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Noha F. Abdelkader,Marawan A. Elbaset,Passant E. Moustafa,Sherehan M. Ibrahim 대한약학회 2022 Archives of Pharmacal Research Vol.45 No.7
Diabetic peripheral neuropathy (DPN) representsa severe microvascular condition that dramatically affectsdiabetic patients despite adequate glycemic control, resultingin high morbidity. Thus, recently, anti-diabetic drugsthat possess glucose-independent mechanisms attractedattention. This work aims to explore the potentiality of theselective sodium-glucose cotransporter-2 inhibitor, empagliflozin (EMPA), to ameliorate streptozotocin-induced DPNin rats with insight into its precise signaling mechanism. Rats were allocated into four groups, where control animalsreceived vehicle daily for 2 weeks. In the remaining groups,DPN was elicited by single intraperitoneal injections offreshly prepared streptozotocin and nicotinamide (52.5 and50 mg/kg, respectively). Then EMPA (3 mg/kg/p.o.) wasgiven to two groups either alone or accompanied with theAMPK inhibitor dorsomorphin (0.2 mg/kg/i.p.). Despite thenon-significant anti-hyperglycemic effect, EMPA improvedsciatic nerve histopathological alterations, scoring, myelination,nerve fibers’ count, and nerve conduction velocity. Moreover, EMPA alleviated responses to different nociceptivestimuli along with improved motor coordination. EMPAmodulated ATP/AMP ratio, upregulated p-AMPK whilereducing p-p38 MAPK expression, p-ERK1/2 and consequentlyp-NF-κB p65 as well as its downstream mediators (TNF-α and IL-1β), besides enhancing SOD activity andlowering MDA content. Moreover, EMPA downregulatedmTOR and stimulated ULK1 as well as beclin-1. Likewise,EMPA reduced miR-21 that enhanced RECK, reducingMMP-2 and -9 contents. EMPA’s beneficial effects werealmost abolished by dorsomorphin administration. In conclusion,EMPA displayed a protective effect against DPNindependently from its anti-hyperglycemic effect, probablyvia modulating the AMPK pathway to modulate oxidativeand inflammatory burden, extracellular matrix remodeling,and autophagy.