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IC50: Zileuton inhibited 5-hydroxyeicosatetraenoic aicd synthesis in rat basophilic leukemia cell and polymorphonuclear leukocytes (IC50 = 0.5 and 0.3 μM), respectively [1].

5-Lipoxygenase pathway is to form leukotrienes, including leukotriene B4 (LTB4), 5-oxo-6E,8Z,11Z,14Z-eicosatetranoic acid and the cysteinyl leukotrienes (LTC4, LTD4 and LTE4) and activates all four leukotriene receptors, BLT1, BLT2, cysLT1 and cysLT2. Zileuton is the only commercially available inhibitor of the 5-Lipoxygenase pathway.

In vitro: Treatment of H9c2 cells with zileuton efficiently induced COX-2 expression and PGE2 biosynthesis in a time- and dose-dependent manner. Zileuton also exerted a profound protective effect against H2O2-induced oxidative stress, a mimic of reperfusion damage in vitro, and this protective effect was abolished by COX-2-selective inhibitor. Furthermore, zileuton-stimulated ERK1/2 and Akt phosphorylation was attenuated by rottlerin, indicating that PKCδ might act upstream of ERK1/2 and Akt. These results suggest that zileuton-induced COX-2 expression is sequentially mediated through PKCδ-dependent activation of ERK1/2 and Akt. Based on these findings, we propose that zileuton might provide a new therapeutic strategy for ischemia/reperfusion injury of the heart [2].

In vivo: To investigate the mechanism underlying zileuton's neuroprotection, SD rats underwent permanent middle cerebral artery occlusion (MCAO), then received treatment with zileuton or vehicle after the onset of ischemia. Zileuton was found to significantly reduce neurological deficit scores, cerebral infarct volume, MPO activity, and the lipid peroxidation levels. It also inhibited the expression of NF-kappaB and decreased the expression and activity of iNOS in rat brain. In addition, zileuton attenuated the release of TNF-alpha and IL-1beta in serum. These results suggested that zileuton reduces inflammatory reaction and brain damage in a rat model of permanent focal cerebral ischemia. The neuroprotective effect of zileuton in cerebral ischemia might be associated with the inhibition of inflammatory reaction [3].

Clinical trial:

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