Neurotoxic action of kainic acid.

a-Kainic acid is a pyrolidine derivative that possesses two carboxylic acid moieties and an isopropylene side chain (Fig. 1). The molecule has three asymmetric centers with the C-3 isopropylene group and C-2 carboxyl side chain oriented in the cis position, whereas the two carboxyl groups have a trans orientation. Kainic acid, which in Japanese means “monster from the sea,” was isolated from the seaweed Digenea simplex, which had been originally used in Japanese folk medicine as an ascaricidal preparation (Tamura, 1954; Ueno et al., 1955; Takemoto, 1978). Shinozaki and Konishi (1970) provided the first evidence of the potent neuroexcitatory effects of kainic acid in ionophoretic studies of rat cortical neurons. They found that kainic acid directly excited cortical neurons, but also potentiated the excitatory effects of ionophoretically applied L-glutamate. Subsequent neurophysiologic investigations confirmed the exceptional excitatory activity of this compound, which ranges from 10to 200-fold more active than L-glutamate when applied to vertebrate spinal neurons (Johnston et al., 1974; Biscoe et al., 1976; Constantini and Nistri, 1976). The fact that kainic acid was a conformationally restricted analogue of L-glutamate led Johnston et al. (1974) to hypothesize that it might be acting as a direct agonist at glutamate receptors. The demonstration of the neurotoxic action of kainic acid, initially reported by Olney et al. (1974), arose from the convergence of two separate lines of research. First, the neurotoxic effects of the acidic amino acids, glutamate and aspartate, in the neural retina after administration to neonatal mice was described 25 years ago by Lucas and Newhouse (1957). Subsequent investigations focused on the neuropathology of the lesions in the retina and in the hypothalamus (Olney, 1969, 1971). Although the mechanism of neuronal damage remained unclear, the glutamate lesion was exploited to define the role of affected neurons in the retinal and hypothalamic function (for review, see Kizer et al., 1978). Secondly, commencing in the 1950s, neurophysiologists demonstrated that glutamic acid and related acidic amino acids excited virtually all neurons within the CNS (Hayashi, 1954; Curtis et al., 1961; Curtis and Watkins, 1963). Neurochemical studies of brain slices incubated in vitro indicated that glutamate caused a marked influx of sodium and water, loss of potassium, and depletion of high-energy phosphates, consistent with its depolarizing action (Harvey and McIlwain, 1968; Okamot0 and Quastel, 1970). A dozen years ago, Olney conjoined these two lines of investigation in linking the neurotoxic action of acidic amino acids to their neuroexcitatory effects (Olney et al., 1971). He and his colleagues demonstrated a compelling correlation between the neurotoxic and neuroexcitatory potency of a number of peripherally administrated acidic amino acids and structurally related compounds in the arcuate nucleus of the neonatal mouse. They established that neuronal damage produced by the active amino acids was unrelated to nonspecific effects such as osmotic load. Further, they noted that the profound swelling of dendrites, the earliest sign of toxic damage in the retina and arcuate nucleus, was consistent with the depolarizing effects of acidic amino acids. Finally, the neuropathologic alterations, which were localized on affected neuronal dendrites and perikarya but spared axons passing through the arcuate, were interpreted as consistent with the localization of excitatory receptors on dendrites. Accordingly, Olney coined the term “excitotoxins” for this group of excitatory acidic amino acids, which appeared to kill neurons selectively by