Glutamate Antagonists in Amyotrophic Lateral Sclerosis

Abstract

Summary Amyotrophic lateral sclerosis (ALS) is a degenerative neurological disorder that is manifested clinically by muscle weakness, wasting, spasticity and bodyweight loss, typically resulting in death from debilitating disease within 2 to 5 years of the onset of symptoms. Pathologically, there is degeneration and loss of the motor neurons in the spinal cord, brainstem and cerebral cortex, Over 90% of ALS cases occur sporadically (i.e. ‘primary’ ALS). The cause is unknown. There is, however, evidence that abnormalities of the excitatory amino acid glutamate are present in patients with ALS, and the possibility exists that the synaptic action of glutamate is abnormally potentiated causing excitotoxic degeneration of motor neurons. Hence, attenuation of glutamatergic transmission may provide the means for therapeutic intervention in ALS. In line with this hypothesis, several strategies for the treatment of ALS have been proposed, These include; (i) the modification of excitatory transmission mediated by glutamate using agents that can interact specifically with subtypes of glutamate receptors; and (ii) modulation of presynaptic glutamatergic mechanisms by, for example, decreasing glutamate release from nerve endings, enhancing removal of glutamate from the synapse, and augmenting glutamate metabolism by synaptic astrocytes. Some of the newer anticonvulsants can attenuate excitatory transmission by decreasing glutamate release and, therefore, these agents have therapeutic potential in ALS, Of these, riluzole has been tested in a sizeable number of patients and found to be effective in prolonging their survival by 2 to 3 months. These results raise the cautious optimism that this strategy may lead to further therapeutic gains in the near future. However, it is presently unclear whether abnormalities of glutamate are a contributing rather than a causative factor in the pathophysiology of ALS, and, as such, a better understanding of the extent of glutamatergic dysfunction in ALS neurodegeneration may lead to improved rational therapies for this disorder.