Empagliflozin mitigates type 2 diabetes-associated peripheral neuropathy: a glucose-independent effect through AMPK signaling

Abstract

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.

Neuroprotective Effect of Gold Nanoparticles and Alpha-Lipoic Acid Mixture against Radiation-Induced Brain Damage in Rats

“…A light microscope was used to examine sections of prepared slides stained with hematoxylin and eosin [ 85 ]. Examination of brain tissue sections was scored according to the degree of necrosis, hemorrhage, and vacuolations as follows: –, no visible abnormalities; +, mild; ++ moderate; +++, severely damaged [ 86 ].…”

Autophagy and its therapeutic potential in diabetic nephropathy

“…Sequestosome 1, known as p62, interacts with LC3II to confine autophagosomes and is repeatedly digested by the autophagy-lysosome system. Significantly, malfunctional autophagy during diabetes causes intracellular accumulation of p62 leading to further inhibition of autophagic flux, thus forming a vicious cycle to promote diabetic complications including diabetic cardiomyopathy, diabetic peripheral neuropathy and DN (20)(21)(22).…”

Current understanding on pathogenesis and effective treatment of glycogen storage disease type Ib with empagliflozin: new insights coming from diabetes for its potential implications in other metabolic disorders

“…Furthermore, empagliflozin improves redox state and oxidative stress, inhibiting reactive oxygen species (ROS) production, reducing the activity of pro-oxidant agents, and improving mitochondrial function (44). Of note, all these processes are implicated in the pathogenesis of metabolic, cardiovascular (CV), renal and neurological consequences of diabetes (42,45). Particularly, in diabetes and obesity the excessive circulating free fatty acids accumulate in the adipose tissue mainly as TG.…”

“…Moreover, it ameliorated motor coordination and mitigated responses to nociceptive stimuli (44). Empagliflozin displayed a protective effect against DPN via regulating the AMPK signaling to reduce oxidative and inflammatory burden, to regulate the extracellular matrix remodeling, and to stimulate autophagy (45,107). The authors hypothesized a restoration of energy levels, via AMPK activation, as in cardiomyocytes (63, 64).…”

“…The authors hypothesized a restoration of energy levels, via AMPK activation, as in cardiomyocytes (63, 64). Furthermore, mTor expression resulted reduced by 47% after empagliflozin administration in the sciatic nerve (45). mTOR inhibition might improve DPN through activation of autophagy to remove any damaged cellular constituents, thus increasing the myelin thickness and the myelinated axons (109) and reducing pain (110).…”