| Popis: |
Systemic or intracerebral injection of the neurotoxin kainic acid (KA) in rats induces a limbic seizure and brain damage syndrome, which has been proposed as an experimental animal model for human temporal lobe epilepsy (Nadler, 1981; Ben-Ari, 1985). The electrographic, neurochemical, metabolic and histopathological consequences involve preferentially limbic structures such as the hippocampal formation, the septum, the amygdaloid complex, the cingulate cortex, the claustrum, and several thalamic nuclei (Ben-Ari et al., 1980; Schwob et al., 1980; Ben-Ari et al., 1981; Lothman and Collins, 1981). If the neurotoxin is injected systemically (i.e., intravenously, intraperitoneally, or subcutaneously), doses from 8 to 12 mg/kg are required to induce a full seizure response (Ben-Ari et al., 1981; Lothman and Collins, 1981; Sperk et al., 1984). Upon central application, doses of 1 µg or less are sufficient (Schwarcz et al., 1978; Ben-Ari et al., 1980; Nadler et al., 1980). This suggests a central site of action and a poor permeability of the blood-brain barrier (BBB) for the neurotoxin. From in vitro studies, it is known that KA can exert a variety of effects on central nervous tissue. In the hippocampal slice preparation, it initiates epileptiform discharges at concentrations down to 20 nM, and produces irreversible depolarization above 1 µM(Robinson and Deadwyler, 1981; Westbrook and Lothman, 1983). In cerebellar slices, 5 µM KA elevates cGMP levels (Garthwaite, 1982) and induces first necrotic changes (Garthwaite and Wilkin, 1982). Sodium permeability (Luini et al., 1981) is stimulated by 10-100 µM KA. To provoke the release of [3H]aspartic acid from cerebellar slices, 10 µM KA (Potashner and Gerard, 1983) or at least 500 µM KA (Ferkany and Coyle, 1983) are necessary. 100 µM KA or more are required to elevate cAMP levels in cerebellar slices (Schmidt et al., 1976). Finally, specific membrane binding sites have been described for the neurotoxin in neuronal tissue, with affinity constants ranging from 1 to 200 nM (London and Coyle, 1979; Berger et al., 1984; Berger et al., in press). It remains to be clarified which of these neurochemical effects are involved in the seizure syndrome induced by KA. In this connection, an estimate of the actual brain tissue concentration of KA after systemic application of a convulsive dose would be of great interest. |
