Nov. 7, 2002 SAN FRANCISCO - While cautioning that their findings still must be evaluated in humans, University of California, San Francisco and Stanford University Medical Center researchers report that the cholesterol-lowering drug atorvastatin (Lipitor) significantly improved, prevented relapses or reversed paralysis in mice with an experimental disease that closely resembles multiple sclerosis.
The study, reported in the November 7 issue of Nature, was conducted in mice with experimental autoimmune encephalomyelitis (EAE), the standard animal model for multiple sclerosis. Multiple sclerosis causes a variety of symptoms, mostly related to motor control. A primary symptom is temporary, recurring paralysis in the limbs, as occurs in the mice.
The researchers examined the effects of atorvastatin in two models of mouse EAE that may reflect conditions that occur in multiple sclerosis. When atorvastatin was given at the onset of symptoms in a model where mice develop chronic paralysis, which can occur in some forms of later-stage multiple sclerosis, the drug lessened the paralysis. In this same model, when the drug was given during the acute attack, it suppressed paralysis.
When the drug was given to mice with relapsing-remitting disease, the most common form of multiple sclerosis, the results were more dramatic. In mice experiencing their first attack, the drug prevented the animals from progressing to the fully established disease. In animals that had already had an initial attack and were developing the symptoms of a first relapse (second attack), the drug reversed the emerging paralysis.
"The findings are provocative," said the senior author of the study, Scott S. Zamvil, MD, PhD, assistant professor of neurology at University of California, San Francisco. At the same time, he cautioned, "we need to do clinical trials in patients to determine if we see the same positive results."
"We just have to hope that we see some of the same beneficial effects in people," says the first author of the study, Sawsan Youssef, PhD, a postdoctoral fellow in the laboratory of co-author Lawrence Steinman, MD, professor of neurology and Director of the Program in Immunology at Stanford University.
Zamvil, of UCSF, has submitted a proposal to the Immune Tolerance Network(1) to conduct a multi-center clinical trial to see if the drug could be used to prevent conversion to definite multiple sclerosis in individuals who have had a first attack, known as a "clinically isolated syndrome." Ultimately, he says, separate trials may need to be done to test if the drug could be useful in different phases of the disease.
Based on the drug doses studied in the mouse models, Zamvil and his colleagues propose using the highest Food and Drug Administration (FDA)-approved dose of atorvastatin (80 mg.) for the trial. Most patients taking statins for the regulation of LDL cholesterol levels are prescribed the lower FDA-approved doses. Notably, while all currently available drugs for multiple sclerosis are administered through injection, statins are taken orally.
Use of statins is associated with a low risk of liver toxicity, and, less frequently, with a potentially more serious medical complication that results from muscle damage. For this reason, and because the drug has not been tested in multiple sclerosis, the researchers strongly urge patients and their physicians to wait for the results of the clinical trials before considering therapy with statins for multiple sclerosis.
"While the drugs are considered relatively safe, their use should be monitored closely by patients' physicians, especially when taken at the highest doses," says Zamvil.
Preventing 'definite' multiple sclerosis
The results of the mouse study are particularly compelling because many people who experience an initial attack of multiple sclerosis – which includes such symptoms as visual impairment, poor balance, paralysis in the limbs, numbness and loss of bladder or bowel control -- don't go on to receive drug treatment, says co-author Olaf Stuve, MD, PhD, a postdoctoral fellow in the Zamvil lab at UCSF. This is because no therapy has yet been marketed to prevent progression to clinically definite multiple sclerosis, and other drugs used are given by injection, which patients frequently choose not to take, he says.
Instead, physicians reevaluate the patient if she or he has a second attack, and make a diagnosis based on several factors, including new or recurrent clinical symptoms and results of magnetic resonance imaging (MRI) scans, which may reveal new lesions in the brain caused by the disease.
The new finding is the most dramatic evidence to date, says Stanford's Youssef, that statins may prove useful in treating multiple sclerosis, which occurs when one of the immune system's key cells, the T helper (Th) cell, or CD4+ T cell, orchestrates an inflammatory attack against the brain's nervous tissue. The primary target of the attack is the myelin sheath, which coats the brain's nerve fibers, or communication wires, through which nerve cells, or neurons, communicate.
The damage to the sheath, known as demyelination, disrupts the ability of neurons to transmit signals swiftly to one another. The destruction causes fatigue, disrupts various motor skills and, more subtly, diminishes some cognitive abilities. In later phases of the more progressive forms of the disease, non-inflammatory toxic molecules damage some of the brain's glial tissue and kill nerve cells.
In 1995, scientists unexpectedly recognized that statins might play a role in regulating inflammation, when they determined that the statin lovastatin reduced the rejection of hearts and increased survival in cardiac-transplant patients, independent of its ability to regulate LDL cholesterol levels. Subsequent studies in cell culture have demonstrated that lovastatin and some other statins inhibit the production of certain pro-inflammatory molecules that are active in the early phases of multiple sclerosis. Other studies suggest that some statins may inhibit molecules that kill nerve cells, which can occur in the later phases of some forms of the disease.
Three types of drugs are currently approved to treat multiple sclerosis. Copaxone and the beta interferons are used to treat relapsing-remitting disease – which, in half of these patients, progresses to a "secondary progressive," or chronic, form -- and Novatrone, a cancer chemotherapy, is used to treat this progressive form. The drugs are effective to varying degrees in roughly a third of patients and are often limited by side effects or toxicities. Statins, by contrast, are relatively well tolerated and generally safe.
Currently, another statin, simvastatin (Zocor), is being tested in a small trial of early relapsing remitting multiple sclerosis.
It's possible, says Zamvil, that statins could prove useful in combination with these drugs, as they act through different molecular mechanisms.
A broad attack on autoimmune diseases
More broadly, Zamvil says, statins could prove effective against certain other auto-immune diseases, such as rheumatoid arthritis and juvenile diabetes, which occur when the same form of the immune system CD4+ T cell turns against the body. In fact, he says, it's possible that the drugs' anti-inflammatory properties actually contribute to the protective effects of statins in heart disease and stroke that traditionally have been attributed to LDL cholesterol reduction.
If statins do prove useful in treating autoimmune diseases, it won't be the first time that a widely used drug has been found to have an effect in multiple medical conditions, notes Stanford's Steinman. He cites aspirin, which, among other conditions, relieves joint pain, helps to prevent stroke and heart attack, and, as recently recognized, may serve as a prophylactic for colonic cancer.
"Sometimes the pathways that we think of in one context involve the same characters in different roles," says Steinman. Still, he says, it would be remarkable if statins, used daily by tens of millions of people for one medical condition, proved useful in another. (Statins also are now being investigated as a possible strategy for preventing the onset of Alzheimer's disease.)
The immunological revolt that causes multiple sclerosis occurs when the roaming CD4+ T cells, conducting surveillance throughout the immune system, receive a molecular miscue, recognizing a site known as the major histocompatibility complex (MHC) class II on two other immune system cells, known as B cells or macrophages. Recognition of the MHC complex prompts the cells to begin differentiating into a subtype known as the T helper (Th) 1 cell, which unleashes destructive cytokines, or chemicals, that incite inflammation, thus setting in motion the cascade of events that lead to damage of the myelin sheath.
In their study, the UCSF-Stanford team built on a finding reported by investigators (Nature Medicine, December 2000) showing that several statins, including atorvastatin, were effective in cell culture in inhibiting production of the MHC class II antigen. Atorvastatin had the most potent effect.
In the current study, the researchers determined that atorvastatin acts by interrupting the inflammatory process. In the mouse models, Youssef, working closely with Zamvil, determined the drug's impact on various phases of the experimental disease. Then, in subsequent studies of brain tissue from the sacrificed mice, and in cell culture studies, they elucidated some of the mechanisms by which the drug works.
Most notably, in the mouse brain tissue, the researchers determined that atorvastatin inhibited production of the harmful pro-inflammatory Th1's cytokines, and promoted production of the beneficial Th2's cytokines, which inhibits inflammation.
In fact, in cell culture studies, they observed that when CD4+ T helper cells that had not yet differentiated, or specialized, and are therefore known as Th0, were exposed to atorvastatin, they were prompted to develop into the protective Th2 cells, rather than into Th1 cells. Then, when the scientists took Th2 cells from mice that were treated with atorvastatin and transferred them to other mice, the recipient mice were protected from developing EAE.
Also in cell culture, the team determined that atorvastatin inhibited macrophages and microglia antigen-presenting cells from expressing the MHC class II complexes – the key step in inciting CD4+ T cells. They also showed that the drug inhibited expression of co-stimulatory molecules on macrophages.
Finally, in addition to studying atorvastatin in the mouse models of chronic paralysis and relapsing remitting EAE, the researchers examined a model of mice genetically engineered to express a receptor on their CD4+ T cells that caused the cells to recognize and latch on to the MHC Class II molecule complex with brain antigen on B cells and macrophages. This recognition in turn provoked the CD4+ T cells to incite the inflammatory response. The animals in this transgenic model developed massive disease. However, as reported in the study, when the mice were treated with atorvastatin, induction of EAE was suppressed. Moreover, when the drug treatment stopped, the animals did not develop the disease in the subsequent days observed.
"The findings are encouraging in mouse studies and cell culture," says co-author Olaf Stuve, MD, PhD, a postdoctoral fellow in the Zamvil lab at UCSF. "The next step is to see whether there are beneficial results in people."
Another next step, says Youseff, will be learning even more precisely how atorvastin acts in the immune system. "We want to see what happens – to really get to the bottom of this."
Co-authors of the study were Juan C. Patarroyo and Manuel Bravo of the University of California, San Francisco Department of Neurology; Pedro J. Ruiz, formerly of the Department of Neurology and Neurological Sciences at Stanford University and now at California Pacific Medical Center; Jennifer L. Radosevich, Eun Mi Hur and Dennis Mitchell of the Department of Neurology and Neurological Sciences, Beckman Center for Molecular Medicine at Stanford University, and Raymond A. Sobel, of the Department of Pathology (Neuropathology) at Stanford.
The study was funded by the National Institutes of Health, the National Multiple Sclerosis Society, the Alexander M. and June L. Maisin Foundation and the Nancy Davis Foundation.
Zamvil received a competitive research award known as the Atorvastatin Research Award from Pfizer Inc. The award, granted after the paper was submitted, will be used to further the research.
(1) Headquartered at the University of California, San Francisco and sponsored by a joint contract from the National Institutes of Health and the Juvenile Diabetes Research Foundation, the Immune Tolerance Network is a collaborative effort of more than 70 leading laboratory scientists, clinical professionals and other technical experts from around the world. http://www.immunetolerance.org/
UCSF Multiple Sclerosis Center: http://mscenter.ucsf.edu/
National Multiple Sclerosis Society http://www.nmss.org/
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