"Bad guy" Kainic Acid
glutamic acid kainic acid domoic acid Kainic acid and its structural relative domoic acid have first been isolated in Japan from sea weed in 1953 and 1959, respectively (in Japanese, kaininso means 'ghost of the sea'). Originally only of interest as potential flavor enhancers (just like glutamate), kainic acid was found useful as an antihelminthic for children in Japan, but later turned out to be neurotoxic. It was presumably domoic acid causing a first mass poisening of sea birds 1961 in Capitola (California): Desoriented sea birds entered en masse coastal villages, very much to the surprise of the residents. A local newspaper article on that strange event was found in the notes of Alfred Hitchcock, who spent his 1961 holydays in nearby Santa Cruz, giving rise to the speculation that he has been inspired by this article to create his famous 1963 movie "The Birds".
In the 70ties, kainic acid was introduced as a tool into neuroscience research. It was discovered that kainic acid acted on a class of hitherto unknown neurotransmitter receptors, mediating the effects of the most abundant excitatory neurotransmitter glutamic acid. At that time, the concept of "neurotransmitters" mediating the communication between neurons was already well established. However the idea, as nice as it might have looked to the theoreticist, suffered from a serious drawback: If it was true, and if all communication between the neurons in the brain had a chemical basis, why did the introduction of chemicals into the brain have only minor or rather unspecific effects? In the 70ties it became clear, why: Because the most important neurotransmitters were just about to be discovered, the excitatory glutamic acid and the inhibitory gamma-amino-butyric acid (GABA). And kainic acid became a first key to elucidate the neurophysiological role of glutamic acid.
It was soon understood that kainic acid in direct contact with neurons had a dramatic impact, and that the initially used experimental doses were very high. In these first explorative investigations, the animals (mostly rats) had symptoms like motor hyperactivity and seizures, and neurons were destroyed in specific brain regions rich in this type of glutamate receptor. Researchers like Haruhiko Shinozaki, John Olney, Edith & Patrick McGeer, Joseph Coyle, Robert Schwarcz, Victor Nadler, and Yezechiel Ben-Ari (ref. 1-6) realized, that the specific pattern of neuropathology caused in rat brains was reminiscent of several human pathological conditions, depending on the dose and the route of application. In that, kainic acid helped to create model conditions for prominent human diseases like Chorea Huntington, Stroke, and Epilepsy, opening new avenues for the development of therapeutic drugs. After adaptation of the dose, kainic acid proved as an appropriate pharmacological means for the local stimulation of neurons, without destroying them.
However, it was not human curiosity taking the highest toll on victims, it was nature again. In 1987, 4 people died on Prince Edward Island (Canada), after eating shell-fish contaminated with high quantities of domoic acid, the first (and up to now only) human casualities. The syndrom was classified as "amnesic shellfish poisening", alluding to the most prominent symptom: loss of short-term memory. In 1991 thousands of pelicans and cormorants died in Monterey Bay, and again domoic acid was identified as the culprit. And in 1998, in the same area hundreds of sea lions were the victims, some of them entering coastal villages in desorientation. Since 1990, analysis of sea mussels for domoic acid content has become routine, not only at the US westcoast, but also in Europe, and the neurotoxin has been found in mussels harvested at the coasts of Ireland, Scotland, Portugal, and Spain.
My first encounter with the dramatic neurobehavioral effects of kainic acid dates back to the time of my diploma thesis in the chemical lab at the University Clinic of Psychiatry (1976/77). In 1975 Robert Schwarcz had left this lab to join the group of Joseph Coyle in Baltimore, but kept close contacts with Manfred Karobath, the supervisor of my work. Due to these contacts, our lab was among the first worldwide to profit from the important discoveries of Schwarcz, Coyle (ref. 3) and others (ref. 1, 2 & 4) on kainic acid. My own research on kainic acid started with my thesis (1978-81) and was later continued in Ben-Ari's lab at the CNRS in Gif-sur-Yvette (France). Back in Vienna, I discovered that as little as 5 ng (nanogram) kainic acid, if applied locally to sensitive sites in a rat's brain, resulted in pronounced behavioral changes, but not necessarily in neuronal damage (7).MB 3/03
References:
(1) Shinozaki,-H; Shibuya,-I (1974) Potentiation of glutamate-induced depolarization by kainic acid in the crayfish opener muscle. Neuropharmacology. 13: 1057-65
(2) Olney,-J-W; Rhee,-V; Ho,-O-L (1974) Kainic acid: a powerful neurotoxic analogue of glutamate. Brain-Res. 77: 507-12
(3) Coyle,-J-T; Schwarcz,-R (1976) Lesion of striatal neurones with kainic acid provides a model for Huntington's chorea. Nature 263: 244-6
(4) McGeer,-E-G; McGeer,-P-L (1976) Duplication of biochemical changes of Huntington's chorea by intrastriatal injections of glutamic and kainic acids. Nature 263: 517-9
(5) Nadler,-J-V; Perry,-B-W; Cotman,-C-W (1978) Intraventricular kainic acid preferentially destroys hippocampal pyramidal cells. Nature 271: 676-7
(6) Ben-Ari,-Y; Lagowska,-J; Tremblay,-E; Le-Gal-La-Salle,-G (1979) A new model of focal status epilepticus: intra-amygdaloid application of kainic acid elicits repetitive secondarily generalized convulsive seizures. Brain-Res. 163: 176-9
(7) Berger,-M-L et al. (1989) Limbic seizures without brain damage after injection of low doses of kainic acid into the amygdala of freely moving rats. Brain Res. 489: 261-72