12/15 Lipoxygenase as a Therapeutic Target in Brain Disorders

Lipoxygenases are a family of lipid-oxidizing enzymes, which generate eicosanoids and related compounds from arachidonic acid and other polyunsaturated fatty acids. These metabolites play important roles in physiology and pathogenesis of host defense mechanisms, cardiovascular diseases, cancer, inflammatory, allergic and neurodegenerative diseases. The 12/15-lipoxygenase (LOX) is special in that it can directly oxidize lipid membranes containing polyunsaturated fatty acids, without the preceding action of a phospholipase, leading to the direct attack on membranous organelles, such as mitochondria. The cytotoxic activity of human 12/15-LOX is up-regulated in neurons and endothelial cells especially after a stroke and thought to contribute to both neuronal cell death and blood-brain barrier leakage. The discovery of inhibitors that selectively target recombinant 12/15-LOX in vitro, as well as possessing activity against the murine orthologous ex vivo, could potentially support a novel therapeutic strategy for the treatment of stroke and other brain disorders related to 12/15-LOX. Here we reviewed 12/15-LOX chemistry shortly, and the diseases in which 12/15-LOX has a role in their pathophysiology and recent advances of 12/15-LOX inhibitors as a treatment option for neurological diseases.