Excitotoxicity
Perhaps one of the best-studied mechanisms for cell death involves abnormal stimulation or activation of neurons in the brain and spinal cord by the amino acid glutamate. Glutamate is an amino acid present in food. It’s also made by every cell in the body. In the brain, glutamate additionally serves as a neurotransmitter—a chemical signal that allows one neuron to "talk" to another. Such conversations underlie the basic operation of the brain. While the brain uses other amino acid-based neurotransmitters, glutamate is by far the most common.

The molecule, however, has an ugly side: excessive glutamate rapidly kills cells in the brain and spinal cord. Normally, nerve cells completely prevent its buildup through glutamate transporters, proteins which "vacuum up" the excess neurotransmitter around cells. Glutamate transporters are found both on nerve cells and on astrocytes, the cells that lie adjacent to them. In ALS, however, something may go wrong.

In the early 1990s, investigators at the Center for ALS Research were the first to suggest that cells of ALS patients and animal models had major defects in glutamate neurotransmission. The Center scientists, as well as others worldwide, proved glutamate-based neurotoxicity is part of ALS, part of a process leading to motor neurons’ death.
A key defect here likely centers on the glutamate transporters. They’re either inefficient or don’t exist in sufficient supply to prevent glutamate buildup. Then the excess glutamate overstimulates nerve cells, ultimately contributing to their death.

This research led to the clinical trials of Riluzole, a drug that retards nerve cells’ release of glutamate. Riluzole has become the first drug to alter the course of neurodegeneration in ALS.
Although the effects of Riluzole are clearly modest, it has been the only drug that reliably shows clinical efficacy compared to the dozens of drugs studied by clinicians around the world in thousands of ALS patients. And, in spite of its mild benefits, Riluzole has provided important clues for the development of more potent therapies.

Although little doubt remains that glutamate toxicity contributes to ALS, research has begun to focus on the specifics, on how and why glutamate might kill motor neurons and on what underlies the loss or shortcomings of glutamate transporters.

Center investigators are leading the way in what they believe may be landmark research. They’ve recently enabled mouse ALS models to make an excess of glutamate transport protein in both brains and spinal cords. Preliminary studies of these mice have shown huge increases in their survival time. Encouraged by this, Center directors are developing a intense and rapid program to investigate glutamate transporter replacement therapies (called EAAT2 replacement therapy) for ALS patients.