5-Lipoxygenase in the Central Nervous System: Therapeutic Implications
5-Lipoxygenase (5-LOX) is a protein with catalytic activity that is essential for transforming arachidonic acid into leukotrienes and that has the ability to bind and possibly affect the function of a number of cellular proteins, including cytoskeletal proteins. A limited number of clinically-used drugs target the 5-LOX pathway, they are either 5-LOX inhibitors or antagonists of leukotriene receptors and are primarily used for the treatment of asthma. 5-LOX is also expressed and enzymatically active in various compartments of the mammalian brain, including central nervous system (CNS) neurons. However, insufficient information is available on the extent to which 5-LOX-related drugs cross the blood-brain barrier. Research into the CNS 5-LOX pathway indicates that 5-LOX may participate in a number of brain pathologies, including developmental neurometabolic diseases, stroke, seizures, Alzheimers disease, aging-associated neurodegeneration, prion disease, multiple sclerosis, and brain tumors. Physiologically, 5-LOX appears to be involved in neurogenesis. The expression of 5-LOX is affected by hormones and appears to be subject to epigenetic regulation via alterations in DNA methylation in the region of the 5-LOX promoter. In this review, we propose that a novel 5-LOX drug therapy could be targeted not only to 5-LOX enzymatic activity and leukotrienes, but also toward modifying 5-LOX expression and the possibility of interfering with non-enzymatic actions of 5-LOX proteins. It is suggested that a new 5- LOX pharmacopoeia, which would be effective in the CNS would significantly advance research on the role of 5-LOX in the brain.
Keywords: 5-Lipoxygenase, 5-LOX PATHWAY, CNS PATHOLOGY, Neurometabolic Diseases, Alzheimers Disease, Prion Disease
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