Brustolim D, Ribeiro-dos-Santos R, Kast RE, et al.. A new chapter opens in anti-inflammatory treatments: the antidepressant bupropion lowers production of tumor necrosis factor-alpha and interferon-gamma in mice
In a wide range of human diseases of inflammatory nature like Crohn's disease, pathology is mediated in part by pro-inflammatory cytokines like tumor necrosis factor-alpha (TNF) or interferon-gamma. We show here that a commonly used generic antidepressant bupropion, in wide use worldwide to treat depression in humans for a decade now, profoundly lowers levels of TNF, interferon-gamma, and interleukin-1 beta in vivo, in a mouse lipopolysaccharide (LPS) induced inflammation model. Mice challenged with an otherwise lethal dose of LPS were protected by bupropion and levels of the anti-inflammatory cytokine interleukin-10 were increased. Previous data in rodents and humans indicate antidepressant effects of bupropion are mediated by its weak reuptake inhibition of norepinephrine and dopamine. Concordant with this, TNF suppression by bupropion in our mouse LPS model was largely abrogated by beta-adrenergic or dopamine D1 receptor antagonists but not by a D2 antagonist. TNF synthesis is controlled by an inverse relationship with intracellular cyclic adenosine monophosphate (cAMP) and stimulation of either beta-adrenoreceptors or D1 dopaminergic receptors result in increased cAMP but stimulation of D2 receptors lowers cAMP. We conclude that bupropion may suppress TNF synthesis by mediating increased signaling at beta-adrenoreceptors and D1 receptors, resulting in increased cAMP that inhibits TNF synthesis. Bupropion is well tolerated also in non-psychiatric populations and has less risk with long term use than current anti-inflammatory, immunosuppressive or TNF suppressive treatments such as prednisone, azathioprine, infliximab, or methotrexate. New anti-inflammatory treatments are needed. We believe a new chapter in antiinflammatory, TNF lowering treatment of disease has been opened. Bupropion's use for this in humans should be explored.
"Again, Tph1−/− mice were protected from an inflammatory disorder, in this case the autoimmune disease asthma. Acute treatment with SSRIs decreases the degree of bronchial hyperreactivity in mice and affects inflammatory signaling in vitro and in vivo , , but it is unclear if - and how - the acute administration of SSRI affects leukocyte-endothelial interactions. We present murine in vivo data elucidating the immediate consequences of fluoxetine administration to fill this gap in knowledge about a drug that many patients suffering from depression take on a regular basis. "
[Show abstract][Hide abstract] ABSTRACT: Activated platelets release serotonin at sites of inflammation where it acts as inflammatory mediator and enhances recruitment of neutrophils. Chronic treatment with selective serotonin reuptake inhibitors (SSRI) depletes the serotonin storage pool in platelets, leading to reduced leukocyte recruitment in murine experiments. Here, we examined the direct and acute effects of SSRI on leukocyte recruitment in murine peritonitis.
C57Bl/6 and Tph1-/- (Tryptophan hydroxylase1) mice underwent acute treatment with the SSRI fluoxetine or vehicle. Serotonin concentrations were measured by ELISA. Leukocyte rolling and adhesion on endothelium was analyzed by intravital microscopy in mesentery venules with and without lipopolysaccharide challenge. Leukocyte extravasation in sterile peritonitis was measured by flow cytometry of abdominal lavage fluid.
Plasma serotonin levels were elevated 2 hours after fluoxetine treatment (0.70±0.1 µg/ml versus 0.27±0.1, p = 0.03, n = 14), while serum serotonin did not change. Without further stimulation, acute fluoxetine treatment increased the number of rolling leukocytes (63±8 versus 165±17/0.04 mm(2)min(-1)) and decreased their velocity (61±6 versus 28±1 µm/s, both p<0.0001, n = 10). In Tph1-/- mice leukocyte rolling was not significantly influenced by acute fluoxetine treatment. Stimulation with lipopolysaccharide decreased rolling velocity and induced leukocyte adhesion, which was enhanced after fluoxetine pretreatment (27±3 versus 36±2/0.04 mm(2), p = 0.008, n = 10). Leukocyte extravasation in sterile peritonitis, however, was not affected by acute fluoxetine treatment.
Acute fluoxetine treatment increased plasma serotonin concentrations and promoted leukocyte-endothelial interactions in-vivo, suggesting that serotonin is a promoter of acute inflammation. E-selectin was upregulated on endothelial cells in the presence of serotonin, possibly explaining the observed increase in leukocyte-endothelial interactions. However transmigration of neutrophils in sterile peritonitis was not affected by higher serotonin concentrations, indicating that the effect of fluoxetine was restricted to early steps in the leukocyte recruitment. Whether SSRI use in humans alters leukocyte recruitment remains to be investigated.
PLoS ONE 02/2014; 9(2):e88316. DOI:10.1371/journal.pone.0088316 · 3.23 Impact Factor
"Amfepramone is considered a selective norepinephrine releasing agent, and norepinephrine may play an important role in adrenergic urticaria, which is considered to be a form of neurogenic reaction that is mainly triggered by stress. Moreover, in recent years, bupropion has been suggested to have effects as an anti-inflammatory agent by down-regulating tumor necrosis factor synthesis, which may slow the course of some inflammatory processes[30,31]. Therefore, we hypothesized that the anti-inflammation effect may delay the allergic reaction and lead to delayed onset urticaria. "
[Show abstract][Hide abstract] ABSTRACT: Bupropion, which is widely used in patients with depressive disorder, may cause allergic reactions. However, the real prevalence of these side effects may be overlooked and underreported due to the delayed onset phenomenon.
This study aimed to estimate the real incidence of bupropion-induced urticaria and clarify the delayed onset phenomenon.
We conducted a nationwide cohort study between 2000 and 2009 using Taiwan's National Health Insurance Dataset. Among 65,988 patients with depressive disorders, we identified new users of bupropion with depressive disorders (bupropion cohort, n = 2,839) and matched them at a ratio of 1:4 regarding age and sex (non-bupropion matched cohort, n = 11,356). The risk of urticaria was compared between the two cohorts.
The risk of urticaria occurrence was higher in bupropion users than in matched controls within 4 weeks of starting the medication (risk ratio 1.81; 95% confidence interval 1.28-2.54; p = 0.001). The occurrence of urticaria in the bupropion cohort were more frequent on Days 15-28 than Day 1-14 (p = 0.002). Cox proportional hazards model showed that a history of urticaria was an independent risk factor for developing bupropion-induced urticaria.
Of the antidepressants, bupropion may pose a higher risk of drug-induced urticaria, and this condition might be ignored due to the delayed onset phenomenon. Depressive patients with a history of urticaria are at higher risk of the adverse drug reaction. This study emphasizes the need for increased clinical awareness of this adverse outcome to bupropion use.
PLoS ONE 11/2013; 8(11):e80064. DOI:10.1371/journal.pone.0080064 · 3.23 Impact Factor
"Interestingly, the antidepressant drug bupropion also displayed a significant anti-edematogenic activity in the CFA model. In fact, it has been demonstrated before that bupropion inhibits TNF-α synthesis in a mouse model of LPS-induced inflammation . Notably, the anti-inflammatory drug celecoxib was able to significantly decrease the immobility time in TST. "
[Show abstract][Hide abstract] 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.
PLoS ONE 09/2013; 8(9):e77227. DOI:10.1371/journal.pone.0077227 · 3.23 Impact Factor
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