Tehran University of Medical Sciences Acta Medica Iranica 0044-6025 63 1 2025 05 11 7 18 Mojtaba Dolatshahi Department of Physiology, School of Medicine, Dezful University of Medical Sciences, Dezful, Iran. Ali Khorsandinezhad Student Research Committee, Dezful University of Medical Sciences, Dezful, Iran. Behnam Ghorbanzadeh Department of Pharmacology, School of Medicine, Dezful University of Medical Sciences, Dezful, Iran. Yousef Paridar Department of Internal Medicine, School of Medicine, Dezful University of Medical Sciences, Dezful, Iran. Donya Nazarinia Department of Physiology, School of Paramedical Sciences, Dezful University of Medical Sciences, Dezful, Iran. 2024 10 06 2024 12 29 This project has studied the effects of metformin on cognition impairment, depression, hyperalgesia, stress oxidative and neuroinflammation in a rodent Alzheimer's disease (AD) model created via LPS (lipopolysaccharide). For defining possible mechanisms, the NO/cGMP/KATP pathway roleplay was considered.  Mice model was created via LPS treatment. Open field forced swimming and hot plate tests were done. Shuttle-box test and Y-maze test were used to assay Learning-memory. Biochemical assay compromised malondialdehyde (MDA) and TNF-alpha concentration and superoxide dismutase (SOD) activity measurement in hippocampus samples. NO-cGMP-KATP pathway contribution was assessed by its agonists/antagonist pre-treatment, 15 min before metformin (150, 200, 250 mg/kg). Initial latency (IL) was increased by LPS injection while it was reduced by metformin (250 mg), in shuttle-box test. Pretreatment with methylene blue, L-NAME and glibenclamide before metformin augmented IL, although it was diminished by L- arginine and sildenafil pretreatment. Also, metformin increased the LPS induced step through latency (STL) reduction. L-NAME, methylene blue and glibenclamide decreased the STL, but it was increased by L-arginine and sildenafil. In Y-maze test, metformin increased the LPS-induced spontaneous alternation reduction. L-NAME, methylene blue and glibenclamide decreased it. LPS added immobility time in forced swimming trial, whereas it was reduced thru metformin. L-NAME, methylene blue and glibenclamide increased the anti-depressive effect of metformin while it was attenuated via L-arginine, sildenafil and diazoxide. LPS treatment diminished the threshold of pain perception in hot-plate test, while metformin didn’t have any significant effect. Metformin reduced the LPS-induced lipid peroxidation (MDA level). But, L-NAME, methylene blue and glibenclamide worsen the lipid peroxidation, whereas it was improved by L-arginine and sildenafil. Metformin improved LPS-induced reduction in SOD activity. SOD activity was reduced by L-NAME, methylene blue and glibenclamide pre-treatment. LPS enhanced TNF-alpha amount that decreased by metformin. Pre-injection with methylene blue, L-NAME and glibenclamide increased TNF-alpha concentrations while L-arginine, sildenafil and diazoxide reduced it. Conclusions: Metformin can improve learning-memory loss, depression, hyperalgesia, neuroinflammation and oxidative stress produced by LPS and NO/cGMP/KATP pathway maybe has a roleplay.  https://acta.tums.ac.ir/index.php/acta/article/view/11284 https://acta.tums.ac.ir/index.php/acta/article/download/11284/5942