Low Dose Lipopolysaccharide-Induced Depressive-Like Phenotype is Mediated by Proinflammatory Cytokines in Mice and Role of Ketamine

Background: Depression is a common mental illness, with an estimated 3.8% of global population affected. In the pathophysiology of depression, ketamine acts quickly in patients. Treatment with low-dose ketamine upon administration to stressed C57BL/6J mice is now a major translational research area to facilitate further innovation. Objectives: The present work was aimed to establish a depressant like animal model after 6 days of LPS injection, where LPS did not promote body weight loss. Materials and Methods: Peripheral administration of low dose of Lipopolysaccharide (LPS) activates cytokines and culminate in a distinct depressive-like behavioral syndrome, measured by increased duration of immobility in the forced swim and anhedonia in sucrose preference tests. Cytokines like TNF-alpha, IL-6, IL-1 beta and IFN-gamma were determined in brain homogenate and in plasma using western blot performed with automated Jess system (ProteinSimple) and ELISA respectively. Results: Ketamine prevents development of depressive-like behavior by decreasing swimming behavior and increasing preference to sucrose in stressed animals. Ketamine treatment reduced the LPS induced secretion of IFN-gamma (p<0.05 for 30 mpk), IL-6 (p<0.05 for 30 mpk), TNF-alpha (p<0.0001 for 30 mpk) and IL-1 beta in plasma. Similarly, ketamine treatment reduced the LPS induced secretion of IFN-gamma (p<0.001 for 10 and 30 mpk), IL-6, TNF-alpha (p<0.01 for 10 and 30 mpk) and IL-1 beta (p<0.05 for 10 mpk, p<0.0001 for 30 mpk) in brain. The plasma and brain concentrations of ketamine were analysed using LC-MS/MS and Brain/ Plasma ratio (B/P) of ketamine at 10 and 30 mpk were calculated as 0.70 and 0.82 respectively. Conclusion: In summary, these data emphasizes that ketamine treatment modulate cytokine level, showed good brain to plasma exposure and provides its anti-stress effects in the C57BL/6 mouse strain, which may be possible reason for the anti-depression property and is relevant to human stress-induced depression.