more resistant to the dehydrogenation enzyme than their LX epimers. In consequence of the operation of this anabolic pathway, LXs have very short half-lives in vivo, the epi-LXs have longer in vivo half-lives and thereby greater potencies than their LX epimers, and synthetic lipoxins that are metabolically resistant to this pathway have been prepared, used in animal models to study LX activities, and tested as potential therapeutic agents in animals and humans. Similar to various other AA metabolites such as LTA4 and 5-oxo-eicosatetraenoic acid, cells and tissues may convert LXs to 20-hydroxy products by omega oxidation; they also have been shown to ligate LXA4 to glutathione to form cysteinyl-lipoxins, initially LXC4, which is then sequentially metabolized to LXD4 and LXE4. The role of these pathways in limiting or contributing to the activity of the LXs has not been fully evaluated. Endocannabinoid system It is found that the anti-inflammatory lipid lipoxin A4 is an endogenous allosteric enhancer of the CB1 cannabinoid receptor. Lipoxin A4 enhance the affinity of anandamide at this receptor to exert cannabimimetic effects in the brain, by allosterically enhancing AEA signaling and thereby potentiating the effects of this endocannabinoid both in vitro and in vivo. In addition to this, lipoxin A4 display a CB1 receptor-dependent protective effect against β-amyloid-induced spatial memory impairment in mice. Lipoxin analogues Relatively stable, i.e. metabolically resistant, synthetic analogues of LXs and aspirin-triggered 15-epi-LXA4s can mimic many of the desirable anti-inflammatory, "pro-resolution" actions of native LXs and are being tested for clinical use. Structurally, these LX analogs often mimic the LXs in being or closely resembling a 20-carbon trihydroxy fatty acid, but are resistant to 15-hydroxyprostaglandin dehydrogenase metabolic inactivation by having a bulky or other structural modification near their 15-hydroxy residues. For example, certain analogs simply alter an LX's structure by: replacing a hydrogen atom with a methyl residue at carbon 15 on LXA4 to form 15-methyl-LXA4; changing the last 4 carbons of LXA4 or 15-epi-LXA4 to a 1-phenoxy residue or 1-phenoxy-4-fluoro residue to form 16-phenoxy-LX4, 15-epi-15-phenoxy-LXA4, 16-(para-fluoro-phenoxy-LXA4, or 15-epi-16-(para-fluoro-phenoxy-LXA4; and forming a bond between carbon 9 and carbon 14 of LXA4 to form an internal phenyl ring analog termed aromatic LXA4; other, more complex structural analogs in development include 15-epi-LXA4 analogs termed ZK-142 and ZK994. Biological activity Cellular studies In the initial phases of many acute inflammatory responses, damaged tissues, invading pathogens, and other local events cause nearby cells to make and release