TORONTO—Despite the fact that neuroprotection trials in stroke, Parkinson’s disease, and other neurodegenerative disorders have thus far produced unremarkable results, Dennis Bourdette, MD, said that should not discourage interest in neuroprotective therapies for multiple sclerosis (MS). Theorizing that the pathogenesis of MS may involve both inflammation and neurodegeneration, Dr. Bourdette believes that neuroprotection could play a key role in the effort to arrest progression of the disease.

“We need to continue to treat early and develop more, better, and safer anti-inflammatory regimens in patients who are early on in the inflammatory phase of the disease,” said Dr. Bourdette. “But we also very much need to keep pushing hard our research agenda aimed at testing and developing neuroprotective and neuroregenerative therapies. We need these now, not in the future.” Dr. Bourdette is Chairman of the Department of Neurology, Oregon Health and Science University, and Codirector of the Veterans Administration/MS Center of Excellence–West in Portland. He made his presentation at the 18th Annual Meeting of the Consortium of MS Centers.

Current disease-modifying therapies in MS consist primarily of anti-inflammatory drugs, but according to Dr. Bourdette, “if you look at the data for our average patient, they are largely ineffective in the treatment of progressive forms of the disease. It is quite possible that progressive axonopathy underlies the progressive disease, and we need to be thinking about applying neuroprotective therapies. Early on, the disease is heavily inflammatory—but as you get into primary progressive disease and secondary progressive disease, inflammation is a minor component. What we may in fact be dealing with is a neurodegenerative process.”

AXONAL INJURY AND BRAIN ATROPHY

The concept of axonal loss in patients with MS has recently garnered more attention, despite the fact that it has been recognized for more than a century. Acute axonal injury occurs with acute inflammatory lesions, but the problem is likely more complex, according to Dr. Bourdette. Clinical evidence supports the theory that chronic demyelination leads to progressive axonal death, likely a contributing factor to the progressive form of MS, he said.

Preventing brain atrophy is a primary focus of MS research. Perhaps the most hopeful long-term strategy in that regard involves early intervention with anti-inflammatory therapy, as well as neuroprotective therapies to prevent oligodendrocyte and axonal injury, according to Dr. Bourdette. “It may be that the progressive part of the disease is not being driven by inflammation early on but by an independent process. We would like to believe and are hopeful that if we are highly effective at shutting down the disease early and prevent a lot of demyelination, that that will eventually translate into decreasing significantly the risk of conversion to secondary progressive MS. But even if that proves to be the case, we all know that there are a lot of people who have primary progressive MS and do not get diagnosed early on. So even for those patients, we need to be thinking about protective therapies. And we need to be thinking about ways of promoting remyelination and ways of providing missing trophic factors.”

SIGNS OF NEUROPROTECTIVE LIFE

Dr. Bourdette cited several studies that offer hope for neuroprotection in MS. For example, Werner et al found that glutamate excitotoxicity in mice with experimental autoimmune encephalomyelitis appeared to be an important mechanism in autoimmune demyelination. Because glutamate receptor antagonists have been studied successfully in stroke and other neurologic disorders, it “would be a reasonable thing to think about applying to MS,” commented Dr. Bourdette.

In addition, Lo et al, in a study using sodium channel blockers, found that half of optic nerve axons were lost at 28 days in untreated mice with experimental allergic encephalomyelitis, while only 12% of the axons were lost if the mice were treated with phenytoin. The investigators concluded that it is possible to achieve substantial protection of white matter axons in these mice with a sodium channel–blocking agent and are now planning a phase II trial to determine if there is potential neuroprotectant use in MS.

Dr. Bourdette and colleagues have conducted their own research with the immunosuppressant drug FK506, which also has been used in liver transplantations and promotes axonal generation. “It is actually neuroprotective,” he said, “and in lower doses than required in immunosuppression.” Dr. Bourdette’s group found that FK506 protects against demyelination and axonal loss in the experimental autoimmune encephalomyelitis model of MS through immunosuppression and neuroprotection. “It’s an interesting agent and another potential agent that might be worth studying as a neuroprotectant, particularly in these low doses that are safe.”

REMYELINATION OF MS

Promoting the process of remyelination is another area worthy of further investigation in MS research, said Dr. Bourdette. “There’s a lot of interest in the possibility of transplantations as a way of promoting remyelination,” he offered. “That might be a reasonable approach to consider in patients with large focal demyelinating lesions in the spinal cord. The ultimate problem there is that those plaques are usually associated with a marked loss of axons.” He added that potential also exists with the use of mesenchymal cells, which naturally migrate to areas of injury, a concept currently being studied in patients with acute heart attacks. Dr. Bourdette believes that a similar approach could be used for patients with MS.

NEUROPROTECTIVE HURDLES

The study of neuroprotective agents presents a number of obstacles, Dr. Bourdette pointed out. One is how to properly measure neuroprotection, and a possible solution is the use of MRI. “We have to show a slowing of clinical disability with a neuroprotective agent,” he said. “It may not establish that the agent worked on a neuroprotective basis, but as far as the patients are concerned, if it actually slowed their disability, perhaps the mechanisms are not so important to them.”

Another major hurdle regarding neuroprotective therapies, again, is the fact that they have been studied extensively in stroke, and to a lesser extent in amyotrophic lateral sclerosis and in Parkinson’s disease, and so far have been unfruitful. “A large number of studies with various neuroprotective agents have not been beneficial,” said Dr. Bourdette. “I don’t think that should deter us from taking similar approaches. It’s a different disease with perhaps a better underlying pathology for the promotion of neuroprotection. [However], it does give one pause when thinking about others that have gone before us in this field with other diseases.”

NR

—Colby Stong

Suggested Reading
Gold BG, Voda J, Yu X, et al. FK506 and a nonimmunosuppressant derivative reduce axonal and myelin damage in experimental autoimmune encephalomyelitis: neuroimmunophilin ligand-mediated neuroprotection in a model of multiple sclerosis. J Neurosci Res. 2004;77:367-377.
Lo AC, Black JA, Waxman SG. Neuroprotection of axons with phenytoin in experimental allergic encephalomyelitis. Neuroreport. 2002;13:1909-1912.
Werner P, Pitt D, Raine CS. Glutamate excitotoxicity—a mechanism for axonal damage and oligodendrocyte death in multiple sclerosis? J Neural Transm Suppl. 2000;375-385.

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