Dapagliflozin improves behavioral dysfunction of Huntington's disease in rats via inhibiting apoptosis-related glycolysis

Huntington's disease is a rare neurodegenerative disorder which is associated with defected glucose metabolism with consequent behavioral disturbance including memory and locomotion. 3-nitropropionic acid (3-NP) can cause, in high single dose, an acute striatal injury/Huntington's disease. Dapagliflozin, which is one of the longest duration of action of SGLTIs family, may be able to diminish that injury and its resultant behavioral disturbances. Forty rats were divided into four groups (n = 10 in each group): normal control group (CTRL), dapagliflozin (CTRL + DAPA) group, 3-nitropropionic acid (3-NP) group, and dapagliflozin plus 3-nitropropionic acid (DAPA + 3-NP) group. Behavioral tests (beam walking test, hanging wire test, limb withdrawal test, Y-maze spontaneous alteration, elevated plus maze) were performed with evaluating neurological scoring. In striatum, neurotransmitters (glutamate, aspartate, GABA, ACh and AChE activity) were measured. In addition, apoptosis and glycolysis markers (NF-κB, Cyt-c, lactate, HK-II activity, P53, calpain, PEA15 and TIGAR) were determined. Inflammation (IL-1β, IL-6, IL-8 and TNF-α) and autophagy (beclin-1, LC3 and DRAM) indicators were measured. Additionally, histopathological screening was conducted. 3-Nitropropionic acid had the ability to perturb the neurotransmission which was reflected in impaired behavioral outcome. All of glycolysis, apoptosis and inflammation markers were elevated after 3-NP acute intoxication but autophagy parameters, except DRAM, were reduced. However, DAPA markedly reversed the abovementioned parameters. Dapagliflozin demonstrated anti-glycolytic, anti-apoptotic, anti-inflammatory and autophagic effects on 3-NP-damaged striatal cells and promoted the behavioral outcome. •3-Nitropropionic acid acute intoxication is able to induce acute striatal damage/Huntington's disease.•3-Nitropropionic acid induced perturbations in neurotransmitters levels in striatum with consequent behavioral difficulties.•3-Nitropropionic acid-induced damage involves glycolysis, apoptosis, inflammation and defected autophagy.•Dapagliflozin abated 3-nitropropionic acid-induced acute striatal damage/Huntington's disease.