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  • br AD and COX LOX pharmacology

    2024-05-23


    AD and COX/5-LOX pharmacology Early studies on the role of cyclooxygenases in AD were inspired by epidemiological data suggesting that COX inhibitors such as nonsteroidal anti-inflammatory drugs (NSAIDs) could be beneficial in AD patients (Lucca et al., 1994, McGeer et al., 1990). This line of research led to the development and trials of selective COX-2 inhibitors as a putative therapy for AD. As summarized in several recent reviews (Choi et al., 2009, Imbimbo, 2009), it appears that selective COX-2 inhibitors may not be an effective therapy in AD patients with mild to severe cognitive impairment. It has been proposed that these drugs and possibly selective COX-1 inhibitors might be beneficial if administered before the onset of AD symptoms (Choi et al., 2009). Some NSAIDs, e.g., aspirin, trigger a peculiar interplay between the COXs and 5-LOX pathways that ultimately shifts the 5-LOX end-products from leukotrienes to lipoxins. Thus, by causing the acetylation of COX-2, aspirin triggers the production of (15R)-15-hydroxy-5,8,11-cis-13-trans-eicosatetraenoic Sirolimus (15R-HETE) that is converted by 5-LOX to 15-epi-LXA4 (Clària and Serhan, 1995). Recently, similar pathway to the production of 15-epi-LXA4 has been described for some non-NSAIDs (Ye et al., 2008). Furthermore, it appears that certain NSAIDs could influence AD pathobiology independent of their COX-inhibitory activity, i.e. by interacting with the gamma-secretase complex (Kukar and Golde, 2008). Compared to the pharmacology of COX inhibition, the clinical pharmacological tools for 5-LOX inhibition are scarce. Except for drugs in various stages of pre-clinical and early clinical development, zileuton appears to be the only choice. With respect to CNS pathologies, it has been shown in a rat model of stroke that zileuton is capable of reducing the extent of brain damage (Tu et al., 2010). Based on the finding that zileuton acts as an inhibitor of the gamma-secretase activity in vitro (Firuzi et al., 2008), it is reasonable to expect that this drug would be tested pre-clinically and clinically for its potential to alter the course of AD. Indirect support for possible benefits of 5-LOX inhibition in AD is provided by findings that drugs that act as functional 5-LOX inhibitors, e.g., minocycline (Chu et al., 2010, Song et al., 2006), are beneficial in AD animal models (Cuello et al., 2010). More commonly used drugs that affect the 5-LOX pathway are the leukotriene receptor inhibitors. Recently, it has been noted that that these drugs may affect CNS functioning because their use has been associated with neuropsychiatric side effects. Although leukotriene receptor inhibitors appear to be neuroprotective in animal models of stroke (Yu et al., 2005) no data are available on their possible effects in AD.
    Conclusion Early work regarding the putative role of COXs and 5-LOX in AD was based on the concept of possible inflammatory mechanisms of AD pathobiology. More recent data indicate that these enzymes and biologically active lipid molecules resulting from their activity could influence CNS and neurodegenerative disorders such as AD via mechanisms unlike classical inflammation (Fig. 1). These mechanisms include the cell-specific localization of CNS COX and 5-LOX, the type of lipid molecules generated by these enzymes, the type and the localization of GPCRs selective for a type of lipid molecule, and the putative interactions of the COX and 5-LOX pathways with intracellular components such as the gamma-secretase complex. Surprisingly, little research has been directed toward understanding the role of eicosanoid receptors in AD. Furthermore, interplay between COXs and 5-LOX pathways, as exemplified by the generation of anti-inflammatory/neuroprotective 15-epi-LXA4, may provide novel insights into the role of these pathways in neurodegenerative disorders. Considering the importance of these multiple mechanism may help us delineate the exact nature of the involvement of COX and 5-LOX in AD and would reinvigorate the search for novel targets for AD therapy.