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

Project description

Cannabidiol-based therapy offers new hope for migraine relief

Migraine is a complex neurovascular condition, with traditional therapies effective for only about 50 % of patients. Cannabis and its endocannabinoids have shown promise in reducing migraine frequency. Recent advances in inhibitors for the enzymes that regulate these endocannabinoids may further enhance their pain-relieving effects. Supported by the Marie Skłodowska-Curie Actions programme, the Migraine Cannabinoid project aims to develop a treatment that reduces migraine-related pain by inhibiting the FAAH and MAGL enzymes. The project will use the serine hydrolase inhibitor AKU-005 to reduce nociceptive activation. Preliminary research suggests that combining delta-9-tetrahydrocannabinol (THC) with allosteric cannabidiol (CBD) agonists can alleviate light aversion in CGRP migraine models. By enhancing endocannabinoids with AKU-005 and CBD, this approach aims to safely inhibit migraine pain pathways.

Objective

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.

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HORIZON-TMA-MSCA-PF-GF - HORIZON TMA MSCA Postdoctoral Fellowships - Global Fellowships

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(opens in new window) HORIZON-MSCA-2024-PF-01

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Coordinator

KING'S COLLEGE LONDON
Net EU contribution

Net EU financial contribution. The sum of money that the participant receives, deducted by the EU contribution to its linked third party. It considers the distribution of the EU financial contribution between direct beneficiaries of the project and other types of participants, like third-party participants.

€ 454 103,40
Address
STRAND
WC2R 2LS London
United Kingdom

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Region
London Inner London — West Westminster
Activity type
Higher or Secondary Education Establishments
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Total cost

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