Clinical evaluation of ALS drugs

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Abstract
The pathogenesis of ALS can be divided into initiating events, propagating events, and terminal events. Oxidative stress is believed to be an initiating event in ALS. [2] The identification of patients with familial ALS who have been found to have mutations in Cu/Zn superoxide dismutase (SOD1) supports this hypothesis. [3] This defect may render motor neurons more susceptible to glutamate-induced toxicity. Propagating events are involved in the spread of the disease process. Glutamate is the principal excitatory neurotransmitter in the brain, mediating many neurologic functions, and there is evidence that glutamate excitotoxicity may be an important factor in the propagation of ALS. [4] Decreased uptake of glutamate may lead to over-stimulation of glutamate receptors which, via increased intracellular calcium, can lead to the activation of a series of enzymes, such as protein kinase C, phospholipases, proteases, protein phosphatases, and nitric oxide synthetase, which contribute to injury of the neuronal cell membrane. [5] Autoimmune mechanisms, such as the formation of anticalcium channel antibodies, are also believed to …