Combinatorial use of cannabidiol and the serine hydrolase inhibitor AKU-005 to enhance endocannabinoids for treatment of migraine

Descripción del proyecto

Un tratamiento basado en el cannabidiol ofrece nuevas esperanzas para aliviar la migraña

La migraña es una enfermedad neurovascular compleja, y los tratamientos tradicionales solo son eficaces en el 50 % de los pacientes. Se ha demostrado que el cannabis y sus endocannabinoides son prometedores para reducir la frecuencia de las migrañas. Los avances recientes en los inhibidores de las enzimas que regulan estos endocannabinoides pueden potenciar aún más sus efectos analgésicos. Apoyado por las Acciones Marie Skłodowska-Curie, el equipo del proyecto Migraine Cannabinoid pretende desarrollar un tratamiento que reduzca el dolor relacionado con la migraña mediante la inhibición de las enzimas FAAH y MAGL. En el proyecto se utilizará el inhibidor de la serina hidrolasa AKU-005 para reducir la activación nociceptiva. Las investigaciones preliminares sugieren que la combinación de delta-9-tetrahidrocannabinol (THC) con agonistas alostéricos del cannabidiol (CBD) puede aliviar la aversión a la luz en modelos de migraña con CGRP. Al potenciar los endocannabinoides con AKU-005 y CBD, con este método se intenta inhibir de forma segura las vías del dolor migrañoso.

Objetivo

Migraine is a common multifaceted neurovascular disease. Traditional medications have limitations and even newer CGRP monoclonal antibodies only effectively treat 50% of patients. Instead of using highly addictive painkillers, such as opioids, there is a great need for alternative, effective and safe medications. Despite psychoactive side-effects of cannabis, its derivative compounds (cannabinoids) have emerged as a new class of analgesic and anti-migraine agents. Indeed, the frequency of migraine headaches decreases with medical marijuana. To avoid cannabis psychotropic effects, an alternative is to recruit the anti-nociceptive actions of endogenous cannabinoids (endocannabinoids). The two main endocannabinoids are 2-arachidonoylglycerol (2-AG) and anandamide (AEA). The anti-nociceptive efficiency of 2-AG and AEA is determined by their enzymatic synthesis, activity on receptors CB1 and CB2, and degradation by monoacylglycerol lipase (MAGL) and fatty acid hydrolase (FAAH), respectively. There is recent progress in the development of selective and potent MAGL and FAAH inhibitors, providing excellent starting points for enhancing endocannabinoid activity. A key point is that the enzymes are distinctly active in different migraine pain signaling areas. Therefore, we propose that at least a dual FAAH and MAGL inhibition would be ideal. We have shown that the serine hydrolases inhibitor AKU-005 potently reduces migraine-related nociceptive activation. Of further relevance, the combination of CB1/2 orthosteric delta-9-tetrahydrocannabinol (THC) and allosteric cannabidiol (CBD) agonists can reduce central and peripheral-induced light aversion in CGRP migraine models. Our hypothesis is that enhancement of endocannabinoids by the inhibitor AKU-005 in combination with CBD treatment could safely inhibit migraine-related pain pathways, representing an alternative, non-addictive therapeutic target to help bridge the therapeutic gap and reduce the significant burden in migraine.