Anti-Inflammatory Activity of a Potent, Selective Leukotriene A₄ Hydrolase Inhibitor in Comparison with the 5-Lipoxygenase Inhibitor Zileuton

Abstract

Leukotriene A 4 hydrolase (LTA 4 H) catalyzes production of the proinflammatory lipid mediator, leukotriene (LT) B 4 , which is implicated in a number of inflammatory diseases. We have identified a potent and selective inhibitor of both the epoxide hydrolase and aminopeptidase activities of recombinant human LTA 4 H (IC 50 , approximately 10 nM). In a murine model of arachidonic acid-induced ear inflammation, the LTA 4 H inhibitor, JNJ-26993135 (1-[4-(benzothiazol-2-yloxy)-benzyl]-piperidine-4-carboxylic acid), dose-dependently inhibited ex vivo LTB 4 production in blood, in parallel with dose-dependent inhibition of neutrophil influx (ED 50 , 1-3 mg/kg) and ear edema. In murine whole blood and in zymosan-induced peritonitis, JNJ-26993135 selectively inhibited LTB 4 production, without affecting cysteinyl leukotriene production, while maintaining or increasing production of the anti-inflammatory mediator, lipoxin (LX) A 4 . The 5-lipoxygenase (5-LO) inhibitor zileuton showed inhibition of LTB 4 , LTC 4 , and LXA 4 production. Although zileuton inhibited LTB 4 production in the peritonitis model more effectively than the LTA 4 H inhibitor, the influx of neutrophils into the peritoneum after 1 and 2 h was significantly higher in zileuton-versus JNJ-26993135-treated animals. This difference may have been mediated by the increased LXA 4 levels in the presence of the LTA 4 H inhibitor. The selective inhibition of LTB 4 production by JNJ-26993135, while increasing levels of the anti-inflammatory mediator, LXA 4 , may translate to superior therapeutic efficacy versus 5-LO or 5-LO-activating protein inhibitors in LTB 4 -mediated inflammatory diseases.

ALOX5AP Overexpression in Adipose Tissue Leads to LXA4 Production and Protection Against Diet-Induced Obesity and Insulin Resistance

“…8). In agreement with our results, blocking LTA 4 hydrolase, the enzyme responsible for converting LTA 4 to LTB 4 , leads to anti-inflammatory effects mediated by an increase in LXA 4 production (61,62). Our data also support the idea that LXA 4 deficiency plays a role in the development of obesity and its complications.…”

Hippocampal CysLT1R knockdown or blockade represses LPS-induced depressive behaviors and neuroinflammatory response in mice

“…One week after infusion, mice were treated with a single LPS administration and then subjected to Western blot assay. Quantification of Western blot showed that infusion of LVCysLT 1 R-shRNA-EGFP but not LV-EGFP significantly suppressed the LPS-induced increase in CysLT 1 R expression in the mouse hippocampus (F (3,12) =30.01, Veh+Veh vs Veh+LPS: P=0.0013; Veh+LPS vs LV-EGFP+LPS: P=0.747; Veh+LPS vs LV-CysLT 1 R-shRNA-EGFP+LPS: P<0.001; Figure 1D, 1E).…”

“…They exert effects through cell surface receptors, such as cysteinyl leukotriene receptor 1 (CysLT 1 R). Leukotriene pathway modifiers, including 5-lipoxygenase inhibitor (zileuton) and CysLT 1 R antagonists (montelukast, zafirlukast, and pranlukast), have been used as anti-asthmatic drugs [11][12][13] . Recently, several studies on CysLT 1 R have focused on its novel pathophysiological role in CNS disorders, such as cognitive impairment [14] , cerebral ischemia [15] , brain trauma [16] and experimental autoimmune encephalomyelitis [17] .…”

Lipoxin and resolvin biosynthesis is dependent on 5‐lipoxygenase activating protein

“…Inhibition of LTA 4 hydrolase selectively inhibits LTB 4 formation while increasing LXA 4 synthesis in a mouse model of zymosan-induced peritonitis. In addition, inhibition of LTA 4 hydrolase was found to attenuate allergic airway inflammation, thereby increasing LXA 4 levels in the bronchoalveolar lavage fluid of mice (32,33).…”

“…Inhibition of these enzymes might elevate available LTA 4 for LX synthesis while inhibiting proinflammatory LTs. This has already been shown for LTA 4 hydrolase inhibition in mouse models of inflammation (32,33). The PMNL/platelet coculture system represents a suitable in vitro system to test the influence of LT synthase inhibitors on LX synthesis.…”