WWL70 targets the link between 2-arachidonoylglycerol and prostanoid pathways

Binding of 2-arachidonoylglycerol (2-AG) to cannabinoid receptors regulates synaptic activity, which leads to a variety of neurological modifications from cellular to organismal levels. 2-AG levels in brain are tightly regulated by several biosynthetic and degradative enzymes. 2-AG metabolism gives rise to arachidonic acid (AA) and prostaglandin glycerol esters (PG-Gs), which are both the key precursors for prostaglandins (PGs) synthesis. Our group previously found that WWL70, an inhibitor of the 2-AG hydrolytic enzyme α/β-hydrolase domain containing 6 (ABHD6), distinctly reduced PGs levels by inhibiting not only 2-AG hydrolysis but also PG-Gs production, possibly due to its inhibition of cyclooxygenase-2 (COX-2). Studies from our group and others have also demonstrated that WWL70 has strong antiinflammatory effects in immune cells and is protective in the animal models of traumatic brain injury, multiple sclerosis, neuropathic pain, and diabetes. WWL70 targets the metabolic pathways from 2-AG to PGs and thus may provide a unique therapeutic potential for inflammatory and neurological diseases.