期刊
JOURNAL OF NEUROSCIENCE
卷 37, 期 35, 页码 8385-8398出版社
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.2900-16.2017
关键词
2-AG; chondroitin sulfate proteoglycans; neuroinflammation; oligodendrocytes; remyelination; TMEV-IDD
资金
- Ministry of the Economy and Competition (MINECO) [SAF2013-42784-R, SAF2016-76449-R]
- Comunidad de Madrid [S2011/BMD-2308]
- Red Espanola de Esclerosis Multiple Grants [RD12/0032/0008, RD16/0015/0021]
- Fondo de Investigacion Sanitaria
- Basque Government [IT764-13]
- MINECO/FEDER [SAF2015-65034-R]
- University of the Basque Country Grant UPV/EHU [UFI11/41]
- MINECO [SAF2013-48271-C2-1-R, BES-2014-068459]
The failure to undergo remyelination is a critical impediment to recovery in multiple sclerosis. Chondroitin sulfate proteoglycans (CSPGs) accumulate at demyelinating lesions creating a nonpermissive environment that impairs axon regeneration and remyelination. Here, we reveal a new role for 2-arachidonoylglycerol (2-AG), the major CNS endocannabinoid, in the modulation of CSPGs deposition in a progressive model of multiple sclerosis, the Theiler's murine encephalomyelitis virus-induced demyelinating disease. Treatment with a potent reversible inhibitor of the enzyme monoacylglycerol lipase, which accounts for 85% of the 2-AG degradation in the mouse CNS, modulates neuroinflammation and reduces CSPGs accumulation and astrogliosis around demyelinated lesions in the spinal cord of Theiler's murine encephalomyelitis virus-infected mice. Inhibition of 2-AG hydrolysis augments the number of mature oligodendrocytes and increases MBP, leading to remyelination and functional recovery of mice. Our findings establish a mechanism for 2-AG promotion of remyelination with implications in axonal repair in CNS demyelinating pathologies.
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