Other Excitotoxins

After kainic acid, ibotenic acid has been the most extensively characterized of the excitotoxins effective with local injection. On a molar basis, ibotenic acid has approximately 20-fold lower potency than kainic acid 

Neurophysiologic and neuropharmacologic studies indicate that N-methy 1-Dr aspartic acid (NMD A) activates a distinct set of excitatory receptors that differ from those sensitive to either quisqualic acid or kainic acid. The excitatory effects of NMDA are selectively antagonized by the divalent cation Mg as well as by D-a-amino adipate and the more potent 2-amino-4-phosphonovaleric acid (Davies et al., 1979). Olney and co-workers (1971) 

In comparative studies of the neurotoxic effects of NMDA and kainic acid in the hippocampal formation, we have found that NMDA is approximately 100-fold less potent as a neurotoxin than kainic acid on a molar basis (Zaczek et aL, 1981). The lesion associated with local injection of NMDA is limited to the injection site in the hippocampal formation and appears to uniformly affect all neuronal perikarya within its circumference. However, doses of NMDA effective in causing significant lesions in the dentate gyrus precipitated a severe electroencephalographic and behavioral seizure disturbance punctuated by frequent tonic-clonic convulsions occasionally resulting in death. Thus, the superiority of NMDA over kainic acid and ibotenic acid for intracerebral injection remains to be established. 

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Some plants regularly eaten by humans contain neurotoxins that pose serious health problems. On Guam, for example, the seeds of Cycas circinalis used to be an important source of carbohydrates. Seeds of Cycas rumphii were ground into flour for tortillas. However, the seeds contain jS-N-methylamino-i-alanine, a suspected excitotoxin that overstimulates and destroys nerve cells. This compound causes a parkinsonism-like disease in macaques (Spencer et al, 1987). Other toxins have been proposed to be responsible for the disease, among them cycasin, another cycad toxin (Stone, 1993). 

Subsequently, several studies have provided more detailed information on domoic acid action as an excitotoxin. The presynaptic action of domoic acid to induce glutamate release was extended to include other excitatoiy and inhibitoiy neurotransmitters and linked to the entiy of calcium through voltage operated calcium channels, suggesting that domoic acid toxicity may involve multiple transmitters (Brown and Nijjar 1995 Duran et al. 1995a Malva et al. 1996). Domoic acid effects on intracellular calcium were next characterized by FURA-2 imaging of the hilar region of individual... 

One study relating chemical exposure to FM has been published. In it, four patients diagnosed with FM are reported to have complete or nearly complete resolution of their symptoms within months of eliminating two excitotoxins—monosodium glutamate (MSG) or MSG plus aspartame from their diets J6°l The authors point out that excitotoxins act as excitatory neurotransmitters that can lead to neurotoxicity when excessively consumed. No other similar studies have been found. 

The maturity of brain plays an important role in neuronal vulnerability to excitotoxins. The CVO regions and neural retina of immature rats and mice (less than 10 days of age) are much more sensitive to peripherally administered excitotoxins than the adult. In contrast, the striatum of the neonatal rat is remarkably resistant to doses of kainic acid that produce extensive lesions in the adult but full vulnerability is attained by three weeks after birth (Campochiaro and Coyle, 1978). Similarly, Honnegar and Richelson (1977) have found that reaggregating brain cultures exhibit increasing sensitivity to the neurotoxic effects of kainic acid with differentiation. At the other extreme, neuronal sensitivity of the striatum to directly injected kainate appears to increase with advancing age (Gaddy et aL, 1979). An age dependence for the neurotoxic action of ibotenic acid and other directly injected excitotoxins has not yet been described. 

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