Blocking an endocannabinoid-degrading enzyme protected myelin and reduced nerve damage in mice with MS-like disease | Research

The takeaway

Inhibiting the enzyme that breaks down endocannabinoid 2-AG protected brain cells that produce myelin from damage and reduced demyelination in two mouse models of multiple sclerosis.

Read this if you have MS and are interested in how the endocannabinoid system relates to myelin protection.

MAGL blockade protected myelin in both immune and toxin MS models

What the researchers found

Researchers tested JZL184, a drug that blocks the enzyme MAGL (which breaks down the endocannabinoid 2-AG), in cell cultures and two different mouse models of multiple sclerosis-like disease. In cultured oligodendrocytes (the cells that produce myelin), MAGL blockade protected against excitotoxic cell death through CB1 receptor activation.

The protection involved reduced calcium overload, preserved mitochondrial function, and decreased reactive oxygen species. In the chronic autoimmune model (EAE), JZL184 treatment decreased disease severity, prevented demyelination, and reduced inflammation. In the cuprizone model (which causes demyelination without immune involvement), JZL184 preserved myelin and suppressed microglial activation.

The endocannabinoid 2-AG itself, applied directly, also protected oligodendrocytes, suggesting the therapeutic benefit comes from boosting the body's own cannabinoid signaling.

Why it matters

Multiple sclerosis involves progressive loss of myelin, and current treatments primarily target the immune system. This study shows the endocannabinoid system can directly protect the myelin-producing cells themselves, suggesting a complementary therapeutic approach.

The numbers in context

MAGL inhibitor JZL184 reduced disease severity in EAE model. Myelin was preserved in both EAE and cuprizone models. Protection depended on CB1 receptor activation. FAAH inhibition (URB597) showed no effect.

How the study worked

Combined in vitro and in vivo study. Cell culture experiments tested MAGL and FAAH inhibitors on oligodendrocyte survival under excitotoxic conditions. Two mouse MS models were used: chronic EAE (immune-mediated) and cuprizone (toxin-induced demyelination). JZL184 was administered therapeutically after disease onset.

What this study cannot tell us

Animal model results do not guarantee human efficacy. JZL184 affects 2-AG levels throughout the body, which could produce unwanted effects. The MS models do not fully replicate human disease complexity. Long-term safety of MAGL inhibition was not assessed.

How to read the evidence

Controlled animal study with two disease models and mechanistic cell culture data, but no human clinical evidence.

When this study was published

Published in 2015. Endocannabinoid-based approaches for MS continue to be investigated.

The bigger picture

The finding that boosting endocannabinoid levels protects myelin through multiple mechanisms (reducing excitotoxicity, inflammation, and oxidative stress) adds scientific rationale to anecdotal reports from MS patients who report benefits from cannabis use.

Questions still open

Could MAGL inhibitors be developed for human MS treatment? Would combining MAGL inhibition with existing immunomodulatory treatments produce additive benefits? What are the long-term consequences of chronically elevated 2-AG?

Common questions

Could boosting endocannabinoids help with MS?

In mouse models, blocking the enzyme that breaks down the endocannabinoid 2-AG protected myelin, reduced inflammation, and decreased disease severity. Whether this translates to human MS treatment remains to be studied.

How is this different from using cannabis for MS?

This approach targets a specific enzyme to boost the body's own endocannabinoid levels rather than introducing plant cannabinoids. It is more targeted and could potentially avoid some of the psychoactive and side effects of whole cannabis.

Read the original research

Blockade of monoacylglycerol lipase inhibits oligodendrocyte excitotoxicity and prevents demyelination in vivo.

Glia, 63(1), 163-76

View on PubMed ↗Publisher’s paper ↗

Citation

Bernal-Chico, Ana; Canedo, Manuel; Manterola, Andrea; Victoria Sánchez-Gómez, María; Pérez-Samartín, Alberto; Rodríguez-Puertas, Rafael; Matute, Carlos; Mato, Susana. (2015). Blockade of monoacylglycerol lipase inhibits oligodendrocyte excitotoxicity and prevents demyelination in vivo.. Glia, 63(1), 163-76. https://doi.org/10.1002/glia.22742