November 2006
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Neurobiology:
Vitamin therapy for MS?
A new clue about the developing brain
Timing brain-cell development
Brain formation involves the carefully timed production of different types of nerve cells: Making too much of one type and too little of another at any given time could lead to brain malformations. Now, Gabriel Corfas, PhD, S. Pablo Sardi, PhD, and colleagues in Children's Hospital Boston's Neurobiology program have discovered a new molecular pathway that influences which kind of cell a neural stem cell will make. There are implications for understanding diseases such as Alzheimer's, schizophrenia and autism.Early in brain development, neural stem cells produce mainly neurons, suppressing the production of astrocytes, the star-shaped cells that support neurons and have important regulatory functions. The pathway that Corfas and Sardi describe in Cell (October issue) involves a protein called erbB4, which straddles the neural stem cell's outer border. After being acted upon by two other important proteins—neuregulin 1, and presenilin—erbB4's inside half travels to the cell nucleus to inhibit astrocyte formation.
Past research has shown that presenilin activity is altered in Alzheimer's disease, and the new findings suggest that defective erbB4 signaling may explain this alteration. Studies have also shown that erbB4 is abundant around the sticky plaques found in the brains of Alzheimer's patients. More generally, erbB4 signaling regulates neuron function and survival. "Further studies of erbB4 signaling could provide important insights into the causes of neurodegeneration," says Corfas.
In addition, the genes for neuregulin1 and erbB4 have been implicated in schizophrenia. Corfas speculates that altered functioning of these genes, leading to premature formation of astrocytes, may cause errors in the brain's wiring, in turn leading to alterations in cognitive function such as those seen in schizophrenia and potentially in other diseases.
A vitamin B3 cousin may reduce multiple sclerosis patients' disabilities
If their findings with mice are any indication, researchers in Children's Hospital Boston's Neurobiology Program have found a potential way to prevent severe long-term disability in people who have multiple sclerosis (MS). In a cover article in the September 20 issue of Journal of Neuroscience, research fellow Shinjiro Kaneko, MD, senior investigator Zhigang He, PhD, and colleagues reported that a form of vitamin B3, called nicotinamide, prevents nerve damage in the chronic, progressive phase of MS, for which there is not good treatment.MS is a neurologic disorder in which nerve fibers are damaged, causing fatigue, difficulty walking, spasticity and other symptoms. Current treatments mainly address the early (relapsing-remitting) stage of MS; they don't completely prevent long-term nerve fiber damage.
Studying mice with an MS-like disease called experimental autoimmune encephalitis, Kaneko and He found that mice that received daily injections of nicotinamide under their skin—particularly those receiving higher doses—had significantly less muscle weakness and paralysis than mice that received placebo injections (see graph above). The nicotinamide seemed to work even after the disease was already established. "The earlier therapy was started, the better the effect," notes Kaneko, "but we hope nicotinamide can help patients who are already in the chronic stage of MS."
Nicotinomide is a key component of nicotinamide adenine dinucleotide (NAD), a compound used by cells to produce energy. The more NAD in the spinal cord, the milder the mice's symptoms, the research showed.
Nicotinamide would seem to be an ideal MS drug because it's inexpensive, widely available and thought to have few side effects. However, the doses used in the mice would translate to extremely high human doses that would require significant safety testing. Nevertheless, Kaneko is looking toward the future. "We hope that our work will initiate a clinical trial," he says.
