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.

• Authors: Izaque S Maciel, Rodrigo B M Silva, Fernanda B Morrone, João B Calixto, Maria M Campos
• Journal: PloS one (PLoS One) Vol. 8 Issue 9 Pg. e77227 ( 2013) ISSN: 1932-6203 [Electronic] United States
• PMID: 24086771 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Analgesics
• Anti-Inflammatory Agents
• Antidepressive Agents
• Brain-Derived Neurotrophic Factor
• Interleukin-1beta
• Pyrazoles
• Sulfonamides
• Bupropion
• Pregabalin
• gamma-Aminobutyric Acid
• Dipyrone
• Freund's Adjuvant
• Cyclooxygenase 2
• Celecoxib

Topics

• Analgesics (pharmacology, therapeutic use)
• Animals
• Anti-Inflammatory Agents (pharmacology, therapeutic use)
• Antidepressive Agents (pharmacology, therapeutic use)
• Behavior, Animal (drug effects)
• Brain-Derived Neurotrophic Factor (metabolism)
• Bupropion (pharmacology, therapeutic use)
• Celecoxib
• Cerebral Cortex (drug effects, metabolism)
• Cyclooxygenase 2 (metabolism)
• Depression (complications, drug therapy, metabolism)
• Dipyrone (pharmacology)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Drug Synergism
• Edema (chemically induced, complications)
• Freund's Adjuvant (adverse effects)
• Inflammation (chemically induced, complications)
• Interleukin-1beta (metabolism)
• Male
• Mice
• Nociception (drug effects)
• Pregabalin
• Pyrazoles (pharmacology, therapeutic use)
• Sulfonamides (pharmacology, therapeutic use)
• gamma-Aminobutyric Acid (analogs & derivatives, pharmacology)