Synergistic Effects of Celecoxib and Bupropion in a Model of Chronic Inflammation-Related Depression in Mice

Abstract

This study was aimed to characterize the depression-like behaviour in the classical model of chronic inflammation induced by Complete Freund’s Adjuvant (CFA). Male Swiss mice received an intraplantar (i.pl.) injection of CFA (50 µl/paw) or vehicle. Behavioural and inflammatory responses were measured at different time-points (1 to 4 weeks), and different pharmacological tools were tested. The brain levels of IL-1β and BDNF, or COX-2 expression were also determined. CFA elicited a time-dependent edema formation and mechanical allodynia, which was accompanied by a significant increase in the immobility time in the tail suspension (TST) or forced-swimming (FST) depression tests. Repeated administration of the antidepressants imipramine (10 mg/kg), fluoxetine (20 mg/kg) and bupropion (30 mg/kg) significantly reversed depression-like behaviour induced by CFA. Predictably, the anti-inflammatory drugs dexamethasone (0.5 mg/kg), indomethacin (10 mg/kg) and celecoxib (30 mg/kg) markedly reduced CFA-induced edema. The oral treatment with the analgesic drugs dipyrone (30 and 300 mg/kg) or pregabalin (30 mg/kg) significantly reversed the mechanical allodyinia induced by CFA. Otherwise, either dipyrone or pregabalin (both 30 mg/kg) did not significantly affect the paw edema or the depressive-like behaviour induced by CFA, whereas the oral treatment with dipyrone (300 mg/kg) was able to reduce the immobility time in TST. Noteworthy, CFA-induced edema was reduced by bupropion (30 mg/kg), and depression behaviour was prevented by celecoxib (30 mg/kg). The co-treatment with bupropion and celecoxib (3 mg/kg each) significantly inhibited both inflammation and depression elicited by CFA. The same combined treatment reduced the brain levels of IL-1β, as well as COX-2 immunopositivity, whilst it failed to affect the reduction of BDNF levels. We provide novel evidence on the relationship between chronic inflammation and depression, suggesting that combination of antidepressant and anti-inflammatory agents bupropion and celecoxib might represent an attractive therapeutic strategy for depression.

Antidepressant Augmentation With Anti-Inflammatory Agents

“…[1][2][3][4] If this is true, then anti-inflammatory drugs may improve depression outcomes by attenuating the neuroinflammatory changes 5 or by other mechanisms, such as increased norepinephrine and serotonin levels. 6 Data from animal models show that NSAIDs in monotherapy 7,8 and in combination with conventional antidepressants 5 indeed attenuate indices of inflammation and depression. What do the clinical data show?…”

Dipyrone ameliorates behavioural changes induced by unpredictable chronic mild stress: gender differences

“…Tramadol and some opioid agonists have been declared to improve depressive symptoms [22,23]. Celecoxib and piroxicam have been shown to display antidepressant effect in human and animal studies [8,[24][25][26]. Acute administration of paracetamol has been shown to cause antidepressant-like effects and display synergistic effect with fluoxetine in FST and tail suspension tests without affect locomotor activity [27].…”

“…Dipyrone has been shown to produce anticonvulsant effect in rats exposed to the audiogenic and electroshock-induced seizures [7]. Dipyrone was also found to reverse the mechanical allodynia induced by CFA, and reduce the immobility time in tail suspension test in a study that compares the depression-like behavior of analgesics and bupropion in a model of chronic inflammation-related depression in mice [8].…”

Bupropion Cannot Reduce Acute Kidney Injury Due to Ischemia-Reperfusion

“…Previous studies have shown that bupropion can reduce the inflammatory response [9], and animal intestinal I/R models have demonstrated a decrease in TNF-α [10]. To our knowledge there are no studies that evaluate the effect of bupropion as a pharmacologic preconditioner in renal I/R.…”