GLUTAMATE ANTAGONISTS IN AMYOTROPHIC-LATERAL-SCLEROSIS - A REVIEW OF THEIR THERAPEUTIC POTENTIAL

Amyotrophic lateral sclerosis (ALS) is a degenerative neurological dis order that is manifested clinically by muscle weakness, wasting, spast icity and body-weight loss, typically resulting in death from debilita ting disease within 2 to 5 years of the onset of symptoms. Pathologica lly. there is degeneration and loss of the motor neurons in the spinal cord, brainstem and cerebral cortex. Over 90% of ALS cases occur spor adically (i.e. 'primary' ALS). The cause is unknown. There is, however , evidence that abnormalities of the excitatory amino acid glutamate a re present in patients with ALS, and the possibility exists that the s ynaptic action of glutamate is abnormally potentiated causing excitoto xic degeneration of motor neurons. Hence, attenuation of glutamatergic transmission may provide the means for therapeutic intervention in AL S. In line with this hypothesis, several strategies for the treatment of ALS have been proposed. These include: (i) the modification of exci tatory transmission mediated by glutamate using agents that can intera ct specifically with subtypes of glutamate receptors, and (ii) modulat ion of presynaptic glutamatergic mechanisms by, for example, decreasin g glutamate release from nerve endings, enhancing removal of glutamate from the synapse, and augmenting glutamate metabolism by synaptic ast rocytes. Some of the newer anticonvulsants can attenuate excitatory tr ansmission by decreasing glutamate release and, therefore, these agent s have therapeutic potential in ALS. Of these, riluzole has been teste d in a sizeable number of patients and found to be effective in prolon ging their survival by 2 to 3 months. These results raise the cautious optimism that this strategy may lend to further therapeutic gains in the near future. However, it is presently unclear whether abnormalitie s of glutamate are a contributing rather than a causative factor in th e pathophysiology of ALS, and, as such, a better understanding of the extent of glutamatergic dysfunction in ALS neurodegoneration may lead to improved rational therapies for this disorder.