TREK-1 channel is Activated By Oxidized Omega-3 metabolites – TA-BOOm

The first part of the project is aimed to detect metabolites of fatty acids of interest. Indeed, during the oxidation of fatty acids, hundreds of metabolites are produced. To detect those having a biological interest, we will use a recently developed technic, the bioactive molecular network. This technic is based on the comparison of different fractions of oxylipins produced by different types of oxidation and after the attribution of an activity score; after a mathematical calculation, the metabolites having the highest probability to be active will be detected.
The synthesis of these metabolites will be performed by the chemist’s team who is renowned for that. The method will depend on the metabolites.
To evaluate the activity of these molecules on TREK-1 channel, we will use the patch-clamp technic in the ruptured whole-cell configuration. This technic is based on the recording of transmembrane ionic current thanks to a glass pipette having the tip sealed on the cell membrane. Experiments with this technic will be performed on a cell line stably expressing TREK-1.
The most active molecules will then be evaluated on different animal models of pain (mice), epilepsy (zebra fish) and cardiac infarction (mice). The molecules the most performant at this stage will be patented in order to be more deeply explored in preclinic experiments.

Polyunsaturated fatty acids belong to the family of molecules activating TREK-1. It is admitted that the more they have double bonds, the more active they are. However, we have preliminary results indicating that there are not only fatty acids per se that are actives but also one or more oxidized metabolites. We already found one metabolite of docosahexaenoic acid. We have also other preliminary results indicating that some metabolites of eicosapentaenoic acid are also active.

The molecules we are focused in are of interest to be natural and for some of them found in organisms. Thus the risk of having side effects is reduced (our preliminary experiments of cytotoxicity are very encouraging). If we take pain as an example, there is a cure that is very efficient, cocaine. The problem with this molecule is that it induces addiction. If we find a very efficient activator of TREK-1, we could obtain important analgesic effects without any side effect. In that case, we could develop this kind of molecule up to the preclinical phase in order to sell a business license to pharmacological enterprise. We will then create a star-up dedicated to the detection of biologically active non-enzymatic metabolites of polyunsaturated fatty acids (not only on TREK-1).

An application has been filed with the Satt AxLR to file a patent to protect the DHA metabolite we discovered. Once the patent has been filed, we will quickly publish the data.

Trek-1 is an ubiquitary ionic channel playing a central role in physiology and its regulation can allow to fight many pathologies such as depression, detection and transmission of the painful signal, cerebral and cardiac ischemia. Its potassium channel is also known to be activated by polyunsaturated fatty acids such AA, EPA and DHA. We recently have shown that DHA (known to be cardioprotective in the secondary prevention after infarction) might exert its properties indirectly by the production of non-enzymatic oxidized PUFAs named NEO-PUFAs with biological effects. We have also shown that Trek-1 does not seem to be activated by DHA itself but rather by NEO-PUFAs derived from oxidation of DHA. This new paradigm opens new perspectives in the big challenge of curing pathologies such as chronic pain. We aim to determine what are the NEO-PUFAs which activate Trek-1 channel and what impact will have these oxidized lipids on cardiac or cerebral ischemia or sensation of pain.