It is already established in the

It is already established in the literature that products synthesized by 5-LO, such as lipoxin A4, can activate PPARγ in a setting of experimental stroke [43]. Interestingly, experiments using 5-LO knockout mice in an endotoxemia model to mimic septic conditions, demonstrated reduced multiple organ injury and dysfunction compared to wild type mice [44]. The authors speculated on the improved disease outcome in 5-LO knockout mice to be associated with a pro-inflammatory role of 5-LO. Based on our results, we would propose that in 5-LO deficient mice, apoptotic cgrp antagonist fail to activate PPARγ and polarize MΦ, thereby maintaining the bactericidal M1 macrophage phenotype. In line, Benjamim et al. observed in the polymicrobial cecal ligation and puncture sepsis 5-LO knockout mouse model a survival improvement compared to wild type mice [45]. However, they found an increased number of bacteria in the peritoneal cavity in combination with decreased neutrophil accumulation, favoring a pro-inflammatory role of 5-LO, important for attracting immune cells to sites of infection. In support of our hypothesis of an anti-inflammatory role of 5-LO, Emerson and LeVine provided evidence, that 5-LO deficiency exacerbates experimental allergic encephalomyelitis in mice by a so far unknown mechanism [46]. However, considering our results demonstrating inhibition of PPARγ activation by the FLAP inhibitor MK-886 as well as the direct 5-LO inhibitors CJ-13610 and zileuton, but only marginally reduced PPARγ-dependent gene induction following leukotriene A4 hydrolase inhibition by bestatin [22], suggests 5-HETE and concomitantly 5-oxo-ETE as possible PPARγ activating compounds [47].
Conclusions
Contributors
Disclosures
Introduction Depression is a chronic, highly prevalent, and recurring mood disorder. In addition to the common symptoms of a mood disorder, most patients exhibit cognitive dysfunction, such as memory deficits, poor sustained attention, and reduced executive function; however, there are few effective treatments for these symptoms [1], [2]. Growing evidence implicates neuroinflammation [3], [4], oxidative stress [5], [6], and neurotrophic factors [7], [8] as key mediators in the pathophysiology of mood disorders and cognitive impairment in depressed patients. Among these mediators, inflammation plays an increasingly prominent role in the pathogenesis of depression and cognitive impairment [9], [10], [11]. Patients with major depression who are otherwise medically healthy have activated inflammatory pathways as exhibited by an up-regulation in the expression of pro-inflammatory cytokines, acute-phase proteins, chemokines, and adhesion molecules [12]. Antidepressants can significantly reduce depressive symptoms through their anti-inflammatory effects [13], [14]. In animal models of depression, several pro-inflammatory cytokines (e.g., interleukin (IL)-1, tumor necrosis factor (TNF)-α, and interferon-gamma) influence neuronal functions through their involvement in apoptosis, excitotoxicity, oxidative stress, and metabolic derangement. Pro-inflammatory cytokines are up-regulated in patients with severe depression, and cytokine immunotherapy elicits depressive symptoms that are amenable to antidepressant treatment [15], [16], [17]. It is suggested that stressors and inflammation share a common ability to impair neurons and alter neurotransmission, ultimately contributing to depression and cognitive impairment. 5-Lipoxygenase (5-LO), a lipid-peroxidizing enzyme involved in the conversion of arachidonic acid into leukotrienes (LTs) by inserting two molecules of oxygen into fatty acids, is widely expressed in central nervous system (CNS) neurons where its expression and activity are enhanced in an age-dependent manner [18], [19]. 5-LO may play a role in the occurrence of neurological and psychiatric disorders. 5-LO levels are up-regulated in the brains of suicide victims [20], and inhibition of 5-LO has potent anti-depressant effects in mice [21]. Absence of the 5-LO gene prevents stress-induced memory deficits, synaptic dysfunction and tauopathy activation in a mouse model of Alzheimer's disease [22]. Currently, the U.S. Food and Drug Administration (FDA) is investigating whether the use of antagonists of the downstream products of 5-LO is associated with mood changes and suicide. Regardless, the relationship between 5-LO antagonists and suicide in patients with depression is not clear. The other targets of 5-LO antagonists might contribute to these mechanisms [20]. These studies imply a possible role of 5-LO in the cognitive deficits observed in depressed patients. However, the link between 5-LO and cognitive dysfunction induced by depression is unknown.