Objective: 

Arachidonic acid (AA) is one of the most abundant lipids in the cellular membrane. AA is then converted into a number of pro-inflammatory mediators including prostaglandins (PGs) and thromboxanes (TXs). Non steroideal anti-inflammatory drugs (NSAIDs) are a family of molecules used in the treatment of inflammation, pain and fever. These compounds block PGs and TXs synthesis inhibiting COX1 and COX2 activities. Our objective is the synthesis of a new NSAID based on the structure of AA.

Methods: 

We have synthesized a new non-toxic lipid derivative: the 2-hydroxy arachidonic acid (2OAA) designed by omputational docking analysis to interfere with COX1 and COX2. To study the effectiveness of 2OAA in an in vivo model we measured TNF-alpha plasma levels in C57BL6/J mice challenged with LPS (20 mg) and treated with 2OAA at 50, 200 and 500 mg/Kg (5 animals per group).

Results: 

Our results demonstrated that 2OAA inhibited COX1 activity and COX2 activity and protein/mRNA expression in human U937 monocytes-derived macrophagues challenged with lipopolysacharide (LPS). In addition 2OAA also demonstrated to inhibit iNOS expression and NO production in mouse BV2 microglial cells. To study the effectiveness of 2OAA in an in vivo model we measured TNF-alpha plasma levels in C57BL6/J mice challenged with LPS. Our results demonstrated that oral administration of 2OAA lowered the TNF-alpha plasma levels induced by LPS. The TNF-alpha plasma level inhibition by 2OAA was greater than the inhibition produced by ibuprofen and cortisone in the same experiment.

Conclusions: 

These results show the potential of 2OAA as a non-toxic anti-inflammatory/antioxidant drug.