NO/cGMP/KATP Pathway and PPAR Receptors Contribution in MLR-1023 Neuroprotection in LPS-Induced Mice Model of AD

Background and Objective: The occurrence of neurodegenerative disease has increased because of relation between diabetes and Alzheimer’s disease. In this study, the effects of MLR-1023 (Tolimidone) on depression, hyperalgesia and hippocampal TNF-α level were studied in a model of Alzheimer’s disorder, produced by Lipopolysaccharide (LPS) injection. The role of PPARγ receptors and NO/cGMP/K_ATP-channels pathway was examined for determining likely engaged mechanisms. Materials and Methods: The AD mice model was made by LPS. The first stage was designed to find the effective dose of MLR-1023. In this stage, MLR-1023 (20, 30 and 40 mg/kg/i.p.) was given to treatment groups. The second stage is to show the potential mechanisms of mice pre-treated with their antagonist/agonist. Behavioral assay was performed including; Open-field assay, forced-swimming behavior and hot-plate exam. Then the mice hippocampus was removed and TNF-α levels were measured. Results: The LPS increased FST immobility but MLR-1023 reduced it. Methylene blue, L-NAME and glibenclamide intensified it. The L-arginine, sildenafil and diazoxide weakened it. The LPS reduced pain threshold, while increased by MLR-1023. The L-NAME, methylene blue, glibenclamide and GW9662 reduced it. It was increased by L-arginine, diazoxide and pioglitazone. The MLR-1023 decreased TNF-α. Methylene blue, L-NAME, glibenclamide and GW9662 increased that. It was decreased by L-arginine, sildenafil and pioglitazone. Conclusion: The MLR-1023 can improve depression, hyperalgesia and neuroinflammation induced by LPS in mice models and NO/cGMP/K_ATP-channels signaling pathway and PPARγ receptors play a probable role in this effect.