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  • Additional evidence for a putative role of

    2024-05-14

    Additional evidence for a putative role of COXs and 5-LOX in AD derives from pharmacological studies using inhibitors of these enzymes (for review, see Firuzi and Praticò, 2006). In addition to helping delineate the pathobiological mechanisms of AD, these results raise hope for discovering novel therapeutic targets and modalities.
    Neurotoxic/neuroprotective action of prostaglandins, leukotrienes, and their receptors in the CNS The two COX enzymes, COX-1 and COX-2, that are capable of converting arachidonic LB Agar Miller to prostaglandin H2 (PGH2), show a differential cell type-specific expression in adult mammalian brain. COX-1 is constitutively expressed in most tissues and in the brain predominantly in microglia (for review, see Choi et al., 2009). On the other hand, in the brain, COX-2 is constitutively expressed in hippocampal neurons and their dendritic spines. Neuronal COX-2 expression is modified by synaptic activity (Kaufmann et al., 1996) as well as by pathological conditions including the beta-amyloid peptide-triggered neurotoxicity (Ryu et al., 2004). Depending upon the differential cellular localization of COX-1 and COX-2, the subsequent conversion of PGH2 into other active molecules may lead to dissimilar ultimate products of COX-1 vs. COX-2 activity. Niemoller and Bazan (2010) stressed the complex nature of the downstream cyclooxygenase signaling pathways that may be responsible for both neurodegeneration and neuroprotection. These include PGE2, a product of COX-2 that activates the G protein-coupled receptors (GPCRs) EP1, EP2, EP3 and EP4. It appears that activation of the G-alpha-coupled EP2 receptor by PGE2 is neuroprotective and drug discovery efforts have been directed toward finding compounds that could potentiate this action of PGE2, i.e., the positive allosteric modulators (potentiators) of the EP2 receptors (Jiang et al., 2010). On the other hand, PGE2 is capable of stimulating the production of amyloid-beta by a coordinated action on both EP2 and EP4 receptors (Hoshino et al., 2009). In addition, it has been suggested that cell type-specific targeting of EP2 receptors may be needed to reduce the amyloid-beta-induced neurodegeneration (Shie et al., 2005). Furthermore, activation of EP1 receptors leads to neurodegeneration that can be reduced by selective EP1 antagonists (Abe et al., 2009). In vitro, the synthesis of 5-LOX metabolites of arachidonic acid has been demonstrated in microglia (Matsuo et al., 1995) and neuronal precursors (Wada et al., 2006). The CNS is capable of producing 5-LOX metabolites (Chinnici et al., 2007, Hynes et al., 1991), possibly via a transcellular synthesis of cysteinyl leukotrienes in neurons and glia (Farias et al., 2007). 5-LOX products play a critical role in neuroplasticity such as the hedgehog-dependent neurite projection (Bijlsma et al., 2008). Generally, the conversion of arachidonic acid by 5-LOX leads to production of leukotrienes and, under certain conditions, lipoxins. These lipid mediators affect cell functioning via corresponding GPCRs (Wada et al., 2006). Various leukotriene receptors are expressed by both neurons and microglia (Okubo et al., 2010). It was shown that 5-LOX pathway plays a significant role in neuronal precursors (e.g., the immature cerebellar granule cells) (Uz et al., 2001) and neural stem cell (NSC) (Wada et al., 2006). Thus, proliferation of NSCs was stimulated by LTB4 and blocked by a LTB4 receptor antagonist, which also caused apoptosis and cell death. In contrast, LXA4 attenuated growth of NSCs (Wada et al., 2006). In addition to proliferation, LTB4 induced differentiation of NSCs into neurons as monitored by neurite outgrowth. These authors suggested that LTB4 and LXA4 directly regulate proliferation and differentiation of NSCs and demonstrated the opposing actions of two different 5-LOX metabolites on NSCs. Recent data indicate that leukotrienes could influence neuronal survival and differentiation via novel types of receptors, e.g., the P2Y-like receptor GPR17 (Daniele et al., 2010).