For release: Friday, October 27, 2006
Researchers have shown that a form of vitamin B3 is beneficial in mice with a disease similar to multiple sclerosis (MS). Although standard doses of the vitamin would not be potent enough for long-term treatment of MS, the findings could be a step toward developing effective drugs against the disease.
Zhigang He, Ph.D., a neuroscientist at Harvard Medical School and Children’s Hospital in Boston, led a research team that tested the vitamin nicotinamide in mice with experimental autoimmune encephalomyelitis (EAE). Like MS, the mouse disease occurs when the body’s own immune cells target the myelin coating around nerve cells and destroy the axons, wire-like sprouts that carry electrical impulses from one nerve cell to another. Dr. He and his team found that mice treated with daily nicotinamide injections had a slower, less severe course of EAE compared to untreated mice.
Dr. He, who was supported by the National Institute of Neurological Disorders and Stroke, said he conducted the study to develop a novel way to treat MS. Most existing therapies, he said, involve the use of immunosuppressant drugs to weaken the immune system – an approach limited by negative side effects, including increased susceptibility to infection. He hoped nicotinamide might work from the other end of the disease, strengthening axons against the immune system’s onslaught.
Ursula Utz, Ph.D., a program director in the NINDS Division of Extramural Research, commented that Dr. He is at the forefront of a positive trend in MS research. “It’s important that researchers have started focusing on the neurodegenerative aspects of MS, and not just exclusively on immunomodulation,” she said.
Dr. He previously had observed that levels of a compound called nicotinamide adenine dinucleotide (NAD) appeared to correlate with the health of axons grown in a laboratory dish. Cells make NAD – a key player in cell metabolism – when they are supplied with nicotinamide.
In this study, published in the September 20 issue of the Journal of Neuroscience,* Dr. He and his team triggered EAE in mice by injecting them with a protein component of myelin, which makes up the insulation around axons. They noted that NAD levels in the spinal cords of the mice dropped as the disease progressed.
When the mice were given daily subcutaneous (under the skin) injections of nicotinamide from the time of EAE induction, their weakness developed more gradually and was less severe than in untreated mice. The spinal cords of treated mice contained more surviving axons than those of untreated mice. They also had less inflammation (a build-up of immune cells) and more intact areas of myelin, suggesting that nicotinamide might have direct effects on the immune system and on myelin-producing cells.
Finally, Dr. He found that nicotinamide given 10 days after EAE induction, when symptoms have already appeared, had similar protective effects on the strength and neuroanatomy of the mice. Dr. Utz said this was the study’s most encouraging result, since there are many drugs that slow EAE in mice when given before the onset of symptoms, but then fail to work against MS in people, who don’t seek treatment until after symptoms appear.
Unfortunately, nicotinamide was effective only at high doses in the mice, and an equivalent dose in humans would be impractical and possibly unsafe. Moreover, even during continuous daily treatment with nicotinamide, NAD levels mysteriously tapered off as EAE progressed in the mice.
To make an end-run around this problem, Dr. He induced EAE in mice carrying a gene that enables them to convert nicotinamide into NAD more efficiently. When those mice were given nicotinamide daily, their NAD levels remained high, and their EAE symptoms were suppressed more effectively than in mice without the extra gene.
This is important evidence that it’s possible to enhance the effects of nicotinamide, said Dr. Utz. “We might be able to find other agents [besides nicotinamide]…that target the NAD pathway and could be used at a lower dose in patients with MS,” she said.
It’s too early to know whether nicotinamide itself would be beneficial for people with MS. Still, Dr. He said he hopes to collaborate with clinical researchers to conduct a trial of short-term nicotinamide to treat the “relapses,” or periodic flare-ups, characteristic of MS.
“The nature of this treatment is to prevent axon degeneration, so what I imagine is that we could provide short-term treatment for acute phases of the disease,” he said. “Once the inflammation [during the relapse] is over, the axons will still be there.”
Both Dr. He and Dr. Utz have cautioned against taking nicotinamide for MS until researchers know more about its mechanism of action and its effects in people.
*Kaneko S, Wang J, Kaneko M, Yiu G, Hurrell JM, Chitnis T, Khoury SJ, He Z. “Protecting axonal degeneration by increasing nicotinamide adenine dinucleotide levels in experimental autoimmune encephalomyelitis models.” Journal of Neuroscience, September 20, 2006, Vol. 26(38), pp. 9794-9804.
- By Daniel Stimson, Ph.D.
Last Modified January 31, 2007