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Abstract：
OBJECTIVE: Vitamin D and rosuvastatin are well-known drugs that mediate beneficial effects in treating type-2 diabetes (T2D) complications; however, their anti-neuropathic potential is debatable. Hence, our study investigates their neurotherapeutic potential and the possible underlying mechanisms using a T2D-associated neuropathy rat model.
METHODS: Diabetic peripheral neuropathy (DPN) was induced with 8 weeks of administration of a high fat fructose diet followed by a single i.p. injection of streptozotocin (35 mg/kg). Six weeks later, DPN developed and rats were divided into five groups; viz., control, untreated DPN, DPN treated with vitamin D (cholecalciferol, 3500 IU/kg/week), DPN treated with rosuvastatin (10 mg/kg/day), or DPN treated with combination vitamin D and rosuvastatin. We determined their anti-neuropathic effects on small nerves (tail flick test); large nerves (electrophysiological and histological examination); neuronal inflammation (TNF-α and IL-18); apoptosis (caspase-3 activity and Bcl-2); mitochondrial function (NRF-1, TFAM, mtDNA, and ATP); and NICD1, Wnt-10α/β-catenin, and TGF-β/Smad-7 pathways.
RESULTS: Two-month treatment with vitamin D and/or rosuvastatin regenerated neuronal function and architecture and abated neuronal inflammation and apoptosis. This was verified by the inhibition of the neuronal content of TNF-α, IL-18, and caspase-3 activity, while augmenting Bcl-2 content in the sciatic nerve. These treatments inhibited the protein expressions of NICD1, Wnt-10α, β-catenin, and TGF-β; increased the sciatic nerve content of Smad-7; and enhanced mitochondrial biogenesis and function.
CONCLUSIONS: Vitamin D and/or rosuvastatin alleviated diabetes-induced neuropathy by suppressing Notch1 and Wnt-10α/β-catenin; modulating TGF-β/Smad-7 signaling pathways; and enhancing mitochondrial function, which lessened neuronal degeneration, demyelination, and fibrosis.
METHODS: Diabetic peripheral neuropathy (DPN) was induced with 8 weeks of administration of a high fat fructose diet followed by a single i.p. injection of streptozotocin (35 mg/kg). Six weeks later, DPN developed and rats were divided into five groups; viz., control, untreated DPN, DPN treated with vitamin D (cholecalciferol, 3500 IU/kg/week), DPN treated with rosuvastatin (10 mg/kg/day), or DPN treated with combination vitamin D and rosuvastatin. We determined their anti-neuropathic effects on small nerves (tail flick test); large nerves (electrophysiological and histological examination); neuronal inflammation (TNF-α and IL-18); apoptosis (caspase-3 activity and Bcl-2); mitochondrial function (NRF-1, TFAM, mtDNA, and ATP); and NICD1, Wnt-10α/β-catenin, and TGF-β/Smad-7 pathways.
RESULTS: Two-month treatment with vitamin D and/or rosuvastatin regenerated neuronal function and architecture and abated neuronal inflammation and apoptosis. This was verified by the inhibition of the neuronal content of TNF-α, IL-18, and caspase-3 activity, while augmenting Bcl-2 content in the sciatic nerve. These treatments inhibited the protein expressions of NICD1, Wnt-10α, β-catenin, and TGF-β; increased the sciatic nerve content of Smad-7; and enhanced mitochondrial biogenesis and function.
CONCLUSIONS: Vitamin D and/or rosuvastatin alleviated diabetes-induced neuropathy by suppressing Notch1 and Wnt-10α/β-catenin; modulating TGF-β/Smad-7 signaling pathways; and enhancing mitochondrial function, which lessened neuronal degeneration, demyelination, and fibrosis.
摘要：
目的：维生素D和瑞舒伐他汀是众所周知的药物，在治疗2型糖尿病（T2D）并发症中具有有益作用；然而，他们的抗神经病潜力是有争议的。因此，我们的研究使用T2D相关神经病变大鼠模型调查了他们的神经治疗潜力和可能的潜在机制.
方法:糖尿病性周围神经病变(DPN)是通过给予高脂肪果糖饮食8周,然后单次腹膜内注射链脲佐菌素(35mg/kg)诱导的。六周后,DPN发育，大鼠分为五组；即。,control,未经处理的DPN，DPN用维生素D治疗（胆钙化醇，3500IU/kg/周)，瑞舒伐他汀治疗DPN（10mg/kg/天），或维生素D和瑞舒伐他汀联合治疗DPN。我们确定了它们对小神经（甩尾试验）;大神经（电生理和组织学检查）;神经元炎症（TNF-α和IL-18）;细胞凋亡（caspase-3活性和Bcl-2）;线粒体功能（NRF-1，TFAM，mtDNA,和ATP）；和NICD1，Wnt-10α/β-catenin，和TGF-β/Smad-7途径。
结果：用维生素D和/或瑞舒伐他汀治疗2个月可再生神经元功能和结构，并减轻神经元炎症和凋亡。这通过抑制TNF-α的神经元含量得到证实，IL-18和caspase-3活性，同时增加坐骨神经中Bcl-2的含量。这些处理抑制了NICD1、Wnt-10α的蛋白表达,β-连环蛋白，和TGF-β；增加Smad-7的坐骨神经含量；并增强线粒体生物发生和功能。
结论：维生素D和/或瑞舒伐他汀通过抑制Notch1和Wnt-10α/β-catenin，调节TGF-β/Smad-7信号通路，增强线粒体功能，减轻糖尿病诱导的神经病变，减轻神经元变性，脱髓鞘,和纤维化。
方法:糖尿病性周围神经病变(DPN)是通过给予高脂肪果糖饮食8周,然后单次腹膜内注射链脲佐菌素(35mg/kg)诱导的。六周后,DPN发育，大鼠分为五组；即。,control,未经处理的DPN，DPN用维生素D治疗（胆钙化醇，3500IU/kg/周)，瑞舒伐他汀治疗DPN（10mg/kg/天），或维生素D和瑞舒伐他汀联合治疗DPN。我们确定了它们对小神经（甩尾试验）;大神经（电生理和组织学检查）;神经元炎症（TNF-α和IL-18）;细胞凋亡（caspase-3活性和Bcl-2）;线粒体功能（NRF-1，TFAM，mtDNA,和ATP）；和NICD1，Wnt-10α/β-catenin，和TGF-β/Smad-7途径。
结果：用维生素D和/或瑞舒伐他汀治疗2个月可再生神经元功能和结构，并减轻神经元炎症和凋亡。这通过抑制TNF-α的神经元含量得到证实，IL-18和caspase-3活性，同时增加坐骨神经中Bcl-2的含量。这些处理抑制了NICD1、Wnt-10α的蛋白表达,β-连环蛋白，和TGF-β；增加Smad-7的坐骨神经含量；并增强线粒体生物发生和功能。
结论：维生素D和/或瑞舒伐他汀通过抑制Notch1和Wnt-10α/β-catenin，调节TGF-β/Smad-7信号通路，增强线粒体功能，减轻糖尿病诱导的神经病变，减轻神经元变性，脱髓鞘,和纤维化。
