Study Finds Targeting a Specific Pathway in the Brain Provides Promising Therapeutic Target for White Matter Diseases Including Multiple Sclerosis
Washington, DC— A new study from Children’s National Health System found that targeting a specific molecular pathway in reactive astrocytes (RAs) provides a promising therapeutic objective in diseases with extensive reactive astrogliosis, including Multiple Sclerosis (MS).
Astrocytes are cells in the central nervous system (CNS) that provide nutrients, recycle neurotransmitters, and help maintain homeostasis. Astrocytes change their cellular and functional properties to become “reactive” in many brain disorders, or after CNS injury. It is still unknown whether RAs are beneficial or represent an obstacle to CNS regeneration. Therefore, it is essential to determine how specific signals produced by RAs impact neural regeneration.
Dr. Gallo’s team previously identified a new intercellular signaling molecule, called endothelin-1 (ET-1), which is expressed at high levels by RAs in MS, and in animal models of the disease. ET-1 limits repair of glial cells by delaying oligodendrocyte progenitor cell (OPC) maturation into oligodendrocytes (OLs) and myelin formation.
Myelination allows nerve impulses to move more rapidly through the CNS and is interrupted in people who have white matter diseases, such as MS. This is referred to as demyelination and causes symptoms including fatigue and weakness, numbness and tingling, vision problems, and difficulty walking. In response to demyelination, OPCs can replace lost OLs and myelin in a process called remyelination. “ET-1 is specifically and selectively involved in promoting the formation of RAs, which in turn inhibit the process of remyelination,” Dr. Gallo said.
The study in Cell Reports took a step further and investigated the specific cellular and molecular mechanisms of action of ET-1 through genetic and pharmacological approaches in an animal model of MS. “In MS and other white matter diseases, myelin regeneration is severely impaired, but the molecular signals that prevent remyelination are unknown. Our research has identified a protein (ET-1) that is normally present in the brain at low levels but is increased and activated after white matter injury and disease to inhibit myelin regeneration,” Dr. Gallo said.
The study found that ET-1 acts selectively through a specific class of endothelin receptors in RAs —and not in OPCs—to inhibit remyelination. “The results of our study suggest that by selectively targeting this pathway and this class of receptors in RAs in the brain, we may be able to develop more effective therapeutic approaches for people with white matter diseases, including MS,” Dr. Gallo said.
MS is a type of white matter disease that affects approximately 1 out of 1,000 people. It most commonly begins between the ages of 20 and 40 years, but symptoms can manifest at any age. There is no cure for MS, but research like this aims to improve therapies currently available in order to prevent worsening of the disease and its symptoms.
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