THE CANADIAN JOURNAL OF NEUROLOGICAL SCIENCES HYPOTHESIS Speculations on Disease States Induced by Excitatory Amino Acids

There is much current interest in excitatory amino acids and their receptors because of their postulated involvement in several disorders of the nervous system. They function as neurotransmitters, but can act as neurotoxins in some situations. They have been implicated in the pathogenesis of cerebral hypoxic/ischemic and hypoglycemic damage, in epilepsy, in some degenerative diseases, and in some forms of neurotoxin-induced cerebral dysfunction. These diseases may reflect abnormality in a system which has evolved to provide synaptic plasticity essential for learning and memory. The purpose of this paper is to explore the ramifications of such a hypothesis. RESUME: Speculations sur la nature des maladies causees par les acides amines excitateurs Des recherches recentes ont implique les acides amines excitateurs et leurs recepteurs dans plusieurs desordres du systeme nerveux central. Ce sont des neurotransmetteurs qui peuvent parfois agir comme des neurotoxines. On les a impliques dans la pathogenese de l'atteinte cerebrale d'origine hypoxique/ischemique et hypoglycemique, dans I'epilepsie, dans certaines maladies degeneratives et dans d'autres formes de dommage neurotoxicologique. On les a egalement impliques dans la genese de la plasticite synaptique si fondamentale pour l'apprentissage et la memoire. II se peut que les atteintes pathologiques soient une maladaption de ce systeme dont 1'evolution en premier lieu visait a fournir une plasticite synaptique dans des conditions physiologiques. Cet article a pour but d'explorer les differentes facettes de cette hypothese. ^ ^ ^ ^ ^ m ? ; „ ; / 2 2 . / 2 < J There is much current interest in excitatory amino acids and their receptors because of their postulated involvement in several disorders of the nervous sytem. The most common excitatory amino acids are glutamate and aspartate, but others are also of importance. They function as excitatory neurotransmitters, but it has been recognised for some years that they can also act as neurotoxins ('excitotoxins').' They have been implicated in the pathogenesis of cerebral ischemic and hypoglycemic damage, in epilepsy, in some degenerative diseases, and in some forms of neurotoxin-induced cerebral dysfunction. As well, they have been postulated to underlie the genesis of learning and memory. If these different lines of investigation are borne out, it would seem unlikely that there would not exist some unifying mechanism to explain the multiple roles of excitatory amino acids. The purpose of this paper is to explore the ramifications of such a hypothesis. Some of the evidence implicating excitatory amino acids in the phenomena listed above will first be reviewed. Cerebral Hypoxia/Ischemia The role of the excitatory amino acids in the pathogenesis of cerebral hypoxic/ischemic damage is the object of intense research efforts, and has recently been reviewed. There is a growing body of evidence suggesting that the neuronal cell damage which follows cerebral hypoxic/ischemic insult may not be the result of the hypoxia per se. It has been established that neuronal cells in culture are relatively insensitive to hypoxic challenge until they have established dendritic connections. In these culture systems the hypoxic insult can be greatly attenuated by pretreatment with blockers of excitatory amino acid receptors, and indeed, cytotoxic changes identical to those following hypoxia can be produced by the transient addition of these transmitters to the culture medium. This would suggest that hypoxic/ischemic cell death might result from the uncontrolled release of excitatory amino acids. In the rat, ischemic damage to the hippocampus can be greatly reduced if the perforant pathway (carrying the major excitatory amino acid input to the hippocampus) is first cut. The same protective effect is not seen in animals with lesions to the fimbria/fornix, which carries the main cholinergic and serotinergic inputs to the hippocampus. Injection of glutamate receptor blockers into the hippocampus provides local protection to subsequent ischemic challenge. Human trials using specific blockers of the excitatory amino acid receptors in situations where transient ischemia might be expected are proposed.