New approaches to the treatment of ALS

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Amyotrophic lateral sclerosis (ALS) is a progressive degenerative motor neuron disease characterized by muscle weakness, wasting, spasticity, and weight loss, and eventually by respiratory failure. There is a degeneration and loss of motor neurons in the spinal cord, brainatem, and cerebral cortex. Death typically occurs within 3 to 4 years of the onset of the disease, although some patients may live considerably longer. [1,2] In the past few years there has been a substantial amount of research into the pathophysiology and treatment of ALS. Although a wide variety of therapeutic approaches have been attempted, until recently there was no drug that had an effect on the natural course of the disease. Riluzole, a glutamate antagonist, is the first such agent and the first drug approved for ALS treatment. Two placebo-controlled trials have demonstrated that the drug prolongs survival in patients with ALS. [3,4] Other investigational therapeutic approaches to the treatment of ALS include the use of neurotrophic factors, antioxidants, and other glutamate inhibitors. This article reviews the agents now available and those under investigation for the treatment of ALS, and discusses potential future approaches to therapy. A number of hypotheses concerning the pathogenesis of ALS have been proposed. These include: oxidative stress mediated by free radicals; neural toxicity (excitotoxicity) caused by the excessive stimulation of glutamate receptors by excitatory amino acids (e.g., glutamate, aspartate); a deficiency of neuronal growth factors; and autoimmunity (calcium channel autoantibodies). [5] There is growing evidence that oxidative stress is important in the initiation of the disease. [6] This hypothesis is supported by the discovery of mutations in the gene encoding for Cu/Zn superoxide dismutase (SOD1) in patients with familial ALS. [7] Glutamate is the principal excitatory neurotransmitter in the brain, and there is evidence that glutamate excitotoxicity is an important factor in the propagation of …