BOSTON—A novel compound called fluorosamine appears to promote remyelination and reduce inflammation in animal models of experimental autoimmune encephalomyelitis (EAE), according to research presented at the 2014 Joint ACTRIMS–ECTRIMS Meeting. Results indicate that the molecule potentially could benefit patients with multiple sclerosis (MS).
V. Wee Yong, PhD, Professor and Head of Translational Neuroscience at the University of Calgary in Canada, and colleagues initiated EAE in animals and allowed them to develop signs of disability. The investigators began treating some of the animals with fluorosamine daily and some with vehicle daily. Disease severity was reduced among animals that received fluorosamine, compared with animals that received vehicle. “If we initiate treatment with fluorosamine at peak EAE, we find that while vehicle-treated animals continue to have significant disability, treatment with fluorosamine reduces clinical severity,” said Dr. Yong.
Investigating CSPGs
The current study follows the investigators’ previous examinations of chondroitin sulfate proteoglycans (CSPGs). This class of chemicals includes versican, aggrecan, neurocan, and brevican. In 2001, Sobel and colleagues found neurocan, veriscan, and aggrecan at the edge of an active MS lesion. In other conditions such as traumatic spinal cord injury, CSPGs have been identified as inhibitors of axonal regeneration.
To determine whether CSPGs affect remyelination, Dr. Yong and colleagues investigated a model of demyelination and remyelination in which lysolecithin was injected into an animal’s spinal cord dorsal column. Within three days of demyelination, the researchers found deposition of versican V1 around cells and in acellular areas in the extracellular matrix. In a later study, Dr. Yong and colleagues found that CSPGs were cleared during the process of remyelination that followed lysolecithin-induced demyelination. The group also found that reducing the deposition of CSPGs promoted remyelination.
In 2012, Dr. Yong’s group performed in vitro stripe assays of human oligodendrocyte precursor cells (OPCs). When the human OPCs were plated onto a setup in which stripes had been coated with bovine serum albumin, the OPCs flourished in environments with and without bovine serum albumin. In contrast, OPCs sent few processes into stripes coated with CSPGs. This finding emphasizes “the nonpermissive nature of the CSPGs,” said Dr. Yong.
The Development of Fluorosamine
To reduce the production of CSPGs following injury, Dr. Yong and colleagues designed fluorosamine. They found that peracetylating fluorosamine with many acetyl groups facilitated the compound’s entry into cells. In an in vitro proof-of-concept study, the investigators activated astrocytes with TGF-β to increase their production of CSPGs. When the astrocytes were incubated with peracetylated fluorosamine, the group observed a “robust downregulation of CSPG production by activated astrocytes,” said Dr. Yong.
In an in vivo proof-of-concept study, the researchers induced demyelination in animals by injecting their spinal cords with lysolecithin. After the animals received fluorosamine treatment, the investigators observed significantly reduced expression of versican in the injured spinal cords.
When the researchers stained tissue samples for oligodendrocytes using OLIG2 and GSTπ, they found a greater number of oligodendrocytes within lesions in animals that underwent lysolecithin-induced demyelination and subsequent treatment with fluorosamine than in animals with demyelination that were untreated. In addition, animals that were treated with fluorosamine had more myelinated profiles than untreated animals. A separate study indicated that fluorosamine reduced inflammation in tissue culture by inhibiting macrophage activation.
—Erik Greb