MLR-1023 Improves Cognition Deficiency and Oxidative Stress in Lipopolysaccharide-Induced Mice Model of Alzheimer’s Disease: Role of PPAR-gamma Receptors and NO-cGMP-KATP Channels Pathway

Abstract

Background: This study investigates the effects of MLR-1023 on cognitive deficiency and oxidative stress in a lipopolysaccharide (LPS)-induced mouse model. Objectives: The role of PPAR-gamma receptors and the NO- cyclic GMP (cGMP)-KATP channel pathway were examined to identify the likely mechanisms. Methods: The model was established by LPS injection. Behavioral assays included shuttle box and Y-maze tests. Superoxide dismutase (SOD) activity and malondialdehyde (MDA) levels were then measured in hippocampal tissue. To explore the probable mechanisms, the mice were pre-treated with agonists and antagonists 15 minutes before MLR-1023 (20 - 40 mg/kg, i.p.) administration. Results: Lipopolysaccharide increased the initial latency (IL) time, while MLR-1023 (40 mg) reduced it. Administration of L-NAME, methylene blue, and glibenclamide with MLR-1023 increased IL duration, while L-arginine, sildenafil, and diazoxide reduced it. Lipopolysaccharide reduced the duration of step-through latency (STL), whereas MLR-1023 increased it. L-NAME, methylene blue, and glibenclamide with MLR-1023 reduced STL duration, but L-arginine, sildenafil, and diazoxide increased it. The spontaneous alternation index decreased with LPS, while MLR-1023 increased it. L-NAME, methylene blue, glibenclamide, and GW9662 decreased this index, whereas L-arginine, sildenafil, diazoxide, and pioglitazone increased it. Lipopolysaccharide increased MDA concentration, while MLR-1023 decreased it. L-NAME, methylene blue, and glibenclamide increased MDA concentration, while L-arginine, diazoxide, and pioglitazone decreased it. Lipopolysaccharide reduced SOD activity, which was improved by MLR-1023. L-NAME, methylene blue, glibenclamide, and GW9662 decreased SOD activity, while sildenafil and pioglitazone increased it. Conclusions: MLR-1023 can improve LPS-induced learning-memory impairment and oxidative stress. The KATP/cGMP/NO pathway and PPARγ receptors are involved in this effect.