Researchers at the Scripps Research Institute (TSRI) have identified a set of compounds that may be used to treat multiple sclerosis (MS). Unlike existing therapies that try to suppress the immune system, the compounds actually boost a population of progenitor cells that can repair MS-damaged nerve fibers.
Benztropine, one of the newly identified compounds used to treat Parkinson’s disease, was found to be highly effective in treating a standard model of multiple sclerosis in mice. This was the case when used alone and in combination with other MS therapies.
Luke L. Lairson, an assistant professor of chemistry at TSRI and a senior author of the study, notes: “We’re excited about these results, and are now considering how to design an initial clinical trial.” However, he cautions that benztropine is a drug with dose-related adverse side effects. Benztropine has not been proven effective at a safe dose in multiple sclerosis patients. He goes on further to say that benztropine should not be used off-label for MS.
About Multiple Sclerosis
Multiple sclerosis is an autoimmune disease of the brain and spinal cord that affects more than 500,000 people in North American and Europe, and more than two million globally. The etiology of MS is not well understood but certain infections and a vitamin D deficiency are believed to be factors. The disease is more common in individuals with Northern European heritage and occurs about twice as often in women than men.
Certain white blood cells known as T-cells infiltrate into the upper spinal column and brain causing inflammation and eventually the loss of myelin. Myelin is an insulating coat found on some nerve fibers (axons). As the axons lose this coat, they are not able to transmit signals efficiently and in time can begin to degenerate. The symptoms associated with MS is a stop-start, “releasing-remitting” pattern that may include limb weakness, tingling and numbness, fatigue, visual problems, slurred speech, memory difficulties and depression.
Interferon beta is used as a current treatment that suppresses the immune attack that demyelinates axons. This therapy is partially effective but has adverse side effects.
Details of the MS Mouse Study
Lairson and his team made use of a complementary approach geared towards restoring a population of progenitor cells known as oligodendrocytes (they form myelin). Under normal conditions these cells keep myelin healthy and in principle could fix these wrappings after MS damages them. However, oligodendrocytes decline in numbers in MS due to some unknown problem with the stem-like precursor cells that produce them. According to Lairson, “Oligodendrocyte precursor cells (OPCs) are present during progressive phases of MS, but for unknown reasons don’t mature into functional oligodendrocytes.”
Lairson and his colleagues screened a library of about 100,000 diverse compounds for any that could potently induce OPCs to differentiate. Several compounds scored well as OPC differentiation-inducers. Most of the compounds they identified were of unknown activity except for benztropine. Benztropine has been well characterized and is FDA-approved for treating Parkinson’s. Vishal A. Deshmukh, first author of the paper who performed most of these experiments, notes, “That was a surprise, and it meant that we could move forward relatively quickly in testing it.”
Deshmukh along with Brian R. Lawson, a senior author of the paper and assistant professor of immunology at TSRI, and his colleague Research Associate Virginie Tardif, began running tests of benztropine in mice with an induced MS-like autoimmune disease. This model is commonly used for testing possible MS drugs. Benztropine demonstrated a powerful ability to prevent autoimmune disease. Moreover, it was effective in treating MS after symptoms were apparent essentially eliminating the disease’s ability to relapse. Although benztropine on its own worked about as well as existing therapies, it demonstrated an ability to complement existing therapies such as two first-line immune-suppressant treatments, interferon-beta and fingolimod.
Lawson notes, “Adding even a suboptimal level of benztropine effectively allowed us, for example, to cut the dose of fingolimod by 90%—and achieve the same disease-modifying effect as a normal dose of fingolimod. In a clinical setting that dose-lowering could translate into a big reduction in fingolimod’s potentially serious side effects.”
The researchers were able to confirm that benztropine boosts the population of mature oligodendrocytes allowing for restoration of the myelin sheaths. This was true even as the immune attack continued. However, the benztropine-treated mice presented with no change in signs of inflammation yet the myelin appeared mostly intact. This suggests that the myelin is being repaired as rapidly as it is being destroyed.
Benztropine has the ability to block activity at acetylcholine and histamine receptors and boosting the activity of dopamine receptors. However, the researchers found evidence that benztropine stimulates OPCs to differentiate mainly by blocking M1 and M3 acetylcholine receptors on these cells.
Peter G. Schultz, the Scripps Family Chair Professor in the Department of Chemistry at TSRI and one of the study’s senior authors, notes, “This work, like our previous studies with hematopoietic and mesenchymal stem cells, illustrates the power of small molecules to control stem and precursor cells in ways that may ultimately lead to a new generation of drugs for regenerative medicine.”
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