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LP204A1 in inflammation

LP204A1 is a PUFA derivative that produces a remarkable anti-inflammatory effect in a LPS-challenged mouse model of inflammation acting through COX1 and COX2. Its efficacy is similar to that of steroid compounds, albeit its non-steroid structure suggests a lower toxicity, aspect that has been initially assessed in preliminary studies in zebra fish, flies and mice.

 

LP204A1 inhibits both COX-1 and COX-2, although it only induces proteaseome-associated degradation of COX-2, the inducible isoform involved in the inflammatory response. This fact further supports its lack of side effects, because drugs that only inhibit COX-1 or COX-2 induce gastric or cardiovascular toxic effects.

 

The lowering in the levels of COX-2 mediated by proteolysis of the enzyme via the ubiquitin-proteasome system indicates that LP204A1 could have a longer effect (12-24 h) in local and general inflammation processes, with all the potential therapeutic applications this may have. In summary, the mechanism of action for LP204A1 is based first on its binding to COX and later enzyme inhibition and proteolysis of COX-2.

 

LP204A1 poc

In-vivo anti-inflammatory effect of Arachidonic acid (AA), cortisone (COR), ibuprofene (IBU) or LP204A1 as determined by the levels of TNFa in serum.


The marked similarity of the structure of LP2014A1 with that of the natural COX-1/2 and 5-LOX substrate, arachidonic acid (AA), justifies the high affinity and lack of toxicity of this drug. In addition, COX cannot hydrolyze LP204A1 due to the extra oxygen atom on C2.

 

A collaboration with an external research group (at the University of Leon, Spain) is currently ongoing to explore potential effect of LP2014A1 as a potential treatment of ischaemic lesion following brain stroke. This reserach is supported by a grant of the Spanish Ministry of Economy and Competitivity (Desarrollo farmacéutico de lípidos de diseño para el tratamiento del ictus y patologías relacionadas (Metabolopatías), ICTUS, Ref: RTC-2015-4094-1)

 


Proyecto financiado por el Ministerio de Economía y Competitividad y cofinanciado por los Fondos Europeos de Desarrollo Regional (FEDER)

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Relevant related documents:

 

::> Neuroprotective effect of 2-hydroxy arachidonic acid in a rat model of transient middle cerebral artery occlusion. Ugidos I.F. Et al. Biochim Biophys Acta. 2017 Sep;1859(9 Pt B):1648-1656.

 

icon 2-Hydroxy Arachidonic Acid: A New Non-Steroidal Anti-Inflammatory Drug (3.8 MB) Lopez et al. PLOS ONE, Aug. 2013

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