The effect of Ibuprofen and Celecoxib on Fluoxetine’s antidepressant activity: Role of tumor necrosis factor alpha and p11 protein

Abstract

Neuroinflammation as a cause of depression has gained much attention recently. NSAIDs, both selective COX-2 and non-selective COX inhibitors, have been proposed to be of clinical use in the treatment of depression either as monotherapy or as adjuncts in combination with antidepressants. The present study was designed to determine whether ibuprofen (a non-selective COX inhibitor) and/or celecoxib (a COX-2 selective inhibitor) inhibit the behavioral and biochemical response to chronic fluoxetine administration in a chronic inflammation-induced model of depressive-like behavior, the BCG inoculation model, in mice. In the present work,no locomotor impairment was found in all the studied groups, indicating that by the 7th day post-BCG inoculation, the acute sickness episode had been completely resolved. All BCG-inoculated groups showed a depressive-like behavior manifested by a significant increase of immobility time in both the FST and the TST compared to the control group. Moreover, BCG inoculation for 21 days resulted in a significant increase in TNF-α level along with a decrease in p11 protein level that resulted in a marked decrease in immune-staining of 5HT1B receptors in 2 brain areas that are relevant to the pathophysiology of depression, the prefrontal cortex and the hippocampus, compared to the control group. The co-administration of either ibuprofen (100mg/kg/day) or celecoxib (20mg/kg/day) along with fluoxetine (20mg/kg/day), abolished the antidepressant effect of this SSRI antidepressant. Both NSAIDs, were found to significantly increase the immobility time in both the FST & TST, that was otherwise decreased in the fluoxetine-treated BCG-inoculated group. Moreover, both NSAIDs abolished fluoxetine’s previously manifested elevation of p11 protein in the BCG-inoculated group. On the histopathological level, both NSAIDs resulted in changes consistent with the pathophysiology of depression along with an obvious decrease in the immune-staining of 5HT1B receptors in both, the prefrontal cortex and the hippocampus of treated mice. Conclusion: The present work confirms the suggested correlation between NSAIDs use, both selective and non-selective, and the resistance to SSRIs, as evident by the abolished antidepressant effect of fluoxetine when either chronic ibuprofen or celecoxib was adjunctively used in the anti-inflammatory dose. Moreover, this current study, revealed that this interference, of NSAIDs with the antidepressant effect of fluoxetine, is related to the decrease in p11 protein, and that a correlation might exist, needing further investigation, between the decrease in TNF-α level and the decrease in p11 protein.