Researchers have found a possible way to protect people with multiple sclerosis (MS) from severe long-term disability: increase nervous-system levels of a vital compound, called nicotinamide adenine dinucleotide (NAD), by giving its chemical precursor -- nicotinamide, a form of vitamin B3.
Current therapies for MS mainly address the relapsing-remitting phase of the disease, but some of these have severe side effects, and most patients eventually enter a chronic progressive phase for which there is no good treatment. Using a mouse model of MS, researchers in the Neurobiology Program at Children's Hospital Boston found strong evidence that nicotinamide may protect against nerve damage in the chronic progressive phase, when the most serious disabilities occur. Their findings appear in a cover article in the September 20 Journal of Neuroscience.
MS is a neurologic disorder in which nerve fibers, or axons, are damaged through inflammation, loss of their insulating myelin coating, and degeneration. This damage disrupts nerves' ability to conduct electrical impulses to and from the brain, causing such symptoms as fatigue, difficulty walking, pain, spasticity, and emotional and cognitive changes. Current treatments mainly protect against inflammation and myelin loss, but do not completely prevent long-term axon damage.
A team led by Shinjiro Kaneko, MD, a research fellow at Children's, and senior investigator Zhigang He, PhD, also from Children's, worked with mice that had an MS-like disease called experimental autoimmune encephalitis (EAE). Through careful experiments, they showed that nicotinamide protected the animals' axons from degeneration -- not only preventing axon inflammation and myelin loss, but also protecting axons that had already lost their myelin from further degradation.
Intriguingly, mice with EAE who received daily nicotinamide injections under their skin had a delayed onset of neurologic disability, and the severity of their deficits was reduced for at least eight weeks after treatment. The greater the dose of nicotinamide, the greater the protective effect. [See accompanying figure.]
On a scale of 1 to 5 (1 indicating mild weakness only in the tail, 4 indicating paralysis involving all four limbs, and 5, death from the disease), mice receiving the highest doses of nicotinamide had neurologic scores between 1 and 2, while control mice had scores between 3 and 4. All differences between treated groups and controls were statistically significant.
Mice with the greatest neurologic deficits had the lowest levels of NAD in their spinal cord, and those with the mildest deficits had the highest NAD levels. Mice that had higher levels of an enzyme that converts nicotinamide to NAD (known as Wlds mice) responded best to treatment.
Moreover, nicotinamide significantly reduced neurologic deficits even when treatment was delayed until 10 days after the induction of EAE, raising hope that it will also be effective in the later stages of MS. "The earlier therapy was started, the better the effect, but we hope nicotinamide can help patients who are already in the chronic stage," says Kaneko.
In other experiments, the researchers demonstrated that nicotinamide works by increasing levels of NAD in the spinal cord and that NAD levels decrease when axons degenerate. Finally, they showed that giving NAD directly also prevented axon degeneration.
NAD is used extensively by cells to produce energy through the breakdown of carbohydrates. Its chemical precursor, nicotinamide, has several characteristics that make it a promising therapeutic agent: it readily crosses the blood-brain barrier, is inexpensive and available in any drugstore, and its close relative, vitamin B3, is already used clinically to treat pellagra (vitamin B3 deficiency), high cholesterol, and other disorders. Although nicotinamide is thought to have few side effects, the doses used in mice would translate to much higher human doses than are normally used clinically, so would need to be tested for safety.
"We hope that our work will initiate a clinical trial, and that nicotinamide could be used in real patients," Kaneko says. "In the early phase of MS, anti-inflammatory drugs may work, but long-term you need to protect against axonal damage."The research was funded by the National Multiple Sclerosis Society and the National Institute of Neurological Disorders and Stroke.
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