Our response to stress is regulated by the ‘bliss molecule’ anandamide but how exactly remained unknown. Until recently, that is. Elliot Mock has now succeeded in developing a new substance that reduces anandamide, called LEI-401. This has made it easier to conduct research into the role of anandamide and how we can target it for new therapies for post-traumatic stress disorder and depression.
You don't think about it, but from vegetable oil, the brain makes indispensable signalling lipid molecules. Our brain uses linoleic acid to produce the signal substance anandamide, known as a bliss molecule or endocannabinoid because it has a similar effect to THC from cannabis. ‘Anandamide is an important link in our stress response,’ says Elliot Mock. ‘That makes it interesting to investigate in relation to post-traumatic stress disorder and depression. The level of anandamide in the brain is fairly stable, but it is reduced in stressful situations, signalling an increase in the stress hormone cortisol in the blood.’
Lowering anandamide levels
Research is hampered by a lack of tools to do targeted research. Anandamide does its subtle work in the brain, and there are few opportunities to intervene. Researchers want to lower anandamide levels in order to map out the effects, as this can provide clues for new therapies. That's why Mock's PhD was aimed at finding a new synthetic substance that can inhibit the production of anandamide. He succeeded, and his research resulted in a comprehensive publication in Nature Chemical Biology in 2020.
‘It is quite unique for a university graduate to have such precious research done.’
Mock focused on a key enzyme involved in the production of anandamide. ‘The main problem was that we had no indication of where to start. I was lucky to be able to apply to the European Lead Factory when I started in 2014. They do robot screenings with 350,000 different substances, which are tested one by one. It is quite unique for a university graduate to have such precious research done.’
In 2016, the screening resulted in a selection of five substances that inhibit the production of anandamide. This gave Mock a starting point for further optimisation towards an inhibitor that has even higher potency, shows good stability and can also penetrate the brain. With the help of master’s student Ioli Kotsogianni, Mock was able to make more than a hundred subtle variants, one of which has optimal properties: LEI-401.
LEI-401 was tested in an intensive collaboration with research groups from Leiden, the United States and Canada – which explains the long list of authors on Mock's publication. Each lab has its expertise, such as brain physiology and behavioural research in mice. The group in the US showed that LEI-401 clearly reduces anandamide in the brains of mice, which has consequences for behaviour in response to stress.
Helping patients with anxiety disorders
Mock: ‘Researchers can now specifically lower the anandamide level in mice and study the consequences. This allows you to investigate basic mechanisms, and it adds strength to the hypothesis that increasing anandamide levels can be useful in cases of chronic stress or depression. This idea is also demonstrated by recent results from phase 1 clinical trials, where an increase in anandamide has beneficial effects in patients with a social anxiety disorder.’
Elliot Mock (Amsterdam, 1989) studied Molecular Science and Technology at Leiden University and TU Delft and received a Master’s in Chemistry from Leiden University. In 2014, he started as a PhD student in the Molecular Physiology lab under the supervision of Mario van der Stelt. Here, he focused on making new inhibitors and probes for the enzymes that produce N-acylethanolamines, a family of lipid signalling molecules that includes anandamide. He obtained his doctorate in 2019. He is currently working as a postdoctoral scientist in the Laboratory of Molecular Neurodegeneration at the University of Oxford, where he studies the molecular mechanisms of Parkinson’s disease.