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October 01, 1996; 47 (4 Suppl 2) Pathogenesis

Excitotoxicity hypothesis

Jeffrey D. Rothstein
First published October 1, 1996, DOI: https://doi.org/10.1212/WNL.47.4_Suppl_2.19S
Jeffrey D. Rothstein
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Excitotoxicity hypothesis
Jeffrey D. Rothstein
Neurology Oct 1996, 47 (4 Suppl 2) 19S-26S; DOI: 10.1212/WNL.47.4_Suppl_2.19S

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In the United States, ALS is often better known by one of its past victims, the famous baseball player Lou Gehrig. Gehrig was also known as the "Iron Horse" for his unbroken record of 2,130 consecutive ball games. The streak ended in 1939 because of the debilitation caused by ALS. It is therefore particularly ironic that the year his record was broken (1995), by the Baltimore Orioles shortstop Cal Ripken, the first drug for the treatment of ALS, riluzole, was approved by the FDA. The neuropharmacologic basis for the use of riluzole centers on its action as a neuroprotectant against glutamate toxicity. This review will outline the scientific and clinical evidence that suggests that glutamate-mediated toxicity may contribute to motor neuron degeneration in ALS.

There are currently four major hypotheses on the pathogenesis of ALS Table 1 that will be discussed in the articles in this publication: the calcium channel autoantibody hypothesis, the excitotoxic hypothesis, the oxidative stress hypothesis, and the cytoskeletal hypothesis. Other ideas as to the etiology of ALS have also been proposed. [1] In fact, it is very likely that ALS may be caused by a variety of different primary insults, all of which culminate in the final phenotype of upper and lower motor degeneration characteristic of ALS. At least two different pathways already exist; SOD1 gene mutations are present in only 15 to 20% of all familial ALS patients and are not present in the sporadic ALS population [2]; thus, other mutations or risk factors must exist to account for the remaining familial and sporadic patient populations.

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Table 1. Theories on the etiology of ALS

Neurotransmitter glutamate: normal and abnormal neurotransmission.

Under normal conditions, when the presynaptic terminal is depolarized, glutamate is released in a calcium-dependent process Figure 1. It diffuses across the synaptic cleft where it can activate specific …

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  • Article
    • Neurotransmitter glutamate: normal and abnormal neurotransmission.
    • ALS defects in glutamate regulation.
    • Hypothesis testing--experimental models.
    • Selective motor neuron degeneration--targeting factors.
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