Background:Mounting evidence demonstrates enhanced systemic levels of inflammatory mediators in depression, indicating that inflammation may play a role in the etiology and course of mood disorders. Indeed, proinflammatory cytokines induce a behavioral state of conservation-withdrawal resembling human depression, characterized by negative mood, fatigue, anhedonia, psychomotor retardation, loss of appetite, and cognitive deficits. Neuroinflammation also contributes to non-responsiveness to current antidepressant (AD) therapies. Namely, response to conventional AD medications is associated with a decrease in inflammatory biomarkers, whereas resistance to treatment is accompanied by increased inflammation.Methods:In this review, we will discuss the utility and shortcomings of pharmacologic AD treatment strategies focused on inflammatory pathways, applied alone or as an adjuvant component to current AD therapies.Results:Mechanisms of cytokine actions on behavior involve activation of inflammatory pathways in the brain, resulting in changes of neurotransmitter metabolism, neuroendocrine function, and neuronal plasticity. Selective serotonin reuptake inhibitors exhibit the most beneficial effects in restraining the inflammation markers in depression. Different anti-inflammatory agents exhibit AD effects via modulating neurotransmitter systems, neuroplasticity markers and glucocorticoid receptor signaling. Anti-inflammatory add-on therapy in depression highlights such treatment as a candidate for enhancement strategy in patients with moderate-to-severe depression.Conclusion:The interactions between the immune system and CNS are not only involved in shaping behavior, but also in responding to therapeutics. Even though, substantial evidence from animal and human research support a beneficial effect of anti-inflammatory add-on therapy in depression, further research with special attention on safety, particularly during prolonged periods of anti-inflammatory co-treatments, is required.

Chronic stress and impaired glucocorticoid receptor (GR) feedback are important factors for the compromised hypothalamic–pituitary–adrenal (HPA) axis activity. We investigated the effects of chronic 21 day isolation of Wistar rats on the extrinsic negative feedback part of HPA axis: hippocampus (HIPPO) and prefrontal cortex (PFC). In addition to serum corticosterone (CORT), we followed GR subcellular localization, GR phosphorylation at serine 232 and serine 246, expression of GR regulated genes: GR, CRF and brain-derived neurotropic factor (BDNF), and activity of c-Jun N-terminal kinase (JNK) and Cdk5 kinases that phosphorylate GR. These parameters were also determined in animals subjected to acute 30 min immobilization, which was taken as ‘normal’ adaptive response to stress. In isolated animals, we found decreased CORT, whereas in animals exposed to acute immobilization, CORT was markedly increased. Even though the GR was predominantly localized in the nucleus of HIPPO and PFC in acute, but not in chronic stress, the expression of GR, CRF, and BDNF genes was similarly regulated under both acute and chronic stresses. Thus, the transcriptional activity of GR under chronic isolation did not seem to be exclusively dependent on high serum CORT levels nor on the subcellular location of the GR protein. Rather, it resulted from the increased Cdk5 activation and phosphorylation of the nuclear GR at serine 232 and the decreased JNK activity reflected in decreased phosphorylation of the nuclear GR at serine 246. Our study suggests that this nuclear isoform of hippocampal and cortical GR may be related to hypocorticism i.e. HPA axis hypoactivity under chronic isolation stress.

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Chronic stress is a contributing risk factor in the development of psychiatric illnesses, including depressive disorders. The mechanisms of their psychopathology are multifaceted and include, besides others, alterations in the brain plasticity. Previously, we investigated the effects of chronic social stress in the limbic brain structures of Wistar rats (hippocampus, HIPPO, and prefrontal cortex, PFC) and found multiple characteristics that resembled alterations described in some clinical studies of depression. We extended our investigations and followed the behavior of stressed animals by the open field test (OFT) and forced swimming test (FST), and the expression and polysialylation of synaptic plasticity markers, neural cell adhesion molecule (NCAM) and L1, in the HIPPO and PFC. We also determined the adrenal gland mass and plasma corticosterone (CORT) as a terminal part of the hypothalamic-pituitary-adrenal axis activity. Our data indicated that stressed animals avoided the central zone in the OFT and displayed decreased swimming, but prolonged immobility in the FST. The animals exhibited marked hypertrophy of the adrenal gland cortex, in spite of decreased serum CORT. Simultaneously, the stressed animals exhibited an increase in NCAM mRNA expression in the HIPPO, but not in the PFC. The synaptosomal NCAM of the HIPPO was markedly polysialylated, while cortical PSA-NCAM was significantly decreased. The results showed that chronic social isolation of Wistar rats causes both anxiety-like and depression-like behavior. These alterations are parallel with molecular changes in the limbic brain, including diminished NCAM sialylation in the PFC. Together with our previous results, the current observations suggest that a chronic social isolation model may potentially be used to study molecular mechanisms that underlie depressive symptomatology.

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