The Ameliorative Effect of Empagliflozin in Vigabatrin-Induced Cerebellar/Neurobehavioral Deficits: Targeting mTOR/AMPK/SIRT-1 Signaling Pathways

Abstract

Introduction. Vigabatrin (VGB) is an antiepileptic drug that acts to irreversibly inhibit the γ-aminobutyric acid (GABA) transaminase enzyme, elevating GABA levels. Broad studies have established that long-term treatment and/or high doses of VGB lead to variable visual defects. However, little attention has been paid to its other side effects, especially those demonstrating cerebellar involvement. Sodium glucose-linked co-transporter 2 (SGLT2) inhibitors are antidiabetic agents with protective effects far greater than expected based on their anti-hyperglycemic effect. Method. Our study herein was designed to investigate the possible ameliorative effect of empagliflozin, the SGLT2 inhibitors, in VGB-induced cerebellar toxicity. A total of 40 male Wistar rats were allocated equally into 4 groups: Group I: control group; Group II: VGB group; Group III empagliflozin treated VGB group; and Group IV: empagliflozin treated group. All groups were subjected to the detection of cerebellar messenger RNA gene expression of silent mating type information regulation 2 homolog 1 (SIRT1) and Nucleoporin p62 (P62). Mammalian target of rapamycin (mTOR), adenosine monophosphate-activated protein kinase (AMPK), and beclin1 levels were assessed by the ELISA technique while malondialdehyde (MDA) level and superoxide dismutase (SOD) activity were detected spectrophotometrically. Immuno-histochemical studies, focusing on glial fibrillary acidic protein (GFAP) and S100 were performed, and the optical color density and the mean area percentage of GFAP positive astrocytes and the number of S 100 positive cells were also counted. Results. Following empagliflozin treatment, we documented significant upregulation of both SIRT1 and P62 mRNA gene expression. Additionally, AMPK, Beclin1 levels, and SOD activity were significantly improved, while both mTOR and MDA levels were significantly reduced. Conclusions. We concluded for the first time that empagliflozin efficiently ameliorated the VGB-induced disrupted mTOR/AMPK/SIRT-1 signaling axis with subsequent improvement of the autophagy machinery and mitigation of the oxidative and inflammatory cellular environment, paving the way for an innovative therapeutic potential in managing VGB-induced neurotoxicity.

SIRT1 mediates the inhibitory effect of Dapagliflozin on EndMT by inhibiting the acetylation of endothelium Notch1

“…Molecular docking, pull-down assays, and CETSA experiments confirm the direct targeting effect of DAPA on SIRT1. In addition to DAPA, other types of SGLT-2 inhibitors, such as Ipragliflozin, Canagliflozin, and Empagliflozin, exhibit the up-regulation of SIRT1 expression and modulation of energy metabolism and mitochondrial function [ 41 – 43 ]. However, apart from our study, the direct targeting of SIRT1 by other SGLT-2 inhibitors has not been previously reported.…”

Synergistic effects of GABA and hypoglycemic drugs

“…Сочетанное применение ГАМК и ингибиторов НГЛТ-2 приводит к повышению экспрессии БК при СД и к активации сигнальной системы TOR/AMPK/SIRT-1, подавлению апоптоза и гибели β-клеток, усилению их регенерации и повышению секреции инсулина. Это объясняет множественные положительные свойства ингибиторов НГЛТ-2: эндотелио-, ангио-, кардио-, нефро-, нейро- и энцефалопротективное действие [ 21 ][ 33 ][ 49 ][ 57 ]. Эмпаглифлозин значительно усиливал экспрессию и активность белка Клото у животных с почечным фиброзом, у которых снижена экспрессия БК.…”