Dapagliflozin as an autophagic enhancer via LKB1/AMPK/SIRT1 pathway in ovariectomized/d-galactose Alzheimer’s rat model

Abstract

Autophagy and mitochondrial deficits are characteristics of early phase of Alzheimer’s disease (AD). Sodium-glucose cotransporter-2 inhibitors have been nominated as a promising class against AD hallmarks. However, there are no available data yet to discuss the impact of gliflozins on autophagic pathways in AD. Peripherally, dapagliflozin’s (DAPA) effect is mostly owed to autophagic signals. Thus, the goal of this study is to screen the power of DAPA centrally on LKB1/AMPK/SIRT1/mTOR signaling in the ovariectomized/d-galactose (OVX/d-Gal) rat model. Animals were arbitrarily distributed between 5 groups; the first group undergone sham operation, while remaining groups undergone OVX followed by d-Gal (150 mg/kg/day; i.p.) for 70 days. After 6 weeks, the third, fourth, and fifth groups received DAPA (1 mg/kg/day; p.o.); concomitantly with the AMPK inhibitor dorsomorphin (DORSO, 25 µg/rat, i.v.) in the fourth group and the SIRT1 inhibitor EX-527 (10 µg/rat, i.v.) in the fifth group. DAPA mitigated cognitive deficits of OVX/d-Gal rats, as mirrored in neurobehavioral task with hippocampal histopathological examination and immunohistochemical aggregates of p-Tau. The neuroprotective effect of DAPA was manifested by elevation of energy sensors; AMP/ATP ratio and LKB1/AMPK protein expressions along with autophagic markers; SIRT1, Beclin1, and LC3B expressions. Downstream the latter, DAPA boosted mTOR and mitochondrial function; TFAM, in contrary lessened BACE1. Herein, DORSO or EX-527 co-administration prohibited DAPA’s actions where DORSO elucidated DAPA’s direct effect on LKB1 while EX-527 mirrored its indirect effect on SIRT1. Therefore, DAPA implied its anti-AD effect, at least in part, via boosting hippocampal LKB1/AMPK/SIRT1/mTOR signaling in OVX/d-Gal rat model. Graphical abstract

Cognitive enhancing effects of pazopanib in D‑galactose/ovariectomized Alzheimer’s rat model: insights into the role of RIPK1/RIPK3/MLKL necroptosis signaling pathway

“…Long-term D-Gal administration along with OVX represents an excellent experimental model for AD simulating the behavioral, neurochemical, and pathological manifestations detected in AD (Hua et al 2007 ). Indeed, various studies have successfully utilized this model to induce AD-like features in experimental animals (Ibrahim et al 2019 , 2022 ; Abd El-Rahman and Fayed 2022 ). In the present investigation, D-Gal/OVX rats demonstrated marked cognitive deterioration and memory dysfunction manifested via their performance in the MWM test and the observed histological alterations.…”

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

“…Also, Lu et al ( 2020 ) showed that EMPA could activate AMPK by stimulating its upstream activator, liver kinase B1(LKB1). In addition, Ibrahim et al ( 2022 ) reported that the SGLT-2 inhibitor dapagliflozin directly phosphorylated LKB1, leading to increased hippocampal expression of p-AMPK in the ovariectomized/D-galactose rat model of Alzheimer’s disease.…”

Neuroprotective potential of Erigeron bonariensis ethanolic extract against ovariectomized/D-galactose-induced memory impairments in female rats in relation to its metabolite fingerprint as revealed using UPLC/MS

“…Group I (SO): sham operation (SO) was conducted on rats and served as the control group. In group II (OVX/D-Gal), bilateral ovariectomy (OVX) was performed on rats according to the operation method discussed by Salama et al ( 2021 ) and after a recovery period of 5 days, they received daily intraperitoneal injection of D-Gal (150 mg/kg) for 42 days (Ibrahim et al 2022 ; El Sayed et al 2023 ). Group III (Donepezil): OVX/D-Gal-subjected rats received donepezil (5 mg/kg/day) (Ademosun et al 2022 ) orally for 42 days, given 1 h prior to D-Gal administration.…”