The 5-lipoxygenase-activating protein (FLAP), an integral membrane protein, facilitates substrate transfer to 5-lipoxygenase which catalyzes leukotriene formation from arachidonic acid, making it an alternative target (in addition to 5-lipoxygenase) to intervene with leukotriene biosynthesis and respective diseases. MK-886, a potent FLAP inhibitor, potently suppresses leukotriene biosynthesis in intact leukocytes with an IC50 of 2.5 nM. Moreover, MK-886 concentration-dependently inhibited COX-1 with an IC50 of 8 μM. In platelets, MK-886 concentration-dependently suppressed the formation of the COX-1-derived products 12-HHT and TxB2 with IC50 values of 13 – 15 μM. Further, 10 μM MK-886 decreased platelet aggregation in washed platelets evoked by collagen or arachidonic acid[3]. In vitro, MK-886 increased GluR1 phosphorylation at both serine 831 and serine 845. In vivo, repeated daily i.p. injections of MK-886 resulted in increased GluR1 phosphorylation in brain samples obtained from the prefrontal cortex supporting the use of MK-886 as a pharmacological tool in studies of not only the 5-LOX pathway but also neuronal GluR1 functioning[4].
MK-886 细胞实验
Cell Line
Concentration
Treated Time
Description
References
Jurkat cells
200 nM
30 minutes
Inhibit LTB4 secretion and reduce Jurkat cell migration
Nat Commun. 2017 Jun 22;8:15890.
C91/PL cells
200 nM
30 minutes
Inhibit LTB4 secretion and reduce contact formation with Jurkat cells
Nat Commun. 2017 Jun 22;8:15890.
Rat pulmonary vascular endothelial cells
10^-5 M
10 minutes
MK-886 significantly reduced the pressor responses induced by angiotensin II and hypoxia
J Clin Invest. 1996 Jun 1;97(11):2491-8.
MK-886 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Mice (C57BL/6)
TsV-induced inflammation model
Intraperitoneal
5 mg/kg
4 h and 0.5 h before and again 4 and 8 h after
To assess the effect of MK886 on TsV-induced inflammation and mortality. Results showed that MK886 increased mortality, decreased LTB4 and IL-1β, and increased PGE2 levels.
Nat Commun. 2016 Feb 23;7:10760.
Humanized mice
HTLV-1 infection model
Intraperitoneal injection
5 nmol
Three times a week for six weeks
To evaluate the effect of MK886 treatment on LTB4 plasma levels and viral load in HTLV-1-infected mice. Results showed that MK886 treatment significantly reduced LTB4 plasma levels and viral load.
Nat Commun. 2017 Jun 22;8:15890.
Mice
Acetic acid-induced visceral pain model
Subcutaneous injection
1 mg/kg
Single administration
MK-886, as a PPAR-α antagonist, blocked the analgesic effects of URB937 in the acetic acid-induced visceral pain model
Nat Neurosci. 2010 Oct;13(10):1265-70
Rats
Chronic hypoxic pulmonary hypertension model
Intraperitoneal injection
30 mg/kg
Once daily for 28 days
MK-886 inhibited the development of chronic hypoxic pulmonary hypertension, reducing pulmonary artery pressure and right ventricular hypertrophy
J Clin Invest. 1996 Jun 1;97(11):2491-8.
Humanized mice
HTLV-1 infection model
Intraperitoneal injection
5 nmol/mouse
Three times a week for 6 weeks
Reduce HTLV-1 proviral load and number of infected clones
Nat Commun. 2017 Jun 22;8:15890.
Rats
Chronic hypoxic pulmonary hypertension model
Intraperitoneal injection
30 mg/kg
Once daily for 28 days
MK-886 reduced the development of chronic hypoxic pulmonary hypertension and right ventricular hypertrophy
J Clin Invest. 1996 Jun 1;97(11):2491-8.
Mice
Zymosan-induced peritonitis
Intraperitoneal injection
1 mg/kg
Single dose, 30 minutes prior
Evaluate the effect of MK886 on reducing LTB4 levels, showing more significant effects in female mice
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