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  • It has been reported that

    2024-04-15

    It has been reported that leukotrienes and their receptors, e.g. the cysteinyl leukotriene receptor 1 (CysLT1) may promote Exo1 receptor injury (Ding et al., 2007) and that increased 5-LOX expression and activity lead to production of brain-toxic molecules (Khan et al., 2010). However, differential effects of leukotrienes (e.g., LTB4) and lipoxins (e.g., LXA4) were observed with respect to neuroprotection. Sobrado et al. (2009) found that rosiglitazone, an anti-diabetic drug, induced 5-LOX expression in ischemic rat brain concomitant with neuroprotection. This type of drug-induced 5-LOX upregulation was accompanied by increased cerebral levels of LXA4 and by inhibited ischemia-induced production of LTB4. Although 5-LOX inhibitors are neuroprotective in models of brain ischemia (Tu et al., 2010), pharmacological inhibition and/or genetic deletion of 5-LOX inhibited the observed rosiglitazone-induced LXA4-mediated neuroprotection. The neuroprotective effect of LXA4 appears to be mediated by the agonistic activity of this molecule on the peroxisome proliferator-activated receptor gamma (PPARgamma) (Sobrado et al., 2009). Hence, an increase of 5-LOX expression/activity may lead to production of both, putatively neurotoxic mediators such as leukotrienes or neuroprotective mediators such as LXA4. The type of the 5-LOX metabolite produced may be influenced by factors such as 5-LOX phosphorylation. For example, 5-LOX phosphorylation at Ser523 determines whether certain drugs (e.g., pioglitazone and atorvastatin) induce production of LTB4 or LXA4 (Ye et al., 2008). Interestingly, Ser523-phosphorylated 5-LOX content is increased in post-mortem brain samples of suicide victims compared to controls (Uz et al., 2008). Regarding AD, the available data suggest that amyloid-beta is capable of increasing the release of microglia-derived leukotrienes (Paris et al., 1999).
    Aging and brain expression of COX and 5-LOX AD is a prototype of aging-associated neurodegenerative disorders. Although certain COX-2 and 5-LOX SNPs have been associated with AD (Listì et al., 2010), other studies point to a lack of such associations (Alvarez et al., 2008). Factors other than DNA sequence variations could influence COX and 5-LOX expression in the brain and could play a role in determining the pathobiological involvement of the COX and 5-LOX pathways in AD. These include aging and possibly epigenetic modifications. Aïd and Bosetti (2007) characterized the effects of aging on COX-1 and COX-2 expression in the hippocampus and cerebral cortex of 4-, 12-, 24- and 30-month-old rats. They found increased hippocampal COX-1 mRNA levels at 12, 24, and 30months, whereas COX-2 mRNA expression was significantly decreased only at 30months. In the cerebral cortex, mRNA levels of both COX-1 and COX-2 were not significantly changed. On the other hand, in humans, the neuronal expression (i.e., immunoreactivity) of COX-2, which was observed in the CA3 Exo1 receptor subdivision of the hippocampus, subiculum, entorhinal cortex and transentorhinal cortex correlated (i.e., increased) with age in the post-mortem brains of nondemented subjects (Fujimi et al., 2007). In the rat (Qu et al., 2000, Uz et al., 1998) and mouse (Chinnici et al., 2007, Dzitoyeva et al., 2009) brain, the expression of 5-LOX increases during aging. This effect was confirmed using both mRNA and protein measurements. Nevertheless, some differences were observed regarding the brain regions in which aging-associated increased 5-LOX expression was significant. Epigenetic mechanisms, which encompass the modification of chromatin structure that leads to regulation of the gene expression, are influenced by environmental factors including aging. For example, Siegmund et al. (2007) studied DNA methylation at the sites of CpG dinucleotides in human cerebral cortex samples in aging subjects and found a progressive aging-associated rise in the DNA methylation of CpG islands of certain CNS genes. In a study using methylation-sensitive restriction endonucleases (AciI, BstUI, HpaII, and HinP1I) to assess 5-LOX DNA methylation in brain and heart tissue samples from young (2months) and old (22months) mice, it was found that in young mice, the 5-LOX mRNA content was significantly greater in the heart compared to the brain; 5-LOX DNA methylation was lower, except in the AciI assay in which it was higher in the heart (Dzitoyeva et al., 2009). Furthermore, in mice, aging decreased 5-LOX mRNA content in the heart and increased it in the brain while increasing 5-LOX DNA methylation and this effect was site- (i.e., enzyme) and tissue-specific. Currently, there is more information available on the epigenetic mechanisms involved in the regulation of human 5-LOX (ALOX5) gene (Katryniok et al., 2010) than on the regulation of the expression of COXs. Studies in the field of oncology have established that COX-2 gene expression is regulated by epigenetic mechanisms such as DNA methylation (de Maat et al., 2007). Further research is needed to determine whether epigenetic regulation plays a role in neuronal COX-2 expression.