TLR-4/Notch1/NF-κB pathway modulation by dapagliflozin: a novel mechanism for neuroprotection in hepatic encephalopathy

Abstract

Acute or chronic liver damage can result in Hepatic Encephalopathy (HE), a potentially fatal neuropsychiatric condition that leads to cerebral and neurological alterations. Dapagliflozin (DAPA), an orally active Sodium/Glucose cotransporter 2 inhibitor with long duration of action. The study aim was to evaluate the potential protective impact of DAPA against HE caused by Thioacetamide (TAA) in rats. HE was achieved via a single intraperitoneal TAA dosage of (300 mg/kg). DAPA was administered orally as (1 mg/kg) for 28 days. A total of forty rats were distributed randomly into 4 equal groups: Control (CTRL), Dapagliflozin (DAPA + CTRL), Thioacetamide (TAA), and Dapagliflozin plus Thioacetamide (DAPA + TAA). TAA induced cognitive impairment was alleviated by DAPA, as evidenced by reduction by 63% in escape latency of Morris water maze (MWM) test, elevation in fall off period of Rotarod test, and reduced serum ammonia, Liver enzymes, and restore normal serum albumin levels. DAPA improved the antioxidant capacity and activity of Glutathione by 87.53%; reduced apoptosis, liver necrosis, and astrocyte inflammation. Moreover, DAPA administration reduced gene expression of both Notch1 by 50% and TLR-4 by 55.65% suppressing release of inflammatory cytokines. In conclusion, DAPA possesses a neuroprotective effect, as confirmed by the enhancement of motor incoordination, cognitive deficits, and histopathological alterations. This neuroprotective impact can be justified by lowering hyperammonemia, improving liver functions, in addition to its antioxidant effect, and suppression of TLR-4/Notch1/NF-κB inflammatory pathway.