular events resulting in reversible neurolysis of these afferent terminals. After 1-3 months, the terminals regenerate with a "healthier" phenotype, increasing ENFD, resulting in vasodilation, which may lead to a microenvironment conducive to improved neuroregeneration. This MOA is supported by clinical evidence demonstrating that repeated HCCTS treatment provides cumulative benefits in pain and improvements in sensory function of the feet compared with baseline. If effects on sensory function are confirmed in large-scale clinical studies, HCCTS could help slow the progression of DPN to more severe forms of diabetic foot syndrome.
糖尿病性周围神经病变（DPN）是糖尿病的一种慢性、进行性并发症。DPN中的疼痛可能很严重，会对患者的生活质量产生不利影响。在本综述中，我们提供了关于高浓度辣椒素局部系统（HCCTS）治疗疼痛性DPN的作用机制（MOA）的最新信息，重点是神经再生。在糖尿病中，高血糖和其他代谢失衡会导致氧化应激和炎症，从而导致外周神经系统内传入神经元（特别是C纤维和Aδ纤维）的轴突退化。支持神经的微血管功能障碍会进一步加剧神经损伤。结果，表皮神经纤维密度（ENFD）降低，剩余传入纤维的物理和化学变化使其对疼痛刺激高度敏感，对正常刺激敏感度降低。由于最长的轴突通常最先受损，DPN通常始于足部，然后是腿部，最后是手部。HCCTS采用了一种基质技术，将高浓度辣椒素（一种TRPV1激动剂）强行扩散到真皮和表皮，靶向DPN中上调且在疼痛产生中起关键作用的TRPV1受体。HCCTS激活神经元细胞膜和内质网上表达的TRPV1受体，导致细胞质钙离子过载，然后引发一系列细胞事件，导致这些传入神经末梢发生可逆性神经溶解。1至3个月后，这些末梢以“更健康”的表型再生，ENFD增加，导致血管舒张，这可能会形成有利于改善神经再生的微环境。这一作用机制得到了临床证据的支持，该证据表明，与基线相比，重复进行HCCTS治疗在疼痛方面具有累积益处，并能改善足部的感觉功能。如果在大规模临床研究中对感觉功能的影响得到证实，HCCTS可能有助于减缓DPN发展为更严重形式的糖尿病足综合征。
