Exploring Dapagliflozin's Influence on Autophagic Flux in Mania-like Behaviour: Insights from the LKB1/AMPK/LC3 Pathway in a Mouse Model.

Abstract

Mania-like episodes are neuropsychiatric disturbances associated with bipolar disorder (BD). Autophagic flux disturbance evolved as one of the molecular mechanisms implicated in mania. Recently, Dapagliflozin (DAPA) has corrected autophagic signaling in several neurological disorders. Yet, no endeavours examined the autophagic impact of DAPA in mania-like behaviours. This study aimed to investigate the effect of DAPA on disrupted autophagic pathways in a mouse model of mania-like behaviour. Mania-like behaviour was induced through paradoxical sleep deprivation (PSD) using the multiple-platform method for a duration of 36 h. Mice were divided into three groups, with DAPA (1 mg/kg/day, orally) administered for one week. Behavioural assessments were conducted on the 7th day. DAPA mitigated anxiety-like behaviour in the open field test and improved motor coordination and muscle tone in the rotarod test. Mechanistically, DAPA activated hippocampal autophagy-related markers; liver kinase B1/AMP-activated protein kinase (LKB1/AMPK) pathway, autophagy related gene 7 (ATG7), and microtubule-associated protein light chain 3II (LC3II). This was associated with reduced levels of the autophagosome receptor p62 protein, which subsequently enhanced GABA_A receptor-associated protein (GABARAP), facilitating the surface presentation of GABA_A receptors. Additionally, DAPA upregulated the GABA_B receptor R2 subunit through trophic factors such as brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF). Furthermore, DAPA mitigated elevated serum stress hormones and restored the balance between proinflammatory and anti-inflammatory cytokines in both cortical and hippocampal tissues. These findings highlight the role of autophagic flux modulation by DAPA and its therapeutic potential in mitigating mania-like behaviours.