Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Kasr El-Aini St., Cairo, 11562, Egypt.
Medical Research and Clinical Studies Institute, Pharmacology, National Research Centre, Giza, Egypt.
Arch Pharm Res. 2022 Jul;45(7):475-493. doi: 10.1007/s12272-022-01391-5. Epub 2022 Jun 29.
Diabetic peripheral neuropathy (DPN) represents a severe microvascular condition that dramatically affects diabetic patients despite adequate glycemic control, resulting in high morbidity. Thus, recently, anti-diabetic drugs that possess glucose-independent mechanisms attracted attention. This work aims to explore the potentiality of the selective sodium-glucose cotransporter-2 inhibitor, empagliflozin (EMPA), to ameliorate streptozotocin-induced DPN in rats with insight into its precise signaling mechanism. Rats were allocated into four groups, where control animals received vehicle daily for 2 weeks. In the remaining groups, DPN was elicited by single intraperitoneal injections of freshly prepared streptozotocin and nicotinamide (52.5 and 50 mg/kg, respectively). Then EMPA (3 mg/kg/p.o.) was given to two groups either alone or accompanied with the AMPK inhibitor dorsomorphin (0.2 mg/kg/i.p.). Despite the non-significant anti-hyperglycemic effect, EMPA improved sciatic nerve histopathological alterations, scoring, myelination, nerve fibers' count, and nerve conduction velocity. Moreover, EMPA alleviated responses to different nociceptive stimuli along with improved motor coordination. EMPA modulated ATP/AMP ratio, upregulated p-AMPK while reducing p-p38 MAPK expression, p-ERK1/2 and consequently p-NF-κB p65 as well as its downstream mediators (TNF-α and IL-1β), besides enhancing SOD activity and lowering MDA content. Moreover, EMPA downregulated mTOR and stimulated ULK1 as well as beclin-1. Likewise, EMPA reduced miR-21 that enhanced RECK, reducing MMP-2 and -9 contents. EMPA's beneficial effects were almost abolished by dorsomorphin administration. In conclusion, EMPA displayed a protective effect against DPN independently from its anti-hyperglycemic effect, probably via modulating the AMPK pathway to modulate oxidative and inflammatory burden, extracellular matrix remodeling, and autophagy.
糖尿病周围神经病变（DPN）是一种严重的微血管疾病，即使糖尿病患者的血糖得到了很好的控制，它仍会导致很高的发病率，严重影响患者的生活质量。因此，近年来，人们对具有葡萄糖非依赖性机制的抗糖尿病药物产生了兴趣。本工作旨在探讨选择性钠-葡萄糖共转运蛋白 2 抑制剂恩格列净（EMPA）改善链脲佐菌素诱导的大鼠 DPN 的潜力，并深入了解其确切的信号机制。大鼠被分为四组，其中对照组动物每天给予载体 2 周。在其余组中，通过单次腹腔注射新鲜制备的链脲佐菌素和烟酰胺（分别为 52.5 和 50mg/kg）诱发 DPN。然后将 EMPA（3mg/kg，po）单独或与 AMPK 抑制剂 dorsomorphin（0.2mg/kg，ip）一起给予两组。尽管 EMPA 对血糖无明显的降血糖作用，但它改善了坐骨神经组织病理学改变、评分、髓鞘形成、神经纤维计数和神经传导速度。此外，EMPA 减轻了对不同伤害性刺激的反应，并改善了运动协调能力。EMPA 调节 ATP/AMP 比值，上调 p-AMPK，同时降低 p-p38 MAPK 表达、p-ERK1/2 以及随后的 p-NF-κB p65 及其下游介质（TNF-α和 IL-1β），同时还增强了 SOD 活性，降低了 MDA 含量。此外，EMPA 下调了 mTOR，并刺激了 ULK1 和 beclin-1。同样，EMPA 降低了 miR-21，从而增强了 RECK，降低了 MMP-2 和 -9 的含量。Dorsomorphin 的给药几乎消除了 EMPA 的有益作用。总之，EMPA 表现出对 DPN 的保护作用，这种作用独立于其降血糖作用，可能是通过调节 AMPK 通路来调节氧化和炎症负担、细胞外基质重塑和自噬。
