Reduction in TNF alpha and oxidative stress by liraglutide: Impact on ketamine-induced cognitive dysfunction and hyperlocomotion in rats

Background: Diabetes and psychotic disorders are occasionally comorbid. Possible pathophysiologies linking these disorders include inflammation and oxidative stress. Glucagon like peptide-1 (GLP-1) agonists modulate glucose metabolism and may exert neuroprotective effects via central GLP-1 receptors. Aim of the work: To explore the effects of GLP-1 agonist, liraglutide, on ketamine-induced hyper-locomotion and cognitive dysfunction and the associated inflammation and oxidative stress in normoglycemic and diabetic rats. Methods: Rats were divided into: Chow fed (non-diabetic) and high fat diet fed/STZ (diabetic) groups: I. nondiabetic/control, non-diabetic/liraglutide, non-diabetic/ketamine, non-diabetic/ketamine/liraglutide groups. II. diabetic/control, diabetic/liraglutide, diabetic/ketamine and diabetic/ketamine/liraglutide groups. Hyperlocomotion and cognitive dysfunction were assessed using open field and water maze tests. Biochemical parameters were measured in serum and hippocampus. Results: Ketamine induced hyperlocomotion and cognitive dysfunction, with hippocampal histopathological changes. Increase in tumour necrosis factor (TNF)-alpha and oxidative stress and reduction in brain-derived neurotrophic factor (BDNF) were noted. These changes were augmented in diabetic compared to non-diabetic rats. Liraglutide significantly improved hyperlocomotion, and cognitive dysfunction and hippocampal histopathological changes in non-diabetic and diabetic rats. Improvement in glucose homeostasis, reduction in TNF alpha and malondialdehyde, and increase in glutathione and BDNF were observed in serum and hippocampus. Conclusion: Beneficial effects of liraglutide on ketamine-induced hyperlocomotion and cognitive dysfunction are associated with reduction in TNF alpha and oxidative stress. Since effects of liraglutide occurred in diabetic and non-diabetic rats, glycemic and non-glycemic effects (via central GLP-1 receptors) might be involved. Targeting oxidative stress and inflammation by GLP-1 agonists, may be a promising approach in psychotic patients with diabetes.