Glutamate glut linked to multiple sclerosis

Picture a crime scene at which a police officer is the criminal, indiscriminately killing bystanders who can’t flee. Then, the rash officer calls in reinforcements, who not only shoot at passersby but poison some of them.

The berserk police are errant immune cells and their innocent victims are sheaths of a substance called myelin that surrounds axons—the impulse-carrying tendrils extending from neurons, or nerve cells. Damaging myelin sheaths kills axons, resulting in the numbness, weakness, slurred speech, and paralysis of multiple sclerosis.

Two studies now indicate that a second wave of immune-cell carnage follows this initial mutiny. In this attack, immune cells produce copious amounts of glutamate, a transmitter of neural signals. The overabundance wreaks havoc on nerve tissue, overpowering the resident nervous-system cells that make myelin.

The new studies of rodents, which appear in the January Nature Medicine, suggest that drugs that counter the action of glutamate might fight multiple sclerosis in people.

Immune cells arriving on the scene of myelin-sheath damage discharge glutamate routinely.

It binds to receptor molecules on the surface of nervous system cells, which respond by taking it in. The myelin-producing cells, called oligodendrocytes, thus accumulate too much glutamate.

Unfortunately, these cells can’t handle this much glutamate, says Peter Werner, a biochemist at Albert Einstein College of Medicine and Beth Israel Medical Center, both in New York, and coauthor of one of the studies. The excess opens channels in the cell membrane and “can literally excite a cell to death,” he says.

Using mice induced to have a condition similar to multiple sclerosis, Werner and his colleagues find that a drug that binds to glutamate receptors, preventing glutamate uptake, saves mice from neurodegeneration.

Comparing 20 mice given the drug, called NBQX, with 20 untreated mice, the researchers note that the treated mice retain the ability to use their hind legs and right themselves, whereas the other mice lose these functions.

In the second study, European researchers show similar success by blocking glutamate receptors. Rats and mice given any of four glutamate-receptor inhibitors, including NBQX, fended off the condition that mimics multiple sclerosis markedly better than untreated animals did, says Lechoslaw Turski, a pharmacologist at Solvay Pharmaceuticals in Weesp, the Netherlands, and a study coauthor. 

The results “provide another avenue of potential therapy for multiple sclerosis,” says Howard L. Weiner, a neuroimmunologist at Brigham and Women’s Hospital and Harvard Medical School, both in Boston. “I think it’s important work.”

Scientists don’t know why immune cells run amok or why myelin in particular attracts their wrath. Much work on multiple sclerosis has centered on these initial immune onslaughts, and scientists have discovered that immune cells release various toxic agents such as hydrogen peroxide. Yet these findings don’t explain all the damage being done.

The new studies “suggest a whole other mechanism by which cell death might occur,” says immunologist David S. Pisetsky of Duke University Medical Center in Durham, N.C. He finds the idea that heavy exposure to a substance as common as glutamate might kill cells “very intriguing.”

NBQX worked well on the rodents, but it can cause kidney damage in people. In a study of patients who have had strokes, researchers are testing a version of NBQX modified to avoid this side effect. During a stroke, when the blood supply is shut off to part of the brain, neurons die and release glutamate. The NBQX derivative has shown signs of inhibiting living cells from taking up this excess glutamate and thereby suffering further damage, Werner says, but results are not yet published.