The Modulatory Properties of Chronic Antidepressant Drugs Treatment on the Brain Chemokine – Chemokine Receptor Network: A Molecular Study in an Animal Model of Depression

Abstract

An increasing number of studies indicate that the chemokine system may be the third major communication system of the brain. Therefore, the role of the chemokine system in the development of brain disorders, including depression, has been recently proposed. However, little is known about the impact of the administration of various antidepressant drugs on the brain chemokine – chemokine receptor axis. In the present study, we used an animal model of depression based on the prenatal stress procedure. We determined whether chronic treatment with tianeptine, venlafaxine, or fluoxetine influenced the evoked by prenatal stress procedure changes in the mRNA and protein levels of the homeostatic chemokines, CXCL12 (SDF-1α), CX3CL1 (fractalkine) and their receptors, in the hippocampus and frontal cortex. Moreover, the impact of mentioned antidepressants on the TGF-β, a molecular pathway related to fractalkine receptor (CX3CR1), was explored. We found that prenatal stress caused anxiety and depressive-like disturbances in adult offspring rats, which were normalized by chronic antidepressant treatment. Furthermore, we showed the stress-evoked CXCL12 upregulation while CXCR4 downregulation in hippocampus and frontal cortex. CXCR7 expression was enhanced in frontal cortex but not hippocampus. Furthermore, the levels of CX3CL1 and CX3CR1 were diminished by prenatal stress in the both examined brain areas. The mentioned changes were normalized with various potency by chronic administration of tested antidepressants. All drugs in hippocampus, while tianeptine and venlafaxine in frontal cortex normalized the CXCL12 level in prenatally stressed offspring. Moreover, in hippocampus only fluoxetine enhanced CXCR4 level, while fluoxetine and tianeptine diminished CXCR7 level in frontal cortex. Additionally, the diminished by prenatal stress levels of CX3CL1 and CX3CR1 in the both examined brain areas were normalized by chronic tianeptine and partially fluoxetine administration. Tianeptine modulate also brain TGF-β signaling in the prenatal stress-induced animal model of depression. Our results provide new evidence that not only prenatal stress-induced behavioral disturbances but also changes of CXCL12 and their receptor and at less extend in CX3CL1–CX3CR1 expression may be normalized by chronic antidepressant drug treatment. In particular, the effect on the CXCL12 and their CXCR4 and CXCR7 receptors requires additional studies to elucidate the possible biological consequences.

Targeting the NLRP3 Inflammasome-Related Pathways via Tianeptine Treatment-Suppressed Microglia Polarization to the M1 Phenotype in Lipopolysaccharide-Stimulated Cultures

“…injection of LPS or IL-1β, and to affect the central balance between pro- and anti-inflammatory cytokines (IL-1β/IL-10) [ 29 ]. In line with our previous data, we demonstrated that tianeptine has the ability to diminish depression-like behavior (in an animal model of depression) via normalization of the IGF-1 family network, as well as through cytokines and the chemokine/chemokine receptor axis [ 30 , 31 ]. Among others, chronic tianeptine treatment diminished malfunction in the fractalkine (CX3CL1) and fractalkine receptor (CX3CR1) axis.…”

The Potential Role of Dysfunctions in Neuron-Microglia Communication in the Pathogenesis of Brain Disorders

“…Accordingly, experimental approaches using diverse types of stress are considered useful animal models to simulate this condition [ 240 ]. In the article by Trojan et al [ 231 ], prenatal stress caused anxiety and depressive-like disturbances in the adult offspring of rats. The changes were followed by the reduction in CX3CL1-CX3CR1 expression in the hippocampi and the frontal cortices of these animals.…”

“…The changes were followed by the reduction in CX3CL1-CX3CR1 expression in the hippocampi and the frontal cortices of these animals. The chronic administration of the antidepressants (tianeptine and fluoxetine) normalized the observed alterations both on the behavioural and biochemical levels [ 231 ]. Additionally, the intracerebroventricular application of exogenous CX3CL1 alleviated the changes in the behaviour and in the inflammatory processes observed in the brains of prenatally stressed rats [ 241 ].…”

Distinct non-inflammatory signature of microglia in post-mortem brain tissue of patients with major depressive disorder

“…Furthermore, selective serotonin and serotonin norepinephrine reuptake inhibitors (SSRI and SNRI, respectively) have been shown to reduce the inflammatory responses of microglia [90][91][92]. In addition, they are able to induce a ramified morphology and increase CX3CR1 expression [93][94][95]. It is not known yet whether antidepressants target the other markers differently expressed in MDD, such as TMEM119, CD163 and CD14.…”