Activating cannabinoid receptor 2 preserves axonal health through GSK-3β/NRF2 axis in adrenoleukodystrophy.
ATP Binding Cassette Transporter, Subfamily D, Member 1
Adrenoleukodystrophy
/ drug therapy
Animals
Clinical Trials, Phase II as Topic
Endocannabinoids
/ therapeutic use
Glycogen Synthase Kinase 3 beta
/ metabolism
Leukocytes, Mononuclear
/ metabolism
Mice
NF-E2-Related Factor 2
/ metabolism
Receptors, Cannabinoid
/ metabolism
Axonal degeneration
CB2r
Endocannabinoids
GSK-3β/NRF2
Lipid droplets
Redox homeostasis
X-linked adrenoleukodystrophy
Journal
Acta neuropathologica
ISSN: 1432-0533
Titre abrégé: Acta Neuropathol
Pays: Germany
ID NLM: 0412041
Informations de publication
Date de publication:
08 2022
08 2022
Historique:
received:
11
01
2022
accepted:
05
06
2022
revised:
04
06
2022
pubmed:
2
7
2022
medline:
20
7
2022
entrez:
1
7
2022
Statut:
ppublish
Résumé
Aberrant endocannabinoid signaling accompanies several neurodegenerative disorders, including multiple sclerosis. Here, we report altered endocannabinoid signaling in X-linked adrenoleukodystrophy (X-ALD), a rare neurometabolic demyelinating syndrome caused by malfunction of the peroxisomal ABCD1 transporter, resulting in the accumulation of very long-chain fatty acids (VLCFAs). We found abnormal levels of cannabinoid receptor 2 (CB2r) and related endocannabinoid enzymes in the brain and peripheral blood mononuclear cells (PBMCs) of X-ALD patients and in the spinal cord of a murine model of X-ALD. Preclinical treatment with a selective agonist of CB2r (JWH133) halted axonal degeneration and associated locomotor deficits, along with normalization of microgliosis. Moreover, the drug improved the main metabolic disturbances underlying this model, particularly in redox and lipid homeostatic pathways, including increased lipid droplets in motor neurons, through the modulation of the GSK-3β/NRF2 axis. JWH133 inhibited Reactive Oxygen Species elicited by excess VLCFAs in primary microglial cultures of Abcd1-null mice. Furthermore, we uncovered intertwined redox and CB2r signaling in the murine spinal cords and in patient PBMC samples obtained from a phase II clinical trial with antioxidants (NCT01495260). These findings highlight CB2r signaling as a potential therapeutic target for X-ALD and perhaps other neurodegenerative disorders that present with dysregulated redox and lipid homeostasis.
Identifiants
pubmed: 35778568
doi: 10.1007/s00401-022-02451-2
pii: 10.1007/s00401-022-02451-2
doi:
Substances chimiques
ATP Binding Cassette Transporter, Subfamily D, Member 1
0
Abcd1 protein, mouse
0
Endocannabinoids
0
NF-E2-Related Factor 2
0
Receptors, Cannabinoid
0
Glycogen Synthase Kinase 3 beta
EC 2.7.11.1
Banques de données
ClinicalTrials.gov
['NCT01495260']
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
241-258Informations de copyright
© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.
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