Investigating diacylglycerol lipase-beta function in inflammation by activity-based protein profiling (ABPP) and lipidomics

The current understanding of the efficacy in anti-inflammatory effects by DAGLβ inhibition is centered around the class of lipid molecules called prostaglandins. To this date, the most effective way to inhibit prostaglandin production is through the inhibition of enzymes called cyclooxygenases (COXs). Nonsteroidal anti-inflammatory drugs (NSAIDs) are one of the most widely used drugs to treat inflammation. NSAIDs reduce inflammation by inhibiting enzymes called cyclooxygenases (COX). Though the utility of COX inhibitors has been demonstrated in a number of inflammatory conditions, it is well accepted that chronic treatment of COX inhibitors leads to severe side effects including internal hemorrhaging, kidney-failure, hypertension…etc.
The study showed that DAGLβ disruption reversed inflammatory pain. In addition, DAGLβ specific inhibitor KT109 also showed a reversal of allodynia in a dose-dependent manner. One of the most surprising data from the study was the complete recovery from nociception developed by chronic constriction injury (sciatic nerve pain model) as well as chemotherapy-induced peripheral neuropathy (CIPN). The mechanism of the action for DAGLβ is not clearly defined in its capacity to be able to mediate pain signaling. The understanding of the pathways that could mediate chronic pain syndromes present as an urgent challenge that is yet to be defined well. Therefore, we decided to investigate the mechanism of how DAGLβ regulates the lipid environment with a focus on its potential as a therapeutic target.