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.
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。