Objective: Major depression is a complex and devastating disease which one-third of patients still do not respond to current treatments. It has been demonstrated that there is a correlation between high levels of plasma cytokines such as IL-1β, IL-6, IL-18 and TNF-α and depression. Also it has been verified that the reduction in plasma cytokine levels accompanied with antidepressant medication and certain immune suppressant drugs were able to shown antidepressant-like effect (1). Ketamine, a noncompetitive glutamatergic NMDA receptor antagonist with proven rapid antidepressant action in sub-anesthetic dose, has recently been proposed to have antiinflammatory properties (2,3). Herein, we aimed to shed light on the effect of acute administration of ketamine on pro-inflammatory cytokines in sub-chronic restraint stress model in rats.
Methods: Sprague-Dawley rats weighing 250-350 g were divided into control, stress and stress+ketamine (10 mg/kg; i.p.) groups (n=6-7 in each). Stress groups were subjected to restraint stress (4 hours/day) for 7 days. Ketamine was administered on Day 7 and 30 min before the stress procedure. Rats were sacrificed after the last stress procedure. Hippocampus and prefrontal cortex (PFC) were dissected for investigating the gene expressions of pro-inflammatory cytokines. qPCR was conducted for gene expression assays for TNF-α, IL-1β, IL-6 and house-keeping gene GAPDH with standard annealing temperatures of 60oC. Data was normalized to GAPDH Cycle Threshold (CT) and it was calculated by log2 transformation and quantified by 2-ddCT relative quantification method. Statistical analysis was done by one-way ANOVA with p<0,05 value as significance.
Results: In stress group, gene expressions of TNF-α, IL-1β and IL-6 were significantly increased in hippocampus compared with control group and those increased levels induced by stress were down regulated by a single dose of ketamine. On the other hand, in the PFC, stress caused a significant increase only TNF-α levels while the elevation in IL-1β and IL-6 levels was not statistically significant. Likewise, ketamine administration did not reduce the cytokines levels in PFC. Moreover, there was a tendency of an increase in PFC IL-1β and IL-6 levels in ketamine+stress group when compared to stress alone.
Conclusions: The results of our study showed that sub-chronic restraint stress induced the levels of pro-inflammatory cytokines in brains of rats. However, one should note that the increase in all cytokine levels was significant only in the hippocampus. Ketamine markedly reduced the elevation of these pro-inflammatory cytokines in the hippocampus but failed in the PFC. However, it is noteworthy to emphasize that stress itself failed to increase the all cytokine levels in PFC. Therefore, ketamine’s anti-inflammatory like effect found in our study which seems to be restricted to the hippocampus could be misleading when considering the data of PFC. In conclusion, the chronic effect of ketamine from the aspects of modulating inflammatory processes should be investigated in further studies. This study was supported by Scientific Research Project Unit of Marmara University (SAG-E-120613-0233).