Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807378, Taiwan.
Department of Anesthesiology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807378, Taiwan.
Medicina (Kaunas). 2023 Mar 11;59(3):553. doi: 10.3390/medicina59030553.
Our previous study demonstrated that consistent treatment of oral cilostazol was effective in reducing levels of painful peripheral neuropathy in streptozotocin-induced type I diabetic rats. As diabetic neuropathy is characterized by hyperglycemia-induced nerve damage in the periphery, this study aims to examine the neuropathology as well as the effects of cilostazol treatments on the integrity of peripheral small nerve fibers in type I diabetic rats. A total of ninety adult male Sprague-Dawley rats were divided into the following groups: (1) naïve (control) group; (2) diabetic rats (DM) group for 8 weeks; DM rats receiving either (3) 10 mg/kg oral cilostazol (Cilo10), (4) 30 mg/kg oral cilostazol (Cilo30), or (5) 100 mg/kg oral cilostazol (Cilo100) for 6 weeks. Pain tolerance thresholds of hind paws toward thermal and mechanical stimuli were assessed. Expressions of PGP9.5, P2X3, CGRP, and TRPV-1 targeting afferent nerve fibers in hind paw skin and glial cells in the spinal dorsal horn were examined via immunohistochemistry and immunofluorescence. Oral cilostazol ameliorated the symptoms of mechanical allodynia but not thermal analgesia in DM rats. Significant reductions in PGP9.5-, P2X3-, CGRP, and TRPV-1-labeled penetrating nerve fibers in the epidermal layer indicated denervation of sensory nerves in the hind paw epidermis of DM rats. Denervation significantly improved in groups that received Cilo30 and Cilo100 in a dose-dependent manner. Cilostazol administration also suppressed microglial hyperactivation and increased astrocyte expressions in spinal dorsal horns. Oral cilostazol ameliorated hyperglycemia-induced peripheral small nerve fiber damage in the periphery of diabetic rats and effectively mitigated diabetic neuropathic pain via a central sensitization mechanism. Our findings present cilostazol not only as an effective option for managing symptoms of neuropathy but also for deterring the development of diabetic neuropathy in the early phase of type I diabetes.
我们之前的研究表明，持续治疗口腔西洛他唑可有效降低链脲佐菌素诱导的 I 型糖尿病大鼠周围性痛性神经病变的水平。由于糖尿病性神经病的特征是周围高血糖诱导的神经损伤，因此本研究旨在检查神经病理学以及西洛他唑治疗对 I 型糖尿病大鼠周围小神经纤维完整性的影响。共 90 只成年雄性 Sprague-Dawley 大鼠分为以下几组：（1）未处理（对照）组；（2）8 周糖尿病大鼠（DM）组；DM 大鼠分别给予（3）10mg/kg 西洛他唑（Cilo10）、（4）30mg/kg 西洛他唑（Cilo30）或（5）100mg/kg 西洛他唑（Cilo100）治疗 6 周。评估后爪对热和机械刺激的疼痛耐受阈值。通过免疫组织化学和免疫荧光法检查后爪皮肤和脊髓背角神经胶质细胞中 PGP9.5、P2X3、CGRP 和 TRPV-1 靶向传入神经纤维的表达。口腔西洛他唑改善了 DM 大鼠机械性痛觉过敏的症状，但对热痛觉无影响。DM 大鼠后爪表皮层 PGP9.5、P2X3、CGRP 和 TRPV-1 标记穿透神经纤维的显著减少表明感觉神经在 DM 大鼠后爪表皮中的去神经支配。去神经支配在接受 Cilo30 和 Cilo100 治疗的组中以剂量依赖性方式显著改善。西洛他唑给药还抑制了脊髓背角的小胶质细胞过度激活和星形胶质细胞表达的增加。口腔西洛他唑改善了糖尿病大鼠周围小神经纤维在周围的损伤，并通过中枢敏化机制有效减轻糖尿病性神经痛。我们的研究结果表明，西洛他唑不仅是治疗神经病变症状的有效选择，而且在 I 型糖尿病早期阶段也可防止糖尿病性神经病的发展。
