INTRODUCTION
The interactions between the immune and nervous systems are the major
concern of psychoneuroimmunology. Current literature repeatedly
highlighted the role of inflammation in depression pathogenesis and
relapse 1,2. Regarding, cytokine production pattern is
indicated to be dysregulated in MDD patients with inflammatory etiology.
Several meta-analyses reported elevated levels of TNF-ɑ, IL6, and IL-1ß
in the blood and brain of MDD patients 3,4. IL-17 role
in the pathophysiology of depression is also established5. Furthermore, mild stimulation of the immune system
with lipopolysaccharides (LPS) could induce the symptoms of depression6,7. Therefore, the contribution of inflammatory
signaling pathways to the pathophysiology of the disorder also took into
consideration in recent documentations. In this regard, studies reported
an imbalanced toll-like receptor (TLR)-mediated inflammatory response in
MDD. TLR4 mRNA and protein levels were found to be increased in both the
periphery and CNS of MDD patients 4,8. The Janus
kinase/signal transducer and activator of transcription (JAK/STAT)
inflammatory signaling pathway is also proposed to be pathologically
linked to depression 9. Regarding, evidence indicated
that JAK2/STAT3 is crucial to neuroimmune system maintenance.
Antidepressants are believed to shift the immune balance toward
anti-inflammatory responses. However, provocation of inflammatory
responses (e.g. increased TNF-ɑ and IL-6 levels) under treatment with
serotonin and norepinephrine reuptake inhibitors (SNRIs) have been
reported previously in both human and mouse models 4.
Despite the development of various classes of antidepressants, over 30%
of patients don’t achieve remission and 60% of remitted patients
develop a new depressive episode 2,3. Recent studies
suggest that inflammatory status prior to the treatment determines the
success of medication in MDD patients at least in the inflammatory form
of the disease 1. Moreover, MDD patients with multiple
failed antidepressant treatments showed higher plasma levels of TNF and
IL-6 10. Despite the existence of relatively large
data discussing cytokine protein levels as immune system mediators in
response to antidepressants, expression of correlated genes following
antidepressant administration has remained disregarded.
During systemic inflammation, pro-inflammatory cytokines can pass
through leaky parts of blood-brain barrier and induce neuroinflammation.
Penetrating the brain, cytokines modulate the synthesis, release, and
reuptake of neurotransmitters relevant to the mood including serotonin,
norepinephrine, and dopamine 11. Evidence implied that
bupropion decreases IL-1ß, TNF-ɑ, and IFN-γ levels while increases IL-10
levels 12. Given that bupropion is a
norepinephrine–dopamine reuptake inhibitor (NDRI) and a serotonin
(5-HT) type 3A receptor inhibitor possessing anti-inflammatory
properties 13, it is expected to have a double point
advantage as an antidepressant. Meanwhile, in an animal study conducted
by Helaly et al, bupropion exerted an inflammatory effect at therapeutic
doses evidenced by positive NF-κB/ p65 stained microglia and neurocytes,
obvious inflammation in hippocampus along with a moderate rise in the
mean of serum IL- 6 levels 14. Moreover, the
association between bupropion administration and a couple of
inflammatory conditions is stated in a considerable number of case
reports 15-18. Some investigations have also stated
the possibility of bupropion-induced psychotic symptoms19.
Based on the aforementioned observations, we hypothesize that the
absence of the desired response to antidepressants, in our case
bupropion, in some patients could be due to the not previously-noticed
pro-inflammatory properties of the drug. To test the hypothesis, we
evaluated the modulation of protein and gene expression of TNF-ɑ, IL-1ß,
IL-17, and IL-10 by bupropion. Gene expression of immunomodulatory
signaling molecules including TLR2, TLR4, JAK2, and STAT3 was also
assessed.