内大麻素系统
肾上腺脑白质营养不良
大麻素受体
大麻素受体2型
大麻素
神经保护
神经科学
生物
化学
药理学
内分泌学
内科学
细胞生物学
受体
医学
过氧化物酶体
兴奋剂
作者
Janani Parameswaran,Leire Goicoechea,Laura Planas‐Serra,Antoni Pastor,Montserrat Ruíz,Noel Y. Calingasan,Cristina Guilera,Ester Aso,Jordi Boada,Reinald Pamplona,Manuel Portero‐Otín,Rafael de la Torre,Isidre Ferrer,Carlos Casasnovas,Aurora Pujol,Stéphane Fourcade
标识
DOI:10.1007/s00401-022-02451-2
摘要
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.
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