Excitotoxins

The concept of excitotoxicity

The amino acids glutamic and aspartic acids are known to be present in high concentrations in the mammalian brain, where they have been shown to act as excitatory neurotransmitters. Over 20 years ago, it was shown that the systemic administration of glutamic acid to newborn rodents resulted in a destruction of retinal cells and also some cells in the central nervous system. Later studies showed that high oral doses of this amino acid also caused brain damage in primates, such toxic effects being particularly apparent on the postsynaptic dendrosomal membranes where the excitatory amino acid receptors are located. Such findings led to the concept of excitotoxicity and, later, to the view that some neurological diseases such as epilepsy could be a consequence of nerve cell damage due to the excessive release of glutamate within the brain.

At least three types of excitatory amino acid receptors have been identified, termed the NMDA, alpha-amino-3-hydroxy-5-methyl-4-isoxa-zole proprionic acid (AMPA) and kainate receptors according to their affinity for specific excitatory amino acids (see p. 57). Antagonists of some of these receptor types, such as MK 801 and D-2-amino-5-phosphonopentano-ate (AP 5), were then shown to protect neurons in vivo against the

Table 14.2. Potencies of some antagonists of NMDA receptors in chick embryo retina in vitro

Potency

Competitive NMDA antagonists

D-2-Amino-5-phosphonopentanoate (AP 5) 25 mM

D-2-Amino-5-phosphonoheptanoate (AP 7) 75 mM

Non-competitive NMDA antagonists

MK801 0.01 mM

Phencyclidine 0.5 mM

Ketamine 5 mM

(+/ -) n-Allylnormetazocine (SKF10047) 10 mM

Dextromethorphan 50 mM

Mixed excitatory amino acids

Cyanonitroquinoxalinedione (CNQX) 50 mM

Kynurenic acid 300 mM

Barbiturates

Amylobarbitone 50 mM

Thiopentone 200 mM

Potencies of compounds expressed as the minimal concentration (mM) required to provide total protection against the excitotoxic effects of NMDA.

neurotoxic effects of glutamate or NMDA. Table 14.2 lists some of the compounds that have been developed as antagonists of the most important of the excitatory amino acid receptors, the NMDA receptor.

So far, only the non-competitive antagonists of the NMDA receptors such as phencyclidine and MK 801 can readily penetrate the blood-brain barrier and therefore protect animals against the toxic effects of exogenous excitatory amino acids. The barbiturates (e.g. thiopentone) have an additional action in blocking both NMDA and non-NMDA (e.g. kainic acid) receptors and are therefore of some interest as broad-spectrum excitotoxin antagonists, while the quinoxalinedione derivative cyanonitroquinoxalinedione (CNQX) was the first compound to be synthesized that showed a greater potency in blocking non-NMDA excitatory amino acid receptors.

The essential features of the NMDA receptor are illustrated diagrammati-cally in Figure 14.8. The NMDA receptor controls the opening of the sodium/ calcium ion channel, which may be blocked by dissociation anaesthetics such as phencyclidine and ketamine or by magnesium ions. In addition to glutamate, glycine can also facilitate the opening of the ion channel by activating a strychnine-insensitive receptor site. It should be remembered that in the spinal cord glycine acts as an inhibitory transmitter by acting on a different type of glycine receptor; strychnine causes characteristic convulsions by blocking the action of glycine on these spinal cord receptors. Zinc ions can

Figure 14.8. Sites of action of endogenous ligands and drugs that modulate the action of excitatory amino acids on the NMDA receptor. Recent evidence shows that glutamate (Glut) and possibly other excitatory amino acids released from presynaptic terminals activate the NMDA receptor site on postsynaptic membranes, resulting in the opening of the Na+/Ca++ channels. Glycine acts on a strychnine-insensitive receptor while polyamines (e.g. spermine and spermidine) also have a modulatory role. Conversely Zn++ and Mg++ and drugs like phencyclidine (PCP) block the ion channel by acting at various sites on the NMDA receptor complex or the ion channel.

Figure 14.8. Sites of action of endogenous ligands and drugs that modulate the action of excitatory amino acids on the NMDA receptor. Recent evidence shows that glutamate (Glut) and possibly other excitatory amino acids released from presynaptic terminals activate the NMDA receptor site on postsynaptic membranes, resulting in the opening of the Na+/Ca++ channels. Glycine acts on a strychnine-insensitive receptor while polyamines (e.g. spermine and spermidine) also have a modulatory role. Conversely Zn++ and Mg++ and drugs like phencyclidine (PCP) block the ion channel by acting at various sites on the NMDA receptor complex or the ion channel.

reduce the effects of glutamate and glycine on the NMDA receptor. In view of the complex inter-relationships between the various agonists that act on the NMDA receptor, it may be speculated that a pathological process affecting any of these factors might create an imbalance which leads to a malfunctioning of excitatory amino acid transmission in the brain.

Environmental excitotoxins

It is well established that monosodium glutamate, a widely used food additive and major component of soya sauce, can destroy nerve cells when administered orally to young animals. Those neurons lying immediately outside the blood-brain barrier, e.g. in the arcuate nucleus of the hypothalamus, are the most vulnerable. It is therefore possible that ingestion of a diet high in glutamate may contribute to degenerative changes in the brain later in life.

Neurolathyrism occurs in some tropical countries as a result of consuming large quantities of the legume Lathyrus sativus, which contains a potent excitatory amino acid analogue that can cause paralysis. In certain South Sea Islands, particularly the island of Guam, ingestion of the seeds of the cycad plant leads to the occurrence of a specific neurological disease with the combined features of amyotrophic lateral sclerosis, Parkinsonism and dementia. The analogue of alanine that causes this neurological disease has been identified.

Excitotoxins and neurodegenerative diseases

Epilepsy and related disorders may arise as a consequence of a dramatic release of glutamate from central nerve terminals. Sustained seizures of the limbic system in experimental animals result in brain damage that resembles that due to glutamate toxicity. Similar pathological changes are seen at autopsy in patients with intractable epilepsy. In animals, such seizure-related brain damage may be reduced by the administration of non-competitive NMDA antagonists (such as MK801, phencyclidine or ketamine), but it would appear that not all seizure activity is suppressed by such drugs.

The precise mechanism whereby persistent seizure activity results in neuronal degeneration is incompletely understood. It seems possible that repetitive depolarization and repolarization of the nerve membrane eventually leads to an energy-deprived state within the cell, thereby preventing the restoration of the cell membrane potential. Each depolarization will also lead to an influx of calcium ions, and an efflux of potassium ions, which if prolonged can result in cell death. The reduced efficiency of glial cells to remove potassium ions and the ability of high extracellular concentrations of potassium ions to depolarize neurons and cause neurodegenerative changes also play a critical role in causing the degenerative changes that are a feature of status epilepticus and intractable epilepsy.

Hypoxia and ischaemia may also cause neurodegenerative changes in the mammalian brain. In animals, cerebral ischaemia has been shown to cause a marked elevation in the extracellular concentrations of glutamate and aspartate, particularly in the hippocampus. Such pathological changes can be prevented by the prior administration of NMDA receptor antagonists. The hypoxic state results in energy deficiency within the brain, so that the mechanism responsible for the maintenance of transmembrane potentials may become compromised. The net effect of the elevation in the extracellular concentrations of excitatory amino acids could be a failure of magnesium ions to reduce the functional activity of the NMDA receptor. This could result in persistent membrane depolarization, excessive intracellular accumulation of calcium ions and the extracellular accumulation of potassium ions. The movement of sodium ions, accompanied by water, into the cell further compromises cellular function and results in cell death. Somewhat similar pathological changes have been postulated to occur following brain and spinal cord injury and in dementia pugilistica, a concussive brain injury associated with boxing.

Other neurological diseases in which a disorder of central excitatory amino acid function has been implicated include Huntington's disease, Alzheimer's disease and Parkinsonism. Experimental studies have shown that the injection of excitatory neurotoxins such as kainic and ibotenic acids into the rat brain results in pathological changes that resemble those seen in Huntington's disease. More recently, an endogenous neurotoxin, quinolinic acid, has been found in human brain which, if present in excessive quantities, selectively destroys the striatum but leaves other regions largely unaffected. While it now seems unlikely that quinolinic acid is the endogenous excitotoxin responsible for the pathological changes found in Huntington's disease, it remains a possibility that some other excitotoxin with similar properties and selectivity of action on striatal function may be involved. The possible involvement of excitotoxins in the pathology of Alzheimer's disease and parkinsonism is considered in the appropriate chapters.

Figure 14.9 summarizes the various factors that contribute to cell death following the production of intracellular reactive oxygen species. The possible mechanism whereby b amyloid contributes to apoptosis is illustrated in Figure 14.10.

Inflammatory changes and the role of the immune system

There is increasing evidence that many of the changes in the brain of the patient with AD are the result of inflammatory mediators. The view is supported by the observation that anti-inflammatory drugs have a neuroprotective action. In patients with AD the acute phase inflammatory response is increased, as indicated by a rise in the pro-inflammatory cytokines interleukins-1 and 6 (IL-1, IL-6) and tumour necrosis factor (TNF) alpha, changes which are accompanied by an increase in the plasma of the acute phase proteins alpha-1 chymotrypsin and alpha-2 macroglobulin. The complement system has also been shown to be active in the brain of the AD patient, a change which is associated with the activation of lytic enzymes that damage the neuronal membranes and which may therefore contribute to premature neuronal death. TNF alpha has also been shown to act as a potent neurotoxin when present in excess in the brain. In addition to the inflammatory cytokines, the activity of cyclooxygenase 2, an enzyme which synthesizes the inflammatory mediator prostaglandin E2 (PGE2) in the brain, has been shown to be increased in the brain of the patient with AD, thereby adding to the cascade of inflammatory changes.

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