Effectiveness of Current Therapies in Providing Neuroprotection for Patients With Relapsing-Remitting Multiple Sclerosis and Primary Progressive Multiple Sclerosis
Neurodegeneration occurs in all stages of multiple sclerosis (MS), but neurological disability is variable among individual patients. Demyelination correlates with the relapsing-remitting stage of MS, and axonal loss correlates with the clinical disability that occurs with the progressive form of the disease. Therapies that are approved for the treatment of patients with relapsing-remitting MS have been shown to be effective in terms of their anti-inflammatory potential. However, results of a 2018 study that evaluated outcomes from clinical trials indicated that the neuroprotective effects of classical MS drugs have not been sufficiently investigated, but available clinical and magnetic resonance imaging end point data have shown limited effects. Results of another recent assessment of the literature indicated (as an expert opinion) that fingolimod may potentially have a neuroprotective effect on relapsing-remitting MS based on its modulatory effect on astrocytes and oligodendroglial cells and its direct effect on cortical neurons. High-dose biotin has been shown to have a stabilizing effect on the progression of MS and may protect against hypoxia-induced axonal degeneration. Current research is exploring dysfunction at the level of transcription factor nuclear factor erythroid-derived 2-like 2 (Nrf2) and mitochondria as targets for drugs that could potentially improve neuronal function and possibly provide neuroprotection. In the meantime, studies of current drugs should include assessments of the long-term prevention of neurodegeneration. Our featured experts in the field discuss whether current therapies are effective in providing neuroprotection in relapsing-remitting MS and primary progressive MS.
Q: Are current therapies effective in providing neuroprotection in relapsing-remitting MS and primary progressive MS?
Professor and Chair
“Improvements in outcomes, such as measures of brain atrophy or some biomarkers associated with neurodegeneration, may indicate a slowing of probable neurodegeneration, but the degree of therapeutic benefit that can be attributed to anti-inflammatory effects versus true direct neuroprotection is still largely unknown.”
It is difficult to answer that question because we do not have very good definitions, biomarkers, or methods to measure neuroprotection. We do see that patients who are treated with currently available therapies for MS, especially those that are highly effective, have improvements in outcomes associated with disability. Improvements in outcomes, such as measures of brain atrophy or some biomarkers associated with neurodegeneration, may indicate a slowing of probable neurodegeneration, but the degree of therapeutic benefit that can be attributed to anti-inflammatory effects versus true direct neuroprotection is still largely unknown.
Chairman, Department of Neurology
“Using alemtuzumab, a drug that is highly effective at immunosuppression, and adding neuroprotection at that point would make sense. But alemtuzumab would have to be combined with a drug that is very effective in stopping the inflammatory cascade in the central nervous system.”
With MS, there are many inflammatory cells in the brain, and, as long as you have the inflammation, it is not like a spinal cord injury or a stroke where the initial insult is gone. There is the initial insult and then one observes the consequence of the injury. In progressive MS, we are trying to stop the inflammation and provide neuroprotection. There is early axonal dropout, and attempts to remyelinate do not make a lot of sense unless you have very effective methods of stopping the inflammation. Using alemtuzumab, a drug that is highly effective at immunosuppression, and adding neuroprotection at that point would make sense. But alemtuzumab would have to be combined with a drug that is very effective in stopping the inflammatory cascade in the central nervous system. Dimethyl fumarate also blocks nuclear factor kappa B (NF-kappa B), and approximately 18% of the genetic variants are in the NF-kappa B pathway. So, the drug may be working by blocking NF-kappa B activity. Recent data suggest that the drug may be working by blocking glycolysis.
Professor of Neurology
“Fingolimod may have neuroprotective effects, particularly through glial cells such as oligodendroglial cells and astrocytes, changing the profile of astrocytes to produce anti-inflammatory, neurotrophic effects.”
Fingolimod may have neuroprotective effects, particularly through glial cells such as oligodendroglial cells and astrocytes, changing the profile of astrocytes to produce anti-inflammatory, neurotrophic effects. Biotin is an important co-factor in myelination and for oligodendrocytes, and it may well protect against this so-called virtual hypoxia that results in axonal death. An early study indicated that high-dose biotin therapy improved results for the Expanded Disability Status Scale and/or the timed 25-foot walk in 12.6% of patients with progressive MS; however, a larger phase 3 trial of greater duration would be needed to corroborate these initial positive findings. Another compound is dimethyl fumarate, which has been suggested to work through the Nrf2 pathway. The University of California, San Francisco, generated a Nrf2 knockout mouse, and dimethyl fumarate still worked in the experimental autoimmune encephalomyelitis mouse model. I do not know how dimethyl fumarate acts, but, presumably, it does not act through Nrf2.
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