No abstract

Depression is a common psychiatric disorder that has been poorly understood. Consequently, current antidepressant agents have clinical limitations. Until today, most have exhibited the slow onset of therapeutic action and, more importantly, their effect on remission has been minimal. Thus, the need to find new forms of therapeutic intervention is urgent. The inflammation hypothesis of depression is widely acknowledged and is one that theories the relationship between the function of the immune system and its contribution to the neurobiology of depression. In this research, we utilized an environmental isolation (EI) approach as a valid animal model of depression, employing biochemical, molecular, and behavioral studies. The aim was to investigate the anti-inflammatory effect of etanercept, a tumor necrosis factor-α inhibitor on a toll-like receptor 7 (TLR 7) signaling pathway in a depressive rat model, and compare these actions to fluoxetine, a standard antidepressant agent. The behavioral analysis indicates that depression-related symptoms are reduced after acute administration of fluoxetine and, to a lesser extent, etanercept, and are prevented by enriched environment (EE) housing conditions. Experimental studies were conducted by evaluating immobility time in the force swim test and pleasant feeling in the sucrose preference test. The mRNA expression of the TLR 7 pathway in the hippocampus showed that TLR 7, MYD88, and TRAF6 were elevated in isolated rats compared to the standard group, and that acute treatment with an antidepressant and anti-inflammatory drugs reversed these effects. This research indicates that stressful events have an impact on behavioral well-being, TLR7 gene expression, and the TLR7 pathway. We also found that peripheral administration of etanercept reduces depressive-like behaviour in isolated rats: this could be due to the indirect modulation of the TLR7 pathway and other TLRs in the brain. Furthermore, fluoxetine treatment reversed depressive-like behaviour and molecularly modulated the expression of TLR7, suggesting that fluoxetine exerts antidepressant effects partially by modulating the TLR7 signaling pathway.

Stress-related disorders are extremely complex and current treatment strategies have limitations. The present study investigated alternative pathological mechanisms using a combination of multiple environmental approaches with biochemical and molecular tools. The aim of the present study was to evaluate blood-brain-barrier (BBB) integrity in socially manipulated animal housing conditions. Multiple environmentally-related models were employed in the current study. The main model proposed (chronically isolated rats) was biochemically validated using the level of peripheral corticosterone. The current study examined and compared the mRNA levels of certain inflammatory and BBB markers in the hippocampal tissue of chronically isolated rats, including claudin-5 ( cldn5 ) and tight junction protein ( tjp ). Animals were divided into four groups: i) Standard housed rats (controls); ii) chronically isolated rats; iii) control rats treated with fluoxetine, which is a standard selective serotonin reuptake inhibitor; and iv) isolated rats treated with fluoxetine. To further examine the effect of environmental conditions on BBB markers, the current study assessed BBB markers in enriched environmental (EE) housing and short-term isolation conditions. The results demonstrated a significant increase in cldn5 and tjp levels in the chronically isolated group. Despite some anomalous results, alterations in mRNA levels were further confirmed in EE housing conditions compared with chronically isolated rats. This trend was also observed in rats subjected to short-term isolation compared with paired controls. Additionally, levels of IL-6, an inflammatory marker associated with neuroinflammation, were markedly increased in the isolated group. However, treatment with fluoxetine treatment reversed these effects. The results indicated that BBB integrity may be compromised in stress-related disorders, highlighting a need for further functional studies on the kinetics of BBB in stress-related models.