WWL70 is identified as a selective inhibitor of the alpha/beta hydrolase domain 6 (ABHD6), exhibiting an IC50 of 70 nM[1]. One hour following treatment with WWL70 at a concentration of 10 μM, there is a 20% increase in 2-Arachidonoylglycerol levels compared to untreated cells. WWL70, at concentrations of 1 μM or 10 μM, entirely prevents LPS-induced elevation of PGE2. It also diminishes the LPS-stimulated mRNA upregulation of mPGES-1 and mPGES-2. The IC50 for WWL70 in the inhibition of PGE2 synthesis is approximately 100 nM[2].
WWL70 细胞实验
Cell Line
Concentration
Treated Time
Description
References
Acute accumbal slices
1 µM
10 minutes
WWL70 mimicked the anti-insulin action of dexamethasone, supporting the involvement of 2-AG in the glucocorticoid-induced insulin resistance
Brain Res Bull. 2016 Jun;124:222-30
Primary microglia cells
10 µM
30 min
Suppressed PGE2 production in LPS-activated microglia
J Neuroinflammation. 2017 Jan 10;14(1):7
BV2 cells
10 µM
30 min
Inhibited 2-AG hydrolysis and elevated intracellular 2-AG levels
J Neuroinflammation. 2017 Jan 10;14(1):7
Primary peritoneal macrophages
10 µM
8 hours
To confirm the effect of ABHD6 inhibition in primary peritoneal macrophages, WWL70 significantly increased 2-AG levels and reduced LPS-induced IL-1β mRNA expression
Proc Natl Acad Sci U S A. 2013 Oct 22;110(43):17558-63
BV2 microglial cells
10 µM
8 hours
To confirm the effect of ABHD6 inhibition in BV2 cells, WWL70 significantly increased 2-AG levels and reduced LPS-induced IL-1β mRNA expression
Proc Natl Acad Sci U S A. 2013 Oct 22;110(43):17558-63
RAW264.7 macrophages
10 µM
8 hours
To confirm the effect of ABHD6 inhibition in RAW264.7 cells, WWL70 significantly increased 2-AG levels and reduced LPS-induced IL-1β mRNA expression
Proc Natl Acad Sci U S A. 2013 Oct 22;110(43):17558-63
J774 macrophages
0.3 µM (EC50)
8 hours
To assess the implication of ABHD6 in 2-AG metabolism by macrophages, WWL70 dose-dependently increased 2-AG levels and reduced LPS-induced IL-1β mRNA expression
Proc Natl Acad Sci U S A. 2013 Oct 22;110(43):17558-63
WWL70 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Mice
Experimental autoimmune encephalomyelitis (EAE)
Intraperitoneal injection
10 mg/kg
Once daily until the end of experiment
Alleviated clinical symptoms and reduced PGE2 production in brain tissues of EAE mice
J Neuroinflammation. 2017 Jan 10;14(1):7
C57BL/6J mice
Chronic constriction injury (CCI) model of sciatic nerve
Intraperitoneal injection
10 mg/kg
Starting 3 hours post-surgery, once daily for 7 days
WWL70 significantly alleviated CCI-induced thermal hyperalgesia and mechanical allodynia, reduced microglia activation, macrophage infiltration, and the production of nociceptive mediators in the ipsilateral lumbar spinal cord dorsal horn, DRG, and sciatic nerve.
J Neuroinflammation. 2018 Jan 8;15(1):9
Mice
LPS-induced inflammation model
Intraperitoneal injection
20 mg/kg
Single administration, assessed after 4 hours
To assess the anti-inflammatory effects of ABHD6 inhibition in vivo, WWL70 significantly reduced LPS-induced proinflammatory cytokine expression without increasing brain 2-AG levels
Proc Natl Acad Sci U S A. 2013 Oct 22;110(43):17558-63
C57BL/6 mice
Traumatic brain injury (TBI) model
Intraperitoneal injection
5 mg/kg or 10 mg/kg
Once daily for 3, 7, or 21 days
WWL70 treatment improved motor coordination and working memory performance, reduced lesion volume in the cortex and neurodegeneration in the dentate gyrus, suppressed the expression of inducible nitric oxide synthase and cyclooxygenase-2, and enhanced the expression of arginase-1 in the ipsilateral cortex at 3 and 7 days post-TBI, suggesting microglia/macrophages shifted from M1 to M2 phenotypes after treatment. The blood-brain barrier dysfunction at 3 and 7 days post-TBI was dramatically reduced.
J Neurotrauma. 2013 Apr 1;30(7):565-79
WWL70 动物研究
Animal study
Post-treatment with WWL70 at a dosage of 5 mg/kg shows no significant effect, whereas a 10 mg/kg dosage markedly enhances performance. WWL70 treatment dose-dependently improves motor coordination in mice with traumatic brain injury (TBI). The time before falling increases in animals treated with 5 mg/kg WWL70 from 74.92±4.8 to 99.57±5.21 on day 3 (p<0.01) and from 87.32±4.42 to 100.14±3.56 on day 7 (p<0.05) post-injury, compared to the vehicle-TBI groups. With a 10 mg/kg dosage, WWL70 treatment begins to enhance motor coordination from day 1 post-injury. WWL70 treatment fully restores the ability of TBI mice to continuously alternate arms during Y maze exploration, achieving a success rate of 69.67±4.98%[3].
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