Preclinical studies indicate that diverse muscarinic receptor antagonists, acting via the M₁ sub-type, promote neuritogenesis from sensory neurons in vitro and prevent and/or reverse both structural and functional indices of neuropathy in rodent models of diabetes. We sought to translate this as a potential therapeutic approach against structural and functional indices of diabetic neuropathy using oxybutynin, a muscarinic antagonist approved for clinical use against overactive bladder. Studies were performed using sensory neurons maintained in vitro, rodent models of type 1 or type 2 diabetes and human subjects with type 2 diabetes and confirmed neuropathy. Oxybutynin promoted significant neurite outgrowth in sensory neuron cultures derived from adult normal rats and STZ-diabetic mice, with maximal efficacy in the 1–100 nmol/l range. This was accompanied by a significantly enhanced mitochondrial energetic profile as reflected by increased basal and maximal respiration and spare respiratory capacity. Systemic (3–10 mg/kg/day s.c.) and topical (3% gel daily) oxybutynin reversed paw heat hypoalgesia in the STZ and db/db mouse models of diabetes and reversed paw tactile allodynia in STZ-diabetic rats. Loss of nerve profiles in the skin and cornea of db/db mice was also prevented by daily topical delivery of 3% oxybutynin for 8 weeks. A randomized, double-blind, placebo-controlled interventional trial was performed in subjects with type 2 diabetes and established peripheral neuropathy. Subjects received daily topical treatment with 3% oxybutynin gel or placebo for 6 months. The a priori designated primary endpoint, significant change in intra-epidermal nerve fibre density (IENFD) in skin biopsies taken before and after 20 weeks of treatments, was met by oxybutynin but not placebo. Secondary endpoints showing significant improvement with oxybutynin treatment included scores on clinical neuropathy, pain and quality of life scales. This proof-of-concept study indicates that muscarinic antagonists suitable for long-term use may offer a novel therapeutic opportunity for treatment of diabetic neuropathy. Trial registry number: NCT03050827.

临床前研究表明，多种毒蕈碱受体拮抗剂通过 M ₁亚型发挥作用，在体外促进感觉神经元的神经突发生，并预防和/或逆转糖尿病啮齿动物模型中神经病变的结构和功能指标。我们试图将其转化为一种潜在的治疗方法，使用奥昔布宁来治疗糖尿病神经病变的结构和功能指标，奥昔布宁是一种被批准用于临床治疗膀胱过度活动症的毒蕈碱拮抗剂。研究使用体外维持的感觉神经元、1 型或 2 型糖尿病的啮齿动物模型以及患有 2 型糖尿病并确诊神经病变的人类受试者进行。奥昔布宁促进成年正常大鼠和 STZ 糖尿病小鼠的感觉神经元培养物中显着的神经突生长，在 1-100 nmol/l 范围内具有最大功效。伴随着线粒体能量分布的显着增强，反映为基础呼吸和最大呼吸以及备用呼吸能力的增加。全身（3-10 mg/kg/天，皮下注射）和局部（每天 3% 凝胶）奥昔布宁可逆转 STZ 和 db/db 糖尿病小鼠模型中的爪热痛觉减退，并逆转 STZ 糖尿病大鼠中的爪触觉异常性疼痛。连续 8 周每天局部施用 3% 奥昔布宁也可以防止 db/db 小鼠皮肤和角膜神经分布的丧失。在患有 2 型糖尿病并已确诊周围神经病变的受试者中进行了一项随机、双盲、安慰剂对照的干预试验。受试者每天接受 3% 奥昔布宁凝胶或安慰剂的局部治疗，持续 6 个月。先验指定的主要终点，即治疗 20 周前后皮肤活检中表皮内神经纤维密度 (IENFD) 的显着变化，奥昔布宁满足了这一要求，但安慰剂却没有满足这一要求。奥昔布宁治疗显着改善的次要终点包括临床神经病变、疼痛和生活质量量表的评分。这项概念验证研究表明，适合长期使用的毒蕈碱拮抗剂可能为治疗糖尿病神经病变提供新的治疗机会。试验注册号：NCT03050827。