Ameliorative effect of palonosetron against binge alcohol-induced neurodamage via targeting miR-155/AKT/mTOR/AMPK-mediated autophagic pathway

Abstract

Binge drinking (BD) is heavy episodic alcohol drinking that is progressively practiced. Vast evidence verified that BD elicits neuronal and cognitive impairments. Debilitated autophagic machinery is a key culprit in BD-induced neurotoxicity. Palonosetron is a potent selective serotonin 5-HT3 receptor antagonist whose impact on BD has not yet been scrutinized. Thus, the present study aimed at exposing the potentiality of palonosetron and its link with AKT/mTOR/AMPK/ULK1 pathway in the BD-rat model. Rats were divided into 4 groups; group 1 received saline and Vanilla Ensure® Plus, whereas groups 2, 3 and 4 received 20 % w/v ethanol in Vanilla Ensure® Plus (intragastric gavage) every 8 h for 4 days, concomitantly with palonosetron (0.1 mg/kg, twice daily; i.p.) in groups 3 and 4, and chloroquine (50 mg/kg/day; i.p.) in group 4. BD impaired memory, locomotor, and cognitive functions, with concomitant TNF-α and IL-1β elevation implicating neuroinflammation-driven cognitive decline. The former effect was, mechanistically, triggered by halting autophagy via augmenting hippocampal pAKT/tAKT, pmTOR/tmTOR and pULK1/tULK1 ratios, while reducing pAMPK/tAMPK, with resultant imbalance of the autophagic markers; Beclin-1, LC3-II/LC3-I, p62 and caspase-3. Aberrant upregulation of miRNA-155 was also detected and was markedly correlated to AKT/mTOR/AMPK and autophagy trajectories. Palonosetron treatment significantly alleviated all the aforementioned deviations. Histopathological analysis further corroborated palonosetron neuroprotective effect. Chloroquine, a classical autophagy inhibitor, blunted palonosetron-induced improvement. The identified parameters were validated using the ShinyGO-0.81 database for functional enrichment analysis and KEGG pathway mapping. For the first time, palonosetron is likely to offer a reliable neuroprotective effect in BD via orchestrating the crosstalk between miRNA-155 and AKT/mTOR/AMPK signaling cascade.