PPARγ Receptors and the NO/cGMP/KATP Pathway in the Improving Effects of Montelukast on LPS-Induced Cognitive Deficit in an Animal Model of Alzheimer's Disease

Abstract

Background: Alzheimer's disease (AD) is the most common neurodegenerative disorder and causes brain damage as well as learning and memory impairment. Although some drugs are beneficial for controlling the symptoms of AD, they cannot completely cure or prevent the disease. Objectives: This study investigated the effects of montelukast (MTK) on lipopolysaccharide (LPS)-induced learning and memory impairment and lipid peroxidation in a mouse model of AD. However, this model reflects inflammation-associated cognitive dysfunction rather than a complete AD model. The roles of PPARγ receptors and the NO/cGMP/KATP channel pathway were also assessed to elucidate the potential mechanisms. Methods: The mouse model of AD was induced by an LPS injection. Learning and memory were evaluated using shuttle-box and Y-maze tests 30 minutes after montelukast treatment. Malondialdehyde (MDA) concentration in hippocampal tissue was measured as a marker of lipid peroxidation. To examine potential mechanisms, the animals were pretreated with agonists and antagonists 15 minutes before montelukast administration (5, 10, and 20 mg/kg, intraperitoneally). Results: Montelukast at doses of 10 and 20 mg/kg reduced the LPS-induced increase in initial latency (IL). Preadministration of glibenclamide, L-NAME, and methylene blue with an effective dose of montelukast (10 mg/kg) increased IL. Montelukast potentiated the LPS-induced reduction in step-through latency (STL). Pretreatment with glibenclamide, methylene blue, and L-NAME decreased STL, whereas diazoxide increased it. L-arginine, sildenafil, pioglitazone, and GW9662 had no significant effect on IL or STL. Montelukast potentiated the LPS-induced reduction in spontaneous alternation percentage. Pretreatment with L-NAME, methylene blue, glibenclamide, and GW9662 decreased this parameter, whereas sildenafil increased it. L-arginine, diazoxide, and pioglitazone had no significant effect. Montelukast reduced the LPS-induced increase in MDA concentration. MDA concentration was increased by pretreatment with glibenclamide, methylene blue, and L-NAME and decreased by pretreatment with L-arginine, diazoxide, and sildenafil. Conclusions: Montelukast ameliorates LPS-induced learning and memory impairment and reduces lipid peroxidation. The KATP/cGMP/NO pathway contributes to this effect. PPARγ receptors do not appear to play a substantial role.