Chondroitin sulfate proteoglycans new target for endocannabinoids CNS repair

Multiple sclerosis is a chronic inflammatory autoimmune demyelinating disease of the central nervous system. It is the most common progressive neurologic disease of young adults worldwide that affects approximately one million people in the United States alone, most of them being young adults. Progressive multiple sclerosis features a compartmentalized immune response in the central nervous system, involving microglial cells and astrocytes, as well as immune-independent processes that drive demyelination and axonal dysfunction. Major challenges for multiple sclerosis research involve understanding the mechanisms of disease progression, developing treatment for progressive multiple sclerosis, and determining the degree to which progressive disease can be prevented by early treatment.

Astrocytes in multiple sclerosis usually deploy neuroprotective properties, but they can also worsen the insult by secreting pro-inflammatory molecules and being essential for glial scar formation at demyelinated lesions where there is an increase in chondroitin sulfate proteoglycans (CSPGs). Studies carried out on animal models of multiple sclerosis showed that the use of cannabinoids is likely to alleviate symptoms and control inflammation, demyelination and neurodegeneration. The endocannabinoid 2-arachidonoylglycerol (2-AG) has been shown to control the migration of oligodendrocyte precursor cells (OPCs) in culture and promote their proliferation and differentiation.

In a new study published in GLIA Spanish researchers: Dr. Ana Feliu, Dr. Leyre Mestre, Dr. Francisco J Carrillo-Salinas, Dr. Miriam Mecha and Dr. Carmen Guaza from the Functional and Systems Neurobiology Department at the Instituto Cajal, CSIC in collaboration with Professor Voon Wee Yong from the Hotchkiss Brain Institute and the Department of Clinical Neurosciences and Oncology at University of Calgary in Canada studied the effect of 2-AG on oligodendrocyte differentiation and production of CSPGs by astrocytes in culture. Their findings showed that the differentiation of rat and human oligodendrocytes was enhanced by 2-AG administration under inhibitory conditions.

The research team noticed a reduction in the levels of CSPGs-brevican and neurocan in rat astrocytes cultures and in the expression of enzymes needed for their synthesis following 2-AG treatment. This was an indication that 2-AG directly impedes the synthesis of CSPGs in astrocyte cultures. Furthermore, the reduction of neurocan by 2-AG was found to be dependent on the CB2 signaling system in astrocyte cultures. However, ELISA results confirmed that CB2 receptors were not involved in the reduction of brevican by 2-AG.

The suppression of 2-AG catabolism, by the inhibition of its hydrolyzing enzymes in rat astrocytes, caused an increase in 2-AG tone which reduced the expression of neurocan and brevican expression, thereby reducing their extracellular levels. In addition, western blots measurements showed that 2-AG hydrolysis inhibitors markedly reduced neurocan and brevican generation.

In human astrocytes in culture, the authors also observed a reduction in CSPG expression and extracellular neurocan levels after 2-AG treatment. These results are believed to be an indication that human astrocytes are likely to be most sensitive to 2-AG. The matrix of 2-AG treated astrocytes was found to be less inhibitory to oligodendrocyte differentiation and it caused more outgrowth of OPC processes, with more junctions, branches and end-points. The same results were obtained in 2-AG treated oligodendrocytes cultured under synthetic inhibitory matrix. The initial cell adhesion had no effect under any experimental condition.

In a nutshell, the research team demonstrated that the endocannabinoid system can be targeted to achieve the neutralization of CSPG accumulation and improvement of oligodendrocyte differentiation. Their findings can be used to advance further the research toward developing better treatments for demyelinating diseases.