Metallothionein synthesis increased by Ninjin-yoei-to, a Kampo medicine protects neuronal death and memory loss after exposure to amyloid ß1-42.

BACKGROUND: It is possible that increased synthesis of metallothioneins (MTs), Zn2+-binding proteins is linked with the protective effect of Ninjin-yoei-to (NYT) on Zn2+ toxicity ferried by amyloid ß1-42 (Aß1-42). METHODS: Judging from the biological half-life (18-20 h) of MTs, the effective period of newly synthesized MT on capturing Zn2+ is estimated to be approximately 2 days. In the present paper, a diet containing 3% NYT was administered to mice for 2 days and then Aß1-42 was injected into the lateral ventricle of mice. RESULTS: MT level in the dentate granule cell layer was elevated 2 days after administration of NYT diet, while the administration reduced intracellular Zn2+ level increased 1 h after Aß1-42 injection, resulting in rescuing neuronal death in the dentate granule cell layer, which was observed 14 days after Aß1-42 injection. Furthermore, Pre-administration of NYT diet rescued object recognition memory loss via affected perforant pathway long-term potentiation after local injection of Aß1-42 into the dentate granule cell layer of rats. CONCLUSION: The present study indicates that pre-administration of NYT diet for 2 days increases synthesis of MTs, which reduces intracellular Zn2+ toxicity ferried by extracellular Aß1-42, resulting in protecting neuronal death in the dentate gyrus and memory loss after exposure to Aß1-42.

Heated Leaf Extract of Coriandrum sativum L. Protects Nigral Dopaminergic Degeneration in Rats.

Coriandrum sativum L. (coriander), which is an annual herb of the Apiaceae family, has been traditionally used as a remedy. Here we tested whether heated extract of coriander leaf protects nigral dopaminergic neurodegeneration after exposure to 6-hydroxydopamine (6-OHDA). After injection of 6-OHDA into the rat substantia nigra pars compacta (SNpc), dopaminergic degeneration, which was determined by tyrosine hydroxylase immunostaining, was rescued by co-injection of CaEDTA, an extracellular Zn2+ chelator, suggesting that extracellular Zn2+ influx is involved in neurodegeneration. Both intracellular Zn2+ dysregulation determined by ZnAF-2 fluorescence and dopaminergic degeneration in the SNpc induced by 6-OHDA were rescued by co-injection of 0.25% coriander extract, which also reduced reactive oxygen species (ROS) production in the SNpc determined by aminophenyl fluorescein fluorescence. The present study suggests that coriander leaf extract protects nigral dopaminergic neurodegeneration induced by intracellular Zn2+ dysregulation. It is likely that the nutraceutical property of coriander leaf extract contributes to the protection via reducing ROS production.

Preventive effect of Ninjin-yoei-to, a Kampo medicine, on amyloid ß1-42-induced neurodegeneration via intracellular Zn2+ toxicity in the dentate gyrus.

Ninjin-yoei-to (NYT), a Kampo medicine, has ameliorative effects on cognitive dysfunction via enhancing cholinergic neuron activity. To explore an efficacy of NYT administration for prevention and cure of Alzheimer's disease, here we examined the effect of NYT on amyloid ß1-42 (Aß1-42)-induced neurodegeneration in the dentate gyrus. A diet containing 3% NYT was administered to mice for 2 weeks and human Aß1-42 was intracerebroventricularly injected. Neurodegeneration in the dentate granule cell layer of the hippocampus, which was determined 2 weeks after the injection, was rescued by administration of the diet for 4 weeks. Aß staining (uptake) was not modified in the dentate granule cell layer by pre-administration of the diet for 2 weeks, while Aß1-42-induced increase in intracellular Zn2+ was reduced, suggesting that pre-administration of NYT prior to Aß injection is effective for reducing Aß1-42-induced Zn2+ toxicity in the dentate gyrus. As a matter of fact, Aß1-42-induced neurodegeneration in the dentate gyrus was rescued by pre-administration of NYT. Interestingly, the level of metallothioneins, intracellular Zn2+-binding proteins, which can capture Zn2+ from Zn-Aß1-42 complexes, was elevated in the dentate granule cell layer by pre-administration of NYT. The present study suggests that pre-administration of NYT prevents Aß1-42-mediated neurodegeneration in the dentate gyurs by induced synthesis of metallothioneins, which reduces intracellular Zn2+ toxicity induced by Aß1-42.

Dehydroeffusol Pprevents Amyloid ß1-42-mediated Hippocampal Neurodegeneration via Reducing Intracellular Zn2+ Toxicity.

Dehydroeffusol, a phenanthrene isolated from Juncus effusus, is a Chinese medicine. To explore an efficacy of dehydroeffusol administration for prevention and cure of Alzheimer's disease, here we examined the effect of dehydroeffusol on amyloid ß1-42 (Aß1-42)-mediated hippocampal neurodegeneration. Dehydroeffusol (15 mg/kg body weight) was orally administered to mice once a day for 6 days and then human Aß1-42 was injected intracerebroventricularly followed by oral administration for 12 days. Neurodegeneration in the dentate granule cell layer, which was determined 2 weeks after Aß1-42 injection, was rescued by dehydroeffusol administration. Aß staining (uptake) was not reduced in the dentate granule cell layer by pre-administration of dehydroeffusol for 6 days, while increase in intracellular Zn2+ induced with Aß1-42 was reduced, suggesting that pre-administration of dehydroeffusol prior to Aß1-42 injection is effective for Aß1-42-mediated neurodegeneration that was linked with intracellular Zn2+ toxicity. As a matter of fact, pre-administration of dehydroeffusol rescued Aß1-42-mediated neurodegeneration. Interestingly, pre-administration of dehydroeffusol increased synthesis of metallothioneins, intracellular Zn2+-binding proteins, in the dentate granule cell layer, which can capture Zn2+ from Zn-Aß1-42 complexes. The present study indicates that pre-administration of dehydroeffusol protects Aß1-42-mediated neurodegeneration in the hippocampus by reducing intracellular Zn2+ toxicity, which is linked with induced synthesis of metallothioneins. Dehydroeffusol, a novel inducer of metallothioneins, may protect Aß1-42-induced pathogenesis in Alzheimer's disease.

Yokukansan, a Herbal Medicine in Japan, Buffers Social Crowding Stress via Ameliorating Glucocorticoid Secretion Response to Vasopressin.

On the basis of the data that yokukansan (YKS), a herbal medicine, ameliorates aggressive behavior and abnormal glucocorticoid secretion of socially isolated mice under zinc deficiency, we tested whether YKS preventively buffers crowding stress-induced attenuations of glucocorticoid secretion response and long-term potentiation (LTP), an index of cognition. YKS-containing water was administered during the period of exposure to social crowding stress for 3 weeks. Serum corticosterone level was not significantly modified by administration of YKS-containing water and was also not increased after social-crowding stress. When vasopressin was injected into crowding-stressed rats to assess corticosterone secretion via pituitary-adorenocortical axis activation, vasopressin-induced increase in serum corticosterone was significantly attenuated compared to non-stressed control rats, indicating that the pituitary-adrenocortical response to vasopressin is affected after exposure to crowding stress. Interestingly, administration of YKS-containing water rescued attenuation of vasopressin-induced increase in serum corticosterone. LTP at Schaffer collateral-CA1 pyramidal cells synapses was attenuated in the hippocampal slices from crowding-stressed rats, while administration of YKS-containing water rescued the attenuation. The present study demonstrates that intake of YKS rescues crowding stress-induced impairments of glucocorticoid secretion response to vasopressin and hippocampal LTP. The intake of YKS may be benefit to buffering chronic stress.

Behavioral Abnormality Induced by Enhanced Hypothalamo-Pituitary-Adrenocortical Axis Activity under Dietary Zinc Deficiency and Its Usefulness as a Model.

Dietary zinc deficiency increases glucocorticoid secretion from the adrenal cortex via enhanced hypothalamo-pituitary-adrenocortical (HPA) axis activity and induces neuropsychological symptoms, i.e., behavioral abnormality. Behavioral abnormality is due to the increase in glucocorticoid secretion rather than disturbance of brain zinc homeostasis, which occurs after the increase in glucocorticoid secretion. A major target of glucocorticoids is the hippocampus and their actions are often associated with disturbance of glutamatergic neurotransmission, which may be linked to behavioral abnormality, such as depressive symptoms and aggressive behavior under zinc deficiency. Glucocorticoid-mediated disturbance of glutamatergic neurotransmission in the hippocampus is also involved in the pathophysiology of, not only psychiatric disorders, such as depression, but also neurodegenerative disorders, e.g., Alzheimer's disease. The evidence suggests that zinc-deficient animals are models for behavioral and psychological symptoms of dementia (BPSD), as well as depression. To understand validity to apply zinc-deficient animals as a behavioral abnormality model, this paper deals with the effect of antidepressive drugs and herbal medicines on hippocampal dysfunctions and behavioral abnormality, which are induced by enhanced HPA axis activity under dietary zinc deficiency.

Influences of yokukansankachimpihange on aggressive behavior of zinc-deficient mice and actions of the ingredients on excessive neural exocytosis in the hippocampus of zinc-deficient rats.

We examined the effect of Yokukansankachimpihange (YKSCH), a form of Yokukansan containing parts of two herbaceous plants, Citrus Unshiu Peel (Chimpi) and Pinellia Tuber (Hange), on aggressive behavior of mice housed individually. Mice were fed a zinc-deficient diet for 2 weeks. In a resident-intruder test, the cumulative duration of aggressive behavior was decreased in zinc-deficient mice administrated drinking water containing YKSCH (approximately 300 mg/kg body weight/day) for 2 weeks. We tested mice for geissoschizine methyl ether (GM), which is contained in Uncaria Hook, and 18ß-glycyrrhetinic acid (GA), a major metabolite of glycyrrhizin contained in Glycyrrhiza, which were contained in YKS and YKSCH. In hippocampal slices from zinc-deficient rats, excess exocytosis at mossy fiber boutons induced with 60 mM KCl was attenuated in the presence of GA (100-500 µM) or GM (100 µM). The intracellular Ca2+ level, which showed an increase induced by 60 mM KCl, was also attenuated in the presence of GA (100-500 µM) or GM (100 µM). These results suggest that GA and GM ameliorate excess glutamate release from mossy fiber boutons by suppressing the increase in intracellular Ca2+ signaling. These ameliorative actions may contribute to decreasing the aggressiveness of mice individually housed under zinc deficiency, potentially by suppressing excess glutamatergic neuron activity in the hippocampus.

Advantageous effect of theanine intake on cognition.

Theanine, γ-glutamylethylamide, is one of the major amino acid components in green tea. On the basis of the preventive effect of theanine intake after weaning on stress-induced impairment of recognition memory, the advantageous effect of theanine intake on recognition memory was examined in young rats, which were fed water containing 0.3% theanine for 3 weeks after weaning. The rats were subjected to object recognition test. Object recognition memory was maintained in theanine-administered rats 48 hours after the training, but not in the control rats. When in vivo dentate gyrus long-term potentiation (LTP) was induced, it was more greatly induced in theanine-administered rats than in the control rats. The levels of brain-derived neurotropic factor and nerve growth factor in the hippocampus were significantly higher in theanine-administered rats than in the control rats. The present study indicates the advantageous effect of theanine intake after weaning on recognition memory. It is likely that theanine intake is of advantage to the development of hippocampal function after weaning.

Preventive effect of theanine intake on stress-induced impairments of hippocamapal long-term potentiation and recognition memory.

Theanine, γ-glutamylethylamide, is one of the major amino acid components in green tea. On the basis of the preventive effect of theanine intake after birth on mild stress-induced attenuation of hippocamapal CA1 long-term potentiation (LTP), the present study evaluated the effect of theanine intake after weaning on stress-induced impairments of LTP and recognition memory. Young rats were fed water containing 0.3% theanine for 3 weeks after weaning and subjected to water immersion stress for 30min, which was more severe than tail suspension stress for 30s used previously. Serum corticosterone levels were lower in theanine-administered rats than in the control rats even after exposure to stress. CA1 LTP induced by a 100-Hz tetanus for 1s was inhibited in the presence of 2-amino-5-phosphonovalerate (APV), an N-methyl-d-aspartate (NMDA) receptor antagonist, in hippocampal slices from the control rats and was attenuated by water immersion stress. In contrast, CA1 LTP was not significantly inhibited in the presence of APV in hippocampal slices from theanine-administered rats and was not attenuated by the stress. Furthermore, object recognition memory was impaired in the control rats, but not in theanine-administered rats. The present study indicates the preventive effect of theanine intake after weaning on stress-induced impairments of hippocampal LTP and recognition memory. It is likely that the modification of corticosterone secretion after theanine intake is involved in the preventive effect.

Therapeutic effect of Yokukansan on social isolation-induced aggressive behavior of zinc-deficient and pair-fed mice.

In patients with dementia including Alzheimer's disease, hallucinations, agitation/aggression and irritability are known to frequently occur and as distressing behavioral and psychological symptoms of dementia (BPSD). On the basis of the evidence on clinical efficacy and safety of Yokukansan, a traditional Japanese herbal medicine, on BPSD, in the present study, Yokukansan was examined in the therapeutic effects on social isolation-induced aggressive behavior of zinc-deficient and pair-fed mice. Yokukansan was p.o. administered for 7 days as a drinking water to isolated mice fed a zinc-deficient diet for 10 days, which exhibited aggressive behavior, and isolated pair-fed mice fed a control diet of the amount consumed by zinc-deficient mice for 10 days, which exhibited aggressive behavior. Aggressive behavior was evaluated by the resident-intruder test. Yokukansan (312 mg/kg/day) attenuated both aggressive behaviors of zinc-deficient and pair-fed mice. Because Yokukansan can suppress abnormal glutamatergic neuron activity, MK-801, an N-methyl-D-aspartate (NMDA) receptor blocker, and aminooxyacetic acid (AOAA), a γ-amino butyric acid (GABA) transaminase blocker, were also examined in the effects on social isolation-induced aggressive behavior. MK-801 (0.1 mg/kg) or AOAA (23 mg/kg) was i.p. injected into isolated aggressive mice. Thirty minutes later, the resident-intruder test was performed to evaluate the effect of the drugs. Both drugs attenuated aggressive behavior of zinc deficient mice, but not that of pair-fed mice. These results suggest that Yokukansan ameliorates social isolation-induced aggressive behavior of zinc-deficient and pair-fed mice through the action against glutamatergic neurotransmitter system and other neurotransmitter systems.

Unique induction of CA1 LTP components after intake of theanine, an amino acid in tea leaves and its effect on stress response.

UNLABELLED: Theanine, γ-glutamylethylamide, is one of the major amino acid components in green tea. This study was undertaken to evaluate the effect of theanine intake on long-term potentiation (LTP) induction at hippocampal CA1 synapses and exposure to acute stress. Young rats were fed water containing 0.3% theanine after birth. KEY FINDINGS: Serum corticosterone level was markedly decreased by theanine intake. Because this decrease can modify synaptic plasticity, the effect of theanine intake was examined focused on CA1 LTP induction. CA1 LTP induced by a 100-Hz tetanus for 1 s was almost the same extent in hippocampal slices from theanine-administered rats, whereas that induced by a 200-Hz tetanus for 1 s was significantly attenuated. 2-Amino-5-phosphonovalerate (APV), an N-methyl-D: -aspartate (NMDA) receptor antagonist, significantly attenuated CA1 LTP induced by a 200-Hz tetanus in the control rats, but not in theanine-administered rats. Interestingly, APV completely blocked CA1 LTP induced by a 100-Hz tetanus in the control rats, while scarcely blocking it in theanine-administered rats. These results indicate that theanine intake reduces NMDA receptor-dependent CA1 LTP, while increasing NMDA receptor-independent CA1 LTP. Furthermore, neither 100-Hz tetanus-induced LTP nor 200-Hz tetanus-induced LTP was attenuated in theanine-administered rats after exposure to tail suspension stress, suggesting that the lack of NMDA receptor-dependent CA1 LTP by theanine intake is involved in ameliorating the attenuation of CA1 LTP after tail suspension. This study is the first to indicate that theanine intake modifies the mechanism of CA1 LTP induction.

Facilitated neurogenesis in the developing hippocampus after intake of theanine, an amino acid in tea leaves, and object recognition memory.

Theanine, γ-glutamylethylamide, is one of the major amino acid components in green tea. In this study, cognitive function and the related mechanism were examined in theanine-administered young rats. Newborn rats were fed theanine through dams, which were fed water containing 0.3% theanine, and then fed water containing 0.3% theanine after weaning. Theanine level in the brain was under the detectable limit 6 weeks after the start of theanine administration. Theanine administration did not influence locomotor activity in the open-field test. However, rearing behavior was significantly increased in theanine-administered rats, suggesting that exploratory activity is increased by theanine intake. Furthermore, object recognition memory was enhanced in theanine-administered rats. The increase in exploratory activity in the open-field test seems to be associated with the enhanced object recognition memory after theanine administration. On the other hand, long-term potentiation (LTP) induction at the perforant path-granule cell synapse was not changed by theanine administration. To check hippocampal neurogenesis, BrdU was injected into rats 3 weeks after the start of theanine administration, and brain-derived neurotropic factor (BDNF) level was significantly increased at this time. Theanine intake significantly increased the number of BrdU-, Ki67-, and DCX-labeled cells in the granule cell layer 6 weeks after the start of theanine administration. This study indicates that 0.3% theanine administration facilitates neurogenesis in the developing hippocampus followed by enhanced recognition memory. Theanine intake may be of benefit to the postnatal development of hippocampal function.

Ameliorative effect of Yokukansan on social isolation-induced aggressive behavior of zinc-deficient young mice.

Yokukansan, a traditional Japanese medicine has been used to cure neuropsychological disorders. In the present study, the effect of Yokukansan on social isolation-induced aggressive behavior was examined in zinc-deficient mice, which were fed a zinc-deficient diet and a drinking water containing Yokukansan for 2 weeks. In the resident-intruder test, the rate of mice that exhibited aggressive behavior in zinc-deficient mice, which was significantly higher than that in the control mice, was significantly decreased by administration of Yokukansan. The basal level of serum glucocorticoid, which was significantly higher in zinc-deficient mice, was lowered by administration of Yokukansan. On the other hand, serum glucocorticoid levels after the resident-intruder test were almost the same between the control and zinc-deficient mice. However, administration of Yokukansan to zinc-deficient mice significantly increased serum glucocorticoid level after the resident-intruder test and the significant difference in the rate of serum corticosterone level after the test to the basal level between the control and zinc-deficient mice was abolished. Dietary zinc deficiency increases the basal levels of serum glucocorticoid, while may insufficiently increase serum glucocorticoid levels in the resident-intruder test. The concentrations of glutamate and GABA (γ-aminobutyric acid) in the brain were significantly higher in zinc-deficient mice, while Yokukansan ameliorated the significant increases. These results indicate that Yokukansan ameliorates social isolation-induced aggressive behavior of zinc-deficient mice, probably via amelioration of abnormal glucocorticoid secretion. The ameliorative effect seems to be linked to the modification of glutamatergic neuron activity after administration of Yokukansan.

Susceptibility to stress in young rats after 2-week zinc deprivation.

Dietary zinc deficiency elicits abnormal behavior in stressful environment. It is possible that abnormal corticosterone secretion in zinc deficiency is linked to abnormal behavior. To understand the increase in depression-like behavior in zinc deficiency, in the present study, serum corticosterone concentration was checked in young rats fed a zinc-deficient diet for 2 weeks after exposure to acute stress. Serum corticosterone concentration was higher in zinc-deficient rats after exposure to water-immersed and forced swim stress. Immobility time in the forced swim test was significantly increased in zinc-deficient rats, but not in pair-fed rats, suggesting that the increase in depression-like behavior is due to zinc deficiency rather than decreased food intake. The increase in immobility time in zinc deficiency was restored to the control level by feeding of the control diet. In dexamethasone suppression test, serum corticosterone concentration was markedly decreased in both the control and zinc-deficient rats. These results suggest that excessive corticosterone secretion after exposure to stress is linked to the increase in depression-like behavior in zinc deficiency. It has been reported that exposure to stress and glucocorticoids facilitates the increase in extracellular glutamate in the hippocampus. When the hippocampus was stimulated with 100mM KCl, the concentration of extracellular glutamate was more increased in zinc-deficient rats. In hippocampal slices from zinc-deficient rats, the decrease in FM4-64 fluorescence (exocytosis) was more facilitated. It is likely that zinc deficiency excessively excites glutamatergic neurons in the hippocampus after exposure to acute stress. This excessive excitation seems to contribute to susceptibility to stress after 2-week zinc deprivation and its related behavior such as the increase in depression-like behavior.

Attenuation of abnormal glutamate release in zinc deficiency by zinc and Yokukansan.

The mechanism of the abnormal increase in extracellular glutamate concentration in the hippocampus induced with 100mM KCl in zinc deficiency is unknown. In the present study, the changes in glutamate release (exocytosis) and GLT-1, a glial glutamate transporter, expression were studied in young rats fed a zinc-deficient diet for 4 weeks. Exocytosis at mossy fiber boutons was enhanced as reported previously and GLT-1 protein was increased in the hippocampus. The enhanced exocytosis is thought to increase extracellular glutamate concentration. However, the basal concentration of extracellular glutamate in the hippocampus was not increased by zinc deficiency, suggesting that GLT-1 protein increased serves to maintain the basal concentration of extracellular glutamate. The enhanced exocytosis was attenuated in the presence of 100microM ZnCl(2), which attenuated the abnormal increase in extracellular glutamate induced with high K(+) in zinc deficiency. The present study indicates that zinc attenuates abnormal glutamate release in zinc deficiency. The enhanced exocytosis was also attenuated in slices from zinc-deficient rats administered Yokukansan, a herbal medicine, in which the abnormal increase in extracellular glutamate induced with high K(+) was attenuated. It is likely that Yokukansan is useful for prevention or cure of abnormal glutamate release. The enhanced exocytosis in zinc deficiency is a possible mechanism on abnormal increase in extracellular glutamate in the hippocampus induced with high K(+).

Suppressive effect of Yokukansan on excessive release of glutamate and aspartate in the hippocampus of zinc-deficient rats.

Yokukansan (TJ-54), a herbal medicine, has been used as a cure for insomnia and irritability in children. Yokukansan also improves behavioral and psychological symptoms such as agitation, aggression and irritability in patients with dementia including Alzheimer's disease, in which the glutamatergic neurotransmitter system is perturbed. However, the action of Yokukansan in synaptic neurotransmission is unknown. In the present study, the action of Yokukansan in the glutamatergic neurotransmitter system was examined in zinc-deficient rats, a neurological disease model, in which the glutamatergic neurotransmitter system is perturbed. Administration of Yokukansan significantly suppressed the increase in extracellular concentrations of glutamate and aspartate in the hippocampus after stimulation with 100 mM KCl, but not the increase in extracellular concentrations of glycine and taurine, suggesting that Yokukansan is involved in modulation of excitatory neurotransmitter systems. The present study demonstrates that Yokukansan is a possible medicine for prevention or cure of neurological diseases associated with excitotoxicity.

Suppressive effect of Saiko-ka-ryukotsu-borei-to, a herbal medicine, on excessive release of glutamate in the hippocampus.

Glutamate is the major excitatory neurotransmitter in the brain, and the excess of glutamate concentration in the synaptic cleft is a cause of neuronal injury or death. To find out a drug suppressing the excess of extracellular glutamate concentration, the effect of Saiko-ka-ryukotsu-borei-to, a herbal medicine, was examined in the control and zinc-deficient rats, a neurological disease model, by using in vivo microdialysis. The excessive increase in extracellular glutamate in the hippocampus was induced by perfusion with 100 mM KCl for 40 min. Administration of Saiko-ka-ryukotsu-borei-to did not appreciably influence the increase in body weight of the control rats and the retarded increase in body weight of zinc-deficient rats. However, administration of Saiko-ka-ryukotsu-borei-to to the control rats completely suppressed the increase in glutamate concentration in the hippocampal extracellular fluid during stimulation with high K+. The suppressive effect of Saiko-ka-ryukotsu-borei-to was also observed in zinc-deficient rats, in which extracellular glutamate concentration was markedly increased during stimulation with high K+. These results suggest that Saiko-ka-ryukotsu-borei-to is a useful drug for prevention or cure of excitotoxicity of glutamate.

Distribution of trace elements in the brain of EL (epilepsy) mice.

The association of essential trace elements with epileptic seizures is poorly understood. On the basis of the evidences that the release of zinc from the brain of epilepsy (EL) mice, an animal model of genetically determined epilepsy, is enhanced by the induction of seizures and that alteration of zinc homeostasis is responsive to susceptibility to seizures, the distribution of trace elements in the brain was studied using EL mice and ddY mice, which form the genetic background for the inbred EL mice. The multitracer technique was applied to determine the distribution of trace elements. Twenty-four hours after intravenous injection of the multitracer, the concentration of 65Zn and 56Co in the brain of untreated EL mice was higher than in ddY mice, while the concentration of 65Zn and 56Co in the brain was decreased in seized EL mice. 75Se concentration in the hippocampus, cerebral cortex and cerebellum of untreated EL mice was lower than in ddY mice, while 75Se concentration in the hippocampus was increased in seized EL mice. 83Rb, an element of homologous series to potassium, concentration in the hippocampus and cerebral cortex of untreated EL mice was lower than in ddY mice, and 83Rb concentration in the cerebral cortex was decreased in seized EL mice. The movement of zinc, cobalt and selenium in the brain may be altered by enhancement of susceptibility to seizures. These results suggest that alteration of homeostasis of zinc, cobalt and selenium in the brain may be involved in the susceptibility, development or termination of seizures in EL mice.