Saleh Nada K, Farrag Sama M, El-Yamany Mohamed F, Kamel Ahmed S
Pharmacology and Toxicology Department, Faculty of Pharmacy, Cairo University, Cairo, 11562, Egypt.
Pharmacology and Toxicology Department, College of Pharmaceutical Sciences and Drug Manufacturing, Misr University for Science and Technology (MUST), Giza, Egypt.
J Neuroimmune Pharmacol. 2025 May 22;20(1):57. doi: 10.1007/s11481-025-10218-1.
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 receptor-associated protein (GABARAP), facilitating the surface presentation of GABA receptors. Additionally, DAPA upregulated the GABA 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.
躁狂样发作是与双相情感障碍（BD）相关的神经精神障碍。自噬流紊乱已成为与躁狂症相关的分子机制之一。最近，达格列净（DAPA）已在几种神经系统疾病中纠正了自噬信号。然而，尚未有研究探讨DAPA对躁狂样行为的自噬影响。本研究旨在调查DAPA对躁狂样行为小鼠模型中自噬途径破坏的影响。使用多平台方法通过矛盾睡眠剥夺（PSD）诱导躁狂样行为36小时。将小鼠分为三组，给予DAPA（1mg/kg/天，口服）一周。在第7天进行行为评估。DAPA减轻了旷场试验中的焦虑样行为，并改善了转棒试验中的运动协调性和肌肉张力。机制上，DAPA激活了海马自噬相关标志物；肝激酶B1/AMP激活蛋白激酶（LKB1/AMPK）途径、自噬相关基因7（ATG7）和微管相关蛋白轻链3II（LC3II）。这与自噬体受体p62蛋白水平降低有关，随后增强了GABA受体相关蛋白（GABARAP），促进了GABA受体的表面表达。此外，DAPA通过脑源性神经营养因子（BDNF）和胶质细胞系源性神经营养因子（GDNF）等营养因子上调了GABA受体R2亚基。此外，DAPA减轻了血清应激激素的升高，并恢复了皮质和海马组织中促炎细胞因子和抗炎细胞因子之间的平衡。这些发现突出了DAPA对自噬流调节的作用及其在减轻躁狂样行为方面的治疗潜力。
