More MS news articles for June 2001

Blocking sodium channels to unblock conduction

http://news.bmn.com/conferences/list/view?fileyear=2001&fileacronyn=WCN&fileday=day4&pagefile=story_2.html

WCN 2001 - Day 4 - Thursday 21 June 2001
Investigator: Kenneth Smith
Thursday Jun 21st, 2001
by Laura Spinney

Lesions in the central nervous system caused by multiple sclerosis (MS) block the conduction of impulses along axons, giving rise to the symptoms of this neuro-degenerative disease. New British research suggests that it may be possible to protect axons from so-called conduction block, pointing to potential therapies.

The lesions caused by the disease occur in patches all over the central nervous system (CNS), and appear far more frequently than the relapses experienced by patients. Patients may have two or three relapses over a two-year period, but they may have up to a hundred or so lesions in that time. The reason for this is that some lesions may occur in "silent" areas of the brain.

Long neuronal axons run through each lesion, across it and out the other side. But the erosion of the axon's myelin sheath that occurs within the lesion blocks electrical conductivity. Incoming impulses, which initially travel along the axon at the speed of a Formula One car, are short-circuited across the demyelinated section, noted Kenneth Smith, head of the Neuroinflammation Research Group at Guy's, King's and St Thomas' School of Medicine in London. If that happens in the optic nerve, for instance, the patient is blinded. Impulses crossing a repaired section of axon still travel far more slowly, at about the speed of a wheelchair, he added.

But demyelination is not the only cause of conduction block. "MS lesions have two components: an inflammatory component and a demyelinating component," said Smith. "Historically the emphasis has always been on the demyelinating component, but in the last ten years or so, the role of inflammation has become more widely appreciated."

Nitric oxide (NO) produced as part of the inflammatory response within a lesion can affect the physiological properties of axons independently of demyelination. The figure above shows the conduction response of two sets of axons. The one on the left undergoes temporary conduction block due to brief exposure to NO and recovers. The one on the right, which is exposed to NO in combination with electrical impulse activity, recovers only temporarily before reverting to permanent conduction block. The latter mimics those axons in an MS lesion which are eventually killed, as shown by the histological sections above.

Now, however, Smith's group has shown that it might be possible to protect axons by partially blocking the sodium channels beneath the myelin sheath, which are essential for conduction. When an axon is exposed as a result of demyelination, it becomes over-excitable, but by blocking some of the sodium channels, says Smith, you can "shave off" some of that excitability. Using a rat model of MS they treated some axon clusters in the dorsal roots of the spinal cord with low doses of the sodium channel blocking agent flecainide, and left others untreated. "The ones that are protected survive and the ones that aren't protected don't," he said.

Clearly the findings, which are unpublished, have therapeutic implications for MS patients. The next step, he says, is to investigate whether the same protective effect is seen with systemic administration of the sodium channel blocker. If experiments in rats show promise, the researchers hope to proceed to clinical trials.