By David N. Leff

Fruit flies, nematodes, clawed frogs, mice and rats are all very well, but dearest to a neurophysiologist's heart is the giant squid (Loligo pealeii). What makes this sea monster so appealing to nervous-system researchers is the immense size of its neuronal axons, and the fact that these are bare of myelin insulation.

By contrast, the phone line-like axons projecting from human nerve cells in brain and spinal cord are insulated in layers of myelin. This protective sheath enables our very fine-diameter axons to transmit their neuroelectric messages with very high and fast conductance. The squid's axons are 10 times as thick - more than 10 microns across - as the average 1-micron human conducting fibers.

"The axon of a giant squid," observed biochemist and neuropathologist Peter Werner, "is so huge it can be seen with the naked eye. The reason why it has to be so big is because it conducts the excitation the slow way, whereas human axons can be smaller, yet work extremely well - unless you start removing their myelin insulation."

That myelin removal is what takes place in the axons of people stricken with multiple sclerosis (MS). This incurable, probably autoimmune, disease afflicts upwards of 1.1 million victims throughout the world, between 250,000 and 350,000 of them in the U.S. Inexplicably, twice as many women as men contract MS, which becomes manifest between 20 and 40 years of age.

"MS is characterized by infiltration of immune cells into the central nervous system [CNS]," Werner explained. "This infiltration is brought about by the fact that the immune system, for unknown reasons, thinks that proteins in myelin are foreign. So you have an immune reaction to myelin. That is the primary event. If a patient comes to see his or her neurologist," he went on, "and complains of restricted vision, loss of sensory input or impaired movement, and this happens more than once, we call it MS." The malady is marked by such flare-ups, of increasing severity and duration, separated by periods of remission.

Among Americans of note afflicted with MS are the movie actor and stand-up comedian, Richard Pryor, who is now confined to a wheelchair, and Montel Williams of TV talk-show fame.

Glutamate Strikes Again

Werner, an assistant professor of neurology at Albert Einstein College of Medicine in The Bronx, N.Y., is corresponding author of an article in the January 2000 issue of Nature Medicine. Its title: "Glutamate excitotoxicity in a model of multiple sclerosis." Our novel finding," he told BioWorld Today, "was the observation that glutamate excitotoxicity is indeed involved in the damage that leads to the plaque in autoimmune demyelination. In MS it's a combination of demyelination, where as far as we knew glutamate is not involved, and the death of oligodendrocytes, in which we showed glutamate involvement."

Giant squids don't come down with MS. Neither do mammals, other than Homo sapiens. But mice can be infected with an inflammatory disease called experimental autoimmune encephalomyelitis (EAE), which mimics MS to all research intents and purposes.

The myelin basic protein, of which axons are denuded by misguided autoimmune cells, is manufactured mainly in the brain, by glial cells called oligodendrocytes. "The old view," Werner recalled, "was that neurons are the actual active cells in the CNS with regard to signal processing and neurotransmitter binding. People thought that the brain's glial cells - from the Greek word for 'glue' - were there only to hold everything else together, to fill up the dead space. And that's not true.

"Almost every glial cell in the brain," he explained, "in particular the oligodendroglia, which are the cells that make the myelin, possess neurotransmitter receptors - notably AMP/kainate receptors, which bind glutamate."

The amino acid glutamate gets a bad rap because of its link to monosodium glutamate (MSG), the allergenic, food-flavoring compound notorious for Chinese restaurant syndrome.

"Glutamate is a very abundant amino acid in the cells of our body," Werner pointed out. "In the brain, the concentration of free glutamate outside the nerve cells is kept low, whereas inside the cells it can rise to over a thousandfold concentration. This very steep gradient is important because glutamate is used by the mammalian CNS as the dominant excitatory neurotransmitter.

"Excitation," he explained, "means that if the ligand, in this case glutamate, binds its receptor, the nerve cells will depolarize, and you will have conductance of an impulse along the axons. There are several classes of glutamate receptors," Werner recounted. "The one we are interested in is called the AMP/kainate. Its antagonist, code-named NBQX, was initially synthesized by the Danish company Novo-Nordisk in the late 1980s, in its attempt to find a treatment for cerebral stroke. NBQX is very effective; a dream compound. It's one of the most powerful AMP/kainate antagonists there is. But NMBX cannot be used in humans for the reason that it causes nephrotoxicity."

What Links Stroke Therapy To MS?

"The basic idea of treating stroke with a glutamate AMP/kainate antagonist is that the spreading brain damage is caused by the dumping of glutamate in the core area around the ischemia, the immediate brain lesion caused by the stroke. I think that core area is irretrievably lost. If you could treat a patient in the first two hours or so after the stroke with an AMP/kainate antagonist, that would prevent glutamate from acting on these receptors. You would prevent those cells - which are compromised but still viable, and could recover - from being excited to death by glutamate. That's the idea behind using it in stroke.

"Now in MS," he continued, "the idea would be, when a relapse episode occurred, if this patient took AMP/kainate antagonist, it would ameliorate damage from the attack on the CNS, and which at least in our EAE mouse model we have prevented to some extent."

Werner concluded: "I would be very interested in getting compounds from companies that can be used in people also, to test in our animal models. So I would be interested in collaborations, if anybody out there has compounds to test clinically. Because I can't get to them; they're all proprietary."