Inhibition of endocannabinoid hydrolases MAGL, FAAH and ABHD6 by AKU-005 reduces ex vivo cortical spreading depression DOI Creative Commons

Flavia Brugia,

Konstantin Ivanov,

Auni Aroviita

et al.

The Journal of Headache and Pain, Journal Year: 2025, Volume and Issue: 26(1)

Published: April 23, 2025

Migraine is a common neurovascular disorder that remains currently untreated in half of the patients. One third migraine patients experience aura, which associated with development cortical spreading depolarization (CSD), wave involving neurons and glial cells. Cannabinoids have proven to be promising class compounds for treatment pain. In this study, we are proposing new strategy counteract CSD downstream events via multicomponent enhancement endocannabinoid system (ECS) by using AKU-005, simultaneously target several key endocannabinoids hydrolases. To end, profiled activity selective hydrolases their inhibition AKU-005 analyzed effect on an ex vivo slice model. The inhibitory profile was evaluated glycerol assay lysates from HEK293 cells expressing mouse human MAGL ABHD6. After cortex slices Wistar rats C57 BL/6 J-OlaHsd mice, were quantified mass spectrometry (LC-MS/MS), MAGL, FAAH, ABHD6 measured activity-based protein profiling (ABPP). studied live calcium imaging. Ex vivo, inhibited ABHD6, increasing 2-arachidonoylglycerol (2-AG) anandamide (AEA) levels rat under both basal conditions. showed milder effect, inhibiting only conditions 2-AG states. vitro analyses confirmed findings revealed mice cortex. previously reported as double MAGL/FAAH-inhibitor, also overexpressed little 2-AG-hydrolyzing enzyme brain. line these results, reduced rodent species, higher efficacy rats. Given distinct activities between brain areas migraine, may multiple serve efficient option aura.

Language: Английский

Combined effects of cannabidiol and Δ9-tetrahydrocannabinol alleviate migraine-like symptoms in mice DOI
Erik Zorrilla, Georgii Krivoshein,

Adisa Kuburas

et al.

Cephalalgia, Journal Year: 2025, Volume and Issue: 45(2)

Published: Feb. 1, 2025

Background The therapeutic use of cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC) to treat migraine has been understudied. Using three mouse models, we examined the impact CBD THC on migraine-relevant behaviors triggered by: 1) calcitonin gene-related peptide (CGRP), 2) sodium nitroprusside (SNP), 3) cortical spreading depolarization (CSD). Methods Both male female CD1 mice were treated with (100 mg/kg) or (1 alone in combinations (1, 30 100 prior injection CGRP SNP. assessed for light aversion (photophobia), squint (non-evoked pain), periorbital tactile hypersensitivity, as well possible adverse effects. In a separate set experiments, CSD events optogenetically induced familial hemiplegic 1 (FHM1) mutant wildtype littermates (WT) (C57BL/6 background), followed by grimace motor assessments without (30 mg/kg). Results mice, 100:1 CBD:THC combination mitigated SNP males females. Rescue CGRP- SNP-induced was observed only CBD:THC. None treatments rescued hypersensitivity either sex. FHM1 WT ratio did not affect characteristics but reduce CSD-induced features (i.e., head pain mimic). No effects any cannabinoid using cognitive, emotional, tests. Conclusions A beneficial effect some most bothersome migraine-related symptoms models. Our findings support potential efficacy combined treatments.

Language: Английский

Citations

1
Cannabinoids in headache: helpful or harmful? DOI
Deena E. Kuruvilla

Current Opinion in Neurology, Journal Year: 2025, Volume and Issue: unknown

Published: March 30, 2025

Purpose of review Cannabinoids have gained attention as a potential treatment for headache disorders, including migraine and cluster headache. While some studies suggest cannabinoids may provide analgesic anti-inflammatory effects, concerns remain regarding their overuse headache, cognitive impairment, psychological dependence. This study critically evaluates the current evidence on in treatment, weighing benefits risks. Recent findings With landscape expanding faster than ever, recent explore immune cells target cannabinoids. Immune express cannabinoid CGRP (calcitonin gene-related peptide) receptors. As result, might potentially modulate efficacy CGRP-targeting drugs. Additionally, emerging that enhance neuronal resilience mitigate central sensitization chronic migraine. Research into optimal delivery mechanisms, inhaled, sublingual, transdermal formulations, is also expanding. Summary are being studied particularly migraine, due to interaction with endocannabinoid system, which regulates pain, inflammation, vascular function. Studies help reduce frequency, alleviate improve sleep, though about dependency, medication retrospective indicate benefits, lack standardized dosing, long-term safety data, controlled trials limits conclusive recommendations. Comparisons conventional treatments show mixed results, presenting variable effectiveness risk adverse effects. Further research, randomized trials, needed establish safety, management.

Language: Английский

Citations

0
Enhancement of the endocannabinoid system through monoacylglycerol lipase inhibition relieves migraine-associated pain in mice DOI Creative Commons

Elizaveta Mangutov,

Yaseen Awad-Igbaria, Kendra Siegersma

et al.

The Journal of Headache and Pain, Journal Year: 2025, Volume and Issue: 26(1)

Published: April 18, 2025

Migraine affects over 1 billion people worldwide and is a leading cause of disability. Targeting the cannabinoid system offers promising approach for pain migraine relief. This study evaluated novel monoacylglycerol lipase (MAGL) inhibitor to prolong endocannabinoid action in acute chronic mouse models migraine. It also examined MAGL receptor (CB1) mRNA expression key head pain-processing regions. C57BL6/J male female mice received human trigger nitroglycerin (NTG) acutely or every other day 9 days. Allodynia was assessed by von Frey hair stimulation periorbital area. A single dose (ABD-1970) tested NTG models. Additionally, ABD-1970 given daily 5 days assess tolerance. In situ hybridization measured transcript MAGL, CB1, neuronal marker Rbfox3 trigeminal ganglia (TG) nucleus caudalis (TNC). injection blocked cephalic allodynia induced NTG. established intermittent Repeated administration did not induce tolerance, continued block NTG-induced after administration. There high CB1 TG TNC, present positive negative cells. effectively migraine-associated pain, likely through prolonged action. effect may be mediated at peripheral central sites considering respectively. The appears modulate mechanisms, target this disorder.

Language: Английский

Citations

0
Inhibition of endocannabinoid hydrolases MAGL, FAAH and ABHD6 by AKU-005 reduces ex vivo cortical spreading depression DOI Creative Commons

Flavia Brugia,

Konstantin Ivanov,

Auni Aroviita

et al.

The Journal of Headache and Pain, Journal Year: 2025, Volume and Issue: 26(1)

Published: April 23, 2025

Migraine is a common neurovascular disorder that remains currently untreated in half of the patients. One third migraine patients experience aura, which associated with development cortical spreading depolarization (CSD), wave involving neurons and glial cells. Cannabinoids have proven to be promising class compounds for treatment pain. In this study, we are proposing new strategy counteract CSD downstream events via multicomponent enhancement endocannabinoid system (ECS) by using AKU-005, simultaneously target several key endocannabinoids hydrolases. To end, profiled activity selective hydrolases their inhibition AKU-005 analyzed effect on an ex vivo slice model. The inhibitory profile was evaluated glycerol assay lysates from HEK293 cells expressing mouse human MAGL ABHD6. After cortex slices Wistar rats C57 BL/6 J-OlaHsd mice, were quantified mass spectrometry (LC-MS/MS), MAGL, FAAH, ABHD6 measured activity-based protein profiling (ABPP). studied live calcium imaging. Ex vivo, inhibited ABHD6, increasing 2-arachidonoylglycerol (2-AG) anandamide (AEA) levels rat under both basal conditions. showed milder effect, inhibiting only conditions 2-AG states. vitro analyses confirmed findings revealed mice cortex. previously reported as double MAGL/FAAH-inhibitor, also overexpressed little 2-AG-hydrolyzing enzyme brain. line these results, reduced rodent species, higher efficacy rats. Given distinct activities between brain areas migraine, may multiple serve efficient option aura.

Language: Английский

Citations

0