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The role of the endogenous convulsant kynurenine (K) in the mechanisms of the development of epileptic seizures in alcoholic persons was studied on a clinical material of 63 patients suffering from alcoholism with the presence on the EEG of paroxysmal alterations without epileptic fits (n = 28) and alcoholic epilepsy (n = 35), epileptic patients not abusing alcohol (n = 20), and practically healthy subjects (n = 10). There was a significant increase of the K concentration in alcoholic patients with paroxysmal disturbances on the EEG or convulsive seizures. That increase directly correlated with the rate of convulsive epileptic fits. The rise of K in patients with alcoholic epilepsy was lower than in epileptic patients, being, however, significantly higher than in practically healthy subjects abusing alcohol and having but paroxysmal alterations on the EEG (without seizures).

Behaviour of SHR, C57B1/6 male mice and common albino male rats treated intracerebroventricularly or intraperitoneally with kynurenine, quinolinic, kynurenic, picolinic, xanthurenic, anthranilic acids and nicotinamide, was studied in the dark/light chamber. Quinolinic acid and its precursor kynurenine diminished dark preference, increased the number of transitions between dark and light compartments, diminished locomotion in light compartment. Biogenic amine phenylethylamine with its typical anxiogenic activity, exerted a similar action. Diazepam acted in the opposite way. Noncompetitive antagonist of the NMDA receptors, kynurenic acid, prevented the effect of quinolinic acid. The hole reflex appears to be a useful simple object to study neuroactive endogenous compounds on.

As many as 30 patients with affective psychoses were examined for the concentration of plasma kynurenine, a neuroactive tryptophan metabolite, and for the parameters of the dexamethasone test. A group of patients suffering from "endogenous anxiety" and endogenous depression were distinguished. In the patients' group with "endogenous anxiety", the concentration of kynurenine at the height psychosis was significantly higher as compared to controls, correlating with the gravity of anxious symptomatology. In the patients' group with endogenous depression, plasma kynurenine was significantly lower than in controls but did not agree with the depression gravity. The dexamethasone test appeared pathological only in the group of patients suffering from endogenous depression and its parameters correlated well with the gravity of depressive symptomatology. In both groups, the study parameters returned to normal after the egress from the morbid condition.

All excitatory amino acid antagonists studied: diethyl esters of aspartic (DEEA) and glutamic (DEEG) acids, 2-amino-3-phosphono-propionic acid (APPA) and 2-amino-4-phosphono-butanoic acid (APBA), diminished the amplitude of excitatory postsynaptic potentials (EPP) of the locust (Locusta migratoria migratorioides) muscle fibers and arbitrary blocked glutamate (GLU) and aspartate (ASP) responses. Kynurenine (KYN) and quinolinic (QUI) acid had no effect on EPP even at a concentration of 2 X 10(-2) M. The antagonists were not strictly selective against intracerebroventricularly administered endogenous convulsants: GLU, ASP, KYN and QUI and in simulation of experimental seizures in mice. The antagonists structurally similar to ASP prevented ASP- and KYN-induced seizures in lower doses than GLU derivatives. Anti-KYN, but not anti-QUI DEEA, DEEG, APPA and APBA efficacy suggests that KYN and QUI act on different structures or binding sites.

Benzobarbital, primidone, phenobarbital, phynytoin and trimethadionum (in order of decreasing activity) were moderately effective against DL-kynurenine (50 micrograms, i. c. v.)-induced seizures in SHR albino male mice. Diazepam was ineffective even in doses of 15 and 25 mg/kg. Against seizures induced by quinolinic acid (5 micrograms, i. c. v.) anticonvulsants, particularly primidone and phenytoin, were more effective than against kynurenine-induced seizures. Diazepam was slightly effective in high doses of 7-15 mg/kg. Primidone and benzobarbital in doses used (10-50 mg/kg) were ineffective against strychnine and pentylenetetrazol. Selective efficacy of primidone and benzobarbital in this model of seizures suggests that kynurenine and quinolinic acid could be involved in the grand mal fits in epileptic patients.

Phenibut, sodium hydroxybutyrate and baclofen are selectively effective against seizures induced in mice by the endogenous metabolites of tryptophan, L-kynurenine and quinolinic acid. The seizures were not affected by the drugs in doses under study. Depakine and aminooxyacetic acid as well as diazepam and phenobarbital appeared the most effective against pentylenetetrazole seizures. GABA and muscimol administered intracerebroventricularly merely prolonged the latency of seizures. Dissimilarities in the GABA-ergic mechanisms of the anticonvulsant effects of the drugs under consideration are discussed.

It has been shown in the behavioural experiments that combined pretreatment with haloperidol (0.25 mg/kg) and caerulein (40 micrograms/kg), and to a lesser extent pretreatment with caerulein alone caused long-term reversal of amphetamine (2 mg/kg) induced hyperexcitability in rats. Administration of proglumide (50 mg/kg), an antagonist of CCK-8 receptors, did not reverse long-term antiamphetamine effect of caerulein. In mice pretreatment with caerulein (50 and 100 micrograms/kg) alone or in combination with haloperidol (0.25 mg/kg) caused hypersensitivity to the behavioural effect of amphetamine (3 mg/kg). Intraventricular (I ng), but not systemic (100-500 micrograms/kg) administration of caerulein selectively antagonized seizures in mice induced by intraventricular administration of quinolinic acid (5 micrograms) and N-methyl-D-aspartate (0.2 microgram). Pretreatment with proglumide (50 mg/kg) reversed the anticonvulsive effect of caerulein in mice. In rats, caerulein failed to affect the seizures caused by intraventricular administration of quinolinic acid. The results of the present study demonstrate the existence of obvious interspecies differences in the behavioural effects of caerulein, the agonist of CCK-8 receptors, in mice and rats.

Derivatives of GABA which are ineffective against seizures produced by typical convulsants (strychnine, pentylenetetrazole, etc.), phenibut and sodium hydroxybutyrate in doses of 200 mg/kg and higher possess marked anticonvulsant action against seizures induced by intraventricular injection of L-kynurenine and quinolinic acid in mice. Phepiron, a cyclic form of phenibut, had dissimilar action on the effects of L-kynurenine and a quinolinic acid, enhancing that produced by the former agent and diminishing tonic extension and lethality after the latter one. GABA and piracetam appeared to be ineffective. Efficacy of GABA derivatives against seizures produced by L-kynurenine and quinolinic acid suggests that the system of GABA plays a significant role in the genesis of seizures produced by kynurenines.

A total of 84 children were investigated: 15 with bronchial asthma, 41 with combined seizure and bronchial obstruction syndrome, 14 with epilepsy. The kynurenine blood level was found to correlate with seizures. It was highest in epilepsy (5.27 +/- 0.99 nM/ml) together with the lowest dioxygenase activity (0.53 +/- 0.29 nM/ml) as measured with the tryptophane loading. The data suggest that kynurenine being a major tryptophane metabolite plays a role in pathogenesis of convulsive states.

A comparative study of the influence of kynurenic acid (KYNA), L-kynurenine (KYN) and ethylimidazole-4-5-dicarboxylic acid (IEM-1442) on neuro-destructive effect of quinolinic acid (QUIN) in hippocampal cell cultures of mouse embryos and on convulsive action of QUIN after its injection into the brain ventricles of adult mice was performed. In presence of KYNA the neuronal destruction in vitro didn't occur under QUIN exposure, while in situ KYNA had no effect on convulsive action of QUIN. On the other hand, KYN and IEM-1442 didn't block the neurodegenerative action of QUIN in vitro, whereas in situ these compounds showed the anticonvulsant, effect. The results obtained suppose, that some anticonvulsants, preventing convulsive effects of QUIN, are not antagonists of the receptors, which mediate its neurodegenerative action.

There is presented a brief review of the authors' and literature data on the excitatory and convulsant effects of kynurenines, mainly 1-kynurenine and quinolinic acid. Particular attention is given to the interactions of kynurenines with the excitatory and inhibitory amino acids, their receptors, benzodiazepine receptor complex, catecholamines, serotonin, acetylcholine. The following trends of studies on the neuroactivity of kynurenines seem to be promising: isolation of specific binding sites for the most active kynurenines--kynurenine, quinolinic and kynurenic acids, the interaction with other endogenous convulsants like beta-carbolines, endorphines, folates, etc., the search of the brain structures triggering or deferring the excitatory and convulsant effects of kynurenines.

Selective antagonists of quinolinic acid (2,3-pyridine dicarboxylic acid, QUIN)--an endogenous convulsant tryptophan metabolite, administered intracerebroventricular to mice, were identified during comparison with the following intracerebroventricular convulsants: l-kynurenine, aspartic, glutamic, N-methyl-DL-aspartic and kainic acids. It is suggested that the antagonism arises due to a common fragment of the structure which consists of two carboxylic groups at two nearest carbon atoms of the ring and of one nitrogen atom in the alpha-position. The selective action of the compounds found against QUIN supports the suggestion that QUIN produces seizures via N-methyl-D-aspartate binding sites.

In frogs (Rana temporaria) injection of L-kynurenine, quinolinic, nicotinic and picolinic acids (10 microgram) into brain ventricles potentiated the stimulant ad convulsant effects of a subthreshold dose of strychnine. Xanthurenic and anthranilic acids were ineffective. At a dose of 100 micrograms picolinic acid produced seizures in 25% of animals, quinolinic acid and L-kynurenine motor excitement in all animals, and the action of nicotinic acid was shown by severe muscle hypotonus. The doses lower than 100 g proved inactive.

Antidepressants-thymoanaleptics chlorimipramine, amitriptyline, imipramine, melitracen potenciated the inhibitory effect of reserpine in a frog (supression of the turning over from the back reflex) stronger than did antidepressants with less marked thymoanaleptic action (Lu-5-003, azaphen, quipazine, desipramine) and also neuroleptics (promazine, stelazine, haloperidol) cholinolytics (atropine and benectyzine) and stimulator--phenamine. The potentiating action of tertiary amines--imipramine, amitriptyline protixen was stronger than that of the corresponding secondary amines (desipramine, norprotixen, nortriptyline). Phenothiazines with the chlorine atom in the second position (chlorprotixen and chlorpromazine) potentiated the effect of reserpine less intensively than did their chlorine-free analogues (protixen, promazine).

In experiments on mice the existence of common mechanisms of action was revealed in picrotoxin and kynurenine and quinolinic acid. Picrotoxin selectively potentiated convulsions induced by kynurenine and quinolinic acid and the antagonists of these endogenous convulsants--picolinic, kynurenic and xanthurenic acids--selectively antagonized picrotoxin convulsions. GABA-ergic preparations, effective in kynurenine convulsions and the anticonvulsants diazepam and phenobarbital, were highly effective against picrotoxin-induced convulsions also. Puphemid and trimethin indicated for treating petit mal epilepsy, proved ineffective. The obtained data suggest the possibility of action of kynurenine and quinolinic acid via picrotoxin-sensitive subunits of the benzodiazepine-GABA-receptor-ionophore complex.

Concentration of neuroactive tryptophane--kynurenine metabolite was studied in healthy men volunteers in conditions of anxiety artificially elicited by caffeine. At peak of the alarm the level of the kynurenine significantly increased and came to norm after anxiety cessation. Possible causes of this increase are discussed. High correlation has been obtained between the kynurenine concentration and initial values of personal and reactive anxiety. The conclusion is made about the participation of the kynurenine in formation of personal and reactive anxiety in man.