Unidad Académica Multidisciplinaria Reynosa-Aztlán, Universidad Autónoma de Tamaulipas, Calle 16 y Lago de Chapala, Col. Aztlán, Reynosa, Tamaulipas, C.P.88740, Mexico.
Pharmacol Rep. 2024 Oct;76(5):1079-1088. doi: 10.1007/s43440-024-00634-0. Epub 2024 Aug 19.
Type-1 diabetes mellitus (T1DM) is associated with numerous health problems, including peripheral neuropathy, osteoporosis, and bone denervation, all of which diminish quality of life. However, there are relatively few therapies to treat these T1DM-related complications. Recent studies have shown that Janus kinase (JAK) inhibitors reverse aging- and rheumatoid arthritis-induced bone loss and reduce pain associated with peripheral nerve injuries, and rheumatoid arthritis. Thus, we assessed whether a JAK1/JAK2 inhibitor, baricitinib, ameliorates mechanical pain sensitivity (a measure of peripheral neuropathy), osteoporosis, and bone denervation in the femur of mice with T1DM.
Female ICR mice (13 weeks old) received five daily administrations of streptozotocin (ip, 50 mg/kg) to induce T1DM. At thirty-one weeks of age, mice were treated with baricitinib (po; 40 mg/kg/bid; for 28 days) or vehicle. Mechanical sensitivity was evaluated at 30, 33, and 35 weeks of age on the plantar surface of the right hind paw. At the end of the treatment, mice were sacrificed, and lower extremities were harvested for microcomputed tomography and immunohistochemistry analyses.
Mice with T1DM exhibited greater blood glucose levels, hind paw mechanical hypersensitivity, trabecular bone loss, and decreased density of calcitonin gene-related peptide-positive and tyrosine hydroxylase-positive axons within the marrow of the femoral neck compared to control mice. Baricitinib treatment significantly reduced mechanical hypersensitivity and ameliorated sensory and sympathetic denervation at the femoral neck, but it did not reverse trabecular bone loss.
Our findings suggest that baricitinib may represent a new therapeutic alternative to treat T1DM-induced peripheral neuropathy and bone denervation.
1 型糖尿病（T1DM）与许多健康问题相关，包括周围神经病变、骨质疏松症和骨去神经支配，所有这些都会降低生活质量。然而，用于治疗这些 T1DM 相关并发症的疗法相对较少。最近的研究表明，Janus 激酶（JAK）抑制剂可逆转衰老和类风湿关节炎引起的骨丢失，并减轻周围神经损伤和类风湿关节炎引起的疼痛。因此，我们评估了 JAK1/JAK2 抑制剂巴瑞替尼是否可以改善 T1DM 小鼠股骨的机械性疼痛敏感性（周围神经病变的一种测量方法）、骨质疏松症和骨去神经支配。
13 周龄雌性 ICR 小鼠（ICR 小鼠，白化实验鼠，广泛应用于药理学、毒理学等研究领域）接受五次链脲佐菌素（ip，50mg/kg）注射以诱导 T1DM。在 31 周龄时，用巴瑞替尼（po；40mg/kg/天，bid；共 28 天）或载体处理小鼠。在右后爪足底表面上，于 30、33 和 35 周龄评估机械敏感性。在治疗结束时，处死小鼠并采集下肢进行 microCT 和免疫组织化学分析。
与对照小鼠相比，患有 T1DM 的小鼠表现出更高的血糖水平、后爪机械性超敏反应、小梁骨丢失以及降钙素基因相关肽阳性和酪氨酸羟化酶阳性轴突在股骨颈骨髓内的密度降低。巴瑞替尼治疗显著降低了机械性超敏反应，并改善了股骨颈的感觉和交感神经去神经支配，但并未逆转小梁骨丢失。
我们的研究结果表明，巴瑞替尼可能代表治疗 T1DM 引起的周围神经病变和骨去神经支配的一种新的治疗选择。
