Previous studies on the chemokines role in depression are

Previous studies on the chemokines role in depression are not detailed enough, and cannot sufficiently demonstrate even a hypothetical mechanism explaining the differences in levels of particular chemokines and their receptors, in relation to the severity of depression [29], [30]. Previous studies on the chemokines allowed a description of the mechanism of chemokine action at the cellular level only. It is known from the studies that chemokines act chemotactically and activate various leukocyte populations through seven-helix G-protein coupled receptors. Chemokines bind to the receptors at two main sites located near disulfide bridges: an N-terminal flexible fragment and a stiffened N loop, which is located after the second cysteine. The receptor recognizes the amino Rp-8-Br-PET-cGMPS residues located in a polypeptide chain forming the N loop [31]. This interaction limits the mobility of the chemokine and facilitates the orientation and interaction of the chemokine's N-terminal fragment with the receptor. It leads to receptor activation through the guanosine diphosphate (GDP) conversion into guanosine-5′-triphosphate (GTP) on the G-protein α subunit. This is followed by G-protein dissociation from the receptor and activation of a number of effector molecules and subsequent signal activation in the cell, which results in chemokine production [32].
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Introduction Posttraumatic stress disorder (PTSD) is a mental disorder that may develop following exposure to a traumatic event. Main symptoms of PTSD are constant flashbacks, memories of tragic or traumatic events that happened in the past, emotional numbness and anxiety. PTSD usually develops during the first 3 months after the traumatic event, but in some cases it can occur years down the track. The probability to develop PTSD depends on individual risk and resilience factors and increases with the number of traumatic events experienced as well as with the stress intensity of the traumatic incidents. The PTSD pathomechanism is based on increased neuron sensitivity and maintained excitation in subcortical structures of the limbic system such as the amygdala, the hippocampus and the locus coeruleus [1]. The amygdala plays a role in processes of conditioning, and of suppressing sensory and cognitive associations related to the traumatic event. It is connected to the cortical sensory system that stores traumatic memories. Through these connections, it plays a role in recalling of traumatic memories [2], [3]. These memories can cause a stress reaction which is responsible for stimulations of both sympatho-adrenal system (SAS) and hypothalamic–pituitary–adrenal axis (HPA). As a result of these processes adrenanalin, noradrenalin and glucocorticoids are released [4]. The prolonged high levels of glucocorticoids inhibit functions of the immune system cells, leading to increased secretion of the proinflammatory cytokines [5]. Cytokines, including CCL-5/RANTES-regulated on activation, normal T-cell expressed and secreted, CXCL-12/SDF-1-stromal derived factor, CCL-2/MCP-1-monocyte chemotactic protein-1, are released in response to stress [6], [7]. In inflammatory reactions chemokines initiate the T-cell immunological response and they are directly involved in mechanisms of body adaptation to stress [8]. The chemokine CCL-5/RANTES is synthesized by T-cells, monocytes, macrophages, NK cells and platelets. CCL-5 production is initiated, e.g., by TNF-α, interleukin-1β (IL-1β) and interferon-γ (IFN-γ), and inhibited by interleukin-10 (IL-10). Effects of CCL-5 result from its interactions with specific receptors bound to G-protein, an intracellular signal transmitter. Amongst receptors of that chemokine, the chemokine receptor type-5 (CCR-5 receptor) found on lymphocytes from the T helper type-1 (Th-1) subpopulation is of particular importance. In PTSD the chemokine CCL-5 is a mediator of the T-cells and monocytes inflow to walls of brain vessels [9].