en Neurophysiology/Pharmacology Neurophysiology/Pharmacology Experimental research article Experimental research article <p><span style="line-height:1.5;"><span style="font-size:12px;"><span style="font-family:Arial;"><strong>Introduction: </strong>Improper glycemic control is associated with diabetic cognitive dysfunction. Several studies have confirmed the neuroprotective effects of metformin and insulin. This study aimed to investigate the effects of metformin and/or insulin therapy on neurocognitive functions in a type 2 diabetes mellitus (T2DM) rat model.<br /> <strong>Methods: </strong>Fifty adult male Wistar rats were used in this study and had free access to water and a normal chow diet. After an acclimatization period, 10 rats were kept on a normal chow diet and considered as the control group. T2DM was induced in the other 40 rats by a high-fat diet and low-dose streptozotocin method. Then, diabetic rats were randomly allocated into 4 equal groups: Non-treated diabetic group; Metformin-treated diabetic group (treated with metformin 250 mg/kg/day for 6 weeks); Insulin-treated diabetic group (treated with NPH insulin 40 U/kg for 6 weeks); and Metformin and insulin-treated diabetic group. Neurocognitive functions were assessed by footprint assay, Y-maze, open field test, and Morris water maze. Glycaemic profile, serum levels of amyloid A, interleukin-18, and nuclear factor-kappa B were analyzed. Brain malondialdehyde and total antioxidant capacity were measured. A histopathological examination of the frontal lobe was performed.<br /> <strong>Results: </strong>Treatment with metformin and/or insulin significantly improved the impaired neurocognitive dysfunction, brain oxidative stress, changes in biochemical parameters, and the associated histopathological changes in the frontal cortex of diabetic rats. The combined therapy showed a better effect than either monotherapy alone.<br /> <strong>Conclusion: </strong>Metformin and insulin therapy may be valuable for the prevention of neurocognitive dysfunction in T2DM.</span></span></span></p> Diabetes mellitus, Memory, Metformin, NF-kB, Oxidative stress 141 156 http://ppj.phypha.ir/browse.php?a_code=A-10-2181-1&slc_lang=en&sid=1 Heba Rady Salem heba.saelm.12@med.menofia.edu.eg 3200319475328460035733 0000000328715190 Yes Medical Physiology Department, Faculty of Medicine, Menoufia University, Shebin El-Kom, Egyp Gergess S. Hanna hannagergess77@gmail.com 3200319475328460035734 0009000054715632 No Medical Physiology Department, Faculty of Medicine, Menoufia University, Shebin El-Kom, Egyp Mohammed H. Hassan drhanafy56@gmail.com 3200319475328460035735 0000000237881599 No Medical Physiology Department, Faculty of Medicine, Menoufia University, Shebin El-Kom, Egyp Safaa El-kotb Safaa_kotb48@yahoo.com 3200319475328460035736 0000006336457072 No Medical Physiology Department, Faculty of Medicine, Menoufia University, Shebin El-Kom, Egyp Samar Rashad drsamarrashad90@gmail.com 3200319475328460035737 0009000419202961 No Medical Physiology Department, Faculty of Medicine, Menoufia University, Shebin El-Kom, Egyp Rania Ibrahim Yassien raniayassien@yahoo.com 3200319475328460035738 0000000277542049 No Histology Department, Faculty of Medicine, Menoufia University, Shebin El-Kom, Egypt Mahmoud Selim Mahmoud.saleem@med.tanta.edu.eg 3200319475328460035739 0009000473956211 No Internal Medicine Department, Faculty of Medicine, Tanta University, Egypt Ghada Samir Amer ghada.amer@med.menofia.edu.eg 3200319475328460035740 0000000339640112 No Medical Physiology Department, Faculty of Medicine, Menoufia University, Shebin El-Kom, Egypt