Aberrant Expression of Cardiac Troponin-T in Lung Cancer Tissues in Association With Pathological Severity.

Background: Cardiac troponin-T (TNNT2) is exclusively present in cardiac muscle. Measurement of TNNT2 is used for diagnosing acute coronary syndrome. However, its expression may not be limited in myocardium. This study aimed at evaluating the expression of TNNT2 in neoplastic tissues. Methods and Results: We used paraffin-embedded blocks of 68 patients with lung cancer (age, 68 ± 11 years old; early-stage, 33; advance-stage, 35) at Miyazaki University Hospital, Japan between January 1, 2017, and March 31, 2019. We stained the slide sections with primary monoclonal antibody against TNNT2 protein, and assessed the frequency of positive staining, and its association with pathological severity. In addition, we examined whether TNNT2 gene is detected in lung cancer tissues of four patients using reverse transcription-polymerase chain reaction. Immunoreactivity for TNNT2 protein was present in the cytoplasm and nucleus of lung cancer cells. The frequency was 37% (25 of 68) in all patients and was irrespective of histologic type (six of 13, squamous cell carcinoma; 18 of 50, adenocarcinoma; 0 of 4, neuroendocrine cell carcinoma; 1 of 1, large cell carcinoma). The prevalence increased with pathological staging [9% (3 of 33) at early-stage (Stage 0-I); 63% (22 of 35) at advance-stage (Stage II-IV and recurrence)]. In addition, frequency of positive staining for TNNT2 increased with pleural (χ2 = 5.877, P = 0.015) and vascular (χ2 = 2.449, P = 0.118) invasions but decreased with lymphatic invasion (χ2 = 3.288, P = 0.070) in specimens performed surgical resection. Furthermore, TNNT2 mRNA was detected in the resected squamous cell carcinoma and adenocarcinoma tissues. Conclusions: Our data suggest the aberrant expression of TNNT2 in lung cancer and its prevalence increases with pathological severity.

Case of reversible Mobitz type II atrioventricular block after the use of injectable antipsychotics.

Although Mobitz type II atrioventricular block is typically an arrhythmia arising from a permanent organic disorder of the His-Purkinje system, reversible factors should also be considered. Here, we report the association between a rare reversible Mobitz type II atrioventricular block and antipsychotic medication in a 75-year-old patient with schizophrenia.

Development of the School Teachers Job Stressor Scale (STJSS).

AIM: Japanese teachers are not only responsible for students but also for tasks outside the classroom, including engagement with parents and the community, and maintaining safety. They work longer hours and have lower self-efficacy than teachers in other countries. Thus, we aimed to develop an assessment scale for job stress in teachers and to evaluate its psychometric properties. METHODS: We developed the "School Teachers Job Stressor Scale (STJSS) Draft" comprising 45 items, based on previous anonymous self-report questionnaires collected from 98 teachers in four elementary and middle schools in Miyazaki City, Japan. Subsequently, the scale draft and the previously validated Brief Job Stress Questionnaire (23-item abridged version) were distributed to 2276 teachers from 73 elementary and middle schools in Miyazaki City. Finally, we analyzed data from 1300 participants. After excluding inappropriate data based on ceiling and floor effect analysis, we carried out a good-poor, item-total correlation, and exploratory factor analyses. We then verified construct validity, criterion-related validity, and reliability using correlation analysis, confirmatory factor analysis, and Cronbach's alpha, respectively. RESULTS: After item-total correlation analysis, five items were excluded. Exploratory factor analysis extracted five factors: "Time spent outside of work," "Self-assessment of one's ability as a teacher," "Relationship with other teachers," "Social interactions outside of teaching," and "Duties outside of teaching." The final version of the STJSS comprised 23 items and five factors. CONCLUSION: The 23-item STJSS developed to measure specific stressors in Japanese teachers to improve their mental health care could provide an accurate assessment tool with adequate reliability and validity.

A survey of the effects of ramelteon on benzodiazepine-dependence: Comparison between a ramelteon add-on group and a continuous benzodiazepine administration group.

In general, long-term benzodiazepine hypnotics are prescribed for patients in whom it is difficult to reduce benzodiazepine hypnotics. Unlike benzodiazepine receptor (BZ)-mediated sleep agents, ramelteon induces quasi-natural physiological sleep owing to its mechanism of action. We conducted a survey of ramelteon and BZ-dependence in patients with insomnia. Study subjects were patients with insomnia (42 cases), who were divided into a ramelteon group (22 cases; administered 8 mg/day of ramelteon before sleep in addition to BZ) and a control group (20 cases; continually administered only BZs), with a mean disease duration of 11.3 ±â€¯9.6 years. All data were analyzed using two-way repeated measures analysis of variance. No significant difference was observed between the ramelteon group and the control group when a questionnaire concerning BZ-dependence and withdrawal symptoms was used. A significant improvement in scores at Week 16 from those at Week 0 was observed in the Pittsburgh Sleep Quality Index excerpt and in the Global Assessment of Functioning in the ramelteon group [corrected].The Wilcoxon rank-sum test showed that the number of concomitantly used BZ hypnotics decreased significantly in the ramelteon group after Week 16, while no such change was observed in the control group. Thus, by adding ramelteon to therapy for patients with long-term insomnia, we were able to reduce the number of benzodiazepine hypnotics that were used concomitantly.

Nurse-led group cognitive behavioral therapy for major depressive disorder among adults in Japan: A preliminary single-group study.

OBJECTIVES: The prevalence and burden of disease of depression necessitates effective and accessible treatment options worldwide. Since April 2016, Japanese national health insurance has covered nurse-administered cognitive behavioral therapy (CBT) for mood disorders. However, empirical support for nurse-led CBT for depression in Asian countries, especially in Japan, is still lacking. This preliminary study aimed to examine the feasibility and acceptability of nurse-led group CBT for Japanese patients with depression. METHODS: In this single-arm study, we evaluated the effects of a 6-week group CBT, led by trained nurses, on patients with major depression. The primary outcome was the Beck Depression Inventory-II (BDI-II). Assessments were conducted at the beginning and end of the intervention. RESULTS: Of 25 participants screened, 23 were eligible for the study (of these, three dropped out during the trial but were included in the analysis). Nurse-led group CBT led to significant improvements in the severity of depression (BDI-II, P < 0.001). The mean total BDI-II score improved from 23.1 (SD = 7.56) to 12.4 (SD = 8.57), and the pre-to post-effect size was large (Cohen's d = 1.33). After CBT, 45% of the participants were judged to be treatment responders, and 34% met the remission criteria. CONCLUSIONS: Our preliminary findings indicate that 6 weeks of nurse-led group CBT produced a favorable treatment outcome for individuals with major depression in a Japanese clinical setting. The results of this study might encourage more Asian nurses to provide CBT as a part of their nursing practice. Further controlled trials that address the limitations of this study are required.

Partial regimen replacement with aripiprazole reduces serum prolactin in patients with a long history of schizophrenia: A case series.

AIM: Aripiprazole (ARP) is a popular antipsychotic drug that has demonstrated ameliorative effects on hyperprolactinemia. However, no study to date has studied the utility of ARP in patients with a long history of schizophrenia and antipsychotic treatment. We therefore examined the effect of partial antipsychotic regimen replacement with ARP on hyperprolactinemia induced by chronic antipsychotic use in patients with schizophrenia. METHODS: Sixteen patients with a schizophrenia diagnosis (F2) based on the International Classification of Diseases (version 10) were recruited. At months 0, 1, 3, and 6 of the study, serum prolactin, body weight, and blood glucose were measured, and QOL and psychotic symptoms were assessed using Global Assessment of Functioning scores and Clinical Global Impressions of Improvement (CGI-I) scores. RESULTS: Nine patients with an average age of 46.7±9.6 years and mean disease duration of 15.9±10.4 years were included in the final analysis. Serum prolactin levels significantly decreased and GAF and CGI-I scores improved significantly over the 6-month period after partial replacement with ARP. Additionally, no changes were observed in body weight or blood glucose over the 6-month period. CONCLUSION: Partial antipsychotic regimen replacement with ARP improves hyperprolactinemia, and may improve the QOL of patients with a long history of schizophrenia. CLINICAL TRIAL REGISTRATION NUMBER: Japan Medical Association, Center for clinical trials D: JMA-IIA00245.

Weight control in schizophrenic patients through Sakata's Charting of Daily Weight Pattern and its associations with temperament and character.

AIM: This study examined whether daily self-monitoring of weight and monthly interviews with a doctor improved eating habits and led to weight loss, and whether temperament and character traits affect weight change in persons with schizophrenia. METHODS: Participants used Sakata's Charting of Daily Weight Pattern to monitor their weight daily. In addition, Sakata's Eating Behavior Questionnaire was administered to evaluate eating-behavior awareness. The Temperament and Character Inventory (TCI) was used to assess participants' temperament and character. Fifty patients were divided into two groups: the intervention group (n = 25) filled in Sakata's Charting of Daily Weight Pattern every day; was interviewed monthly by a doctor about weight management; was weighed monthly. The non-intervention group (n = 25) was only weighed monthly. RESULTS: The body mass index (mean ± standard error: 0.59 ± 0.10 kg/m(2), p < 0.001) of the intervention group decreased significantly while their scores on Sakata's Eating Behavior Questionnaire significantly improved albeit marginally. Conversely, body mass index increased significantly (0.66 ± 0.18 kg/m(2), p < 0.001) in the non-intervention group, whose scores on Sakata's Eating Behavior Questionnaire did not change significantly. Weight change and TCI scores were not correlated for the intervention group, but scores for "self-directedness" and weight gain in the non-intervention group had a marginally significant negative correlation (r = -0.33, p < 0.10). CONCLUSION: Our results suggest that monitoring one's weight daily on Sakata's Charting of Daily Weight Pattern led to improvements in eating behavior and a decrease in BMI of patients with schizophrenia.

Levetiracetam enhances endogenous antioxidant in the hippocampus of rats: in vivo evaluation by brain microdialysis combined with ESR spectroscopy.

We have attempted to explore the neuroprotective effectiveness of levetiracetam (LEV) by measuring its in vivo antioxidant effect in the hippocampus of rats in a freely moving state. Male Wistar rats were used for the estimation of the in vivo antioxidant effect of LEV through microdialysis combined with electron spin resonance spectroscopy. The antioxidant effect was examined using the principle by which a systemically administered blood-brain barrier-permeable nitroxide radical (PCAM) decreases in an exponential decay manner that is correlated with the amount of antioxidant in the brain. The PCAM decay ratio during perfusion with normal Ringer's solution was compared with that during 32 microM and 100 microM LEV co-perfusion. The in vivo antioxidant effect was examined. In addition, the expressions of the cystine/glutamate exchanger (xCT) and the inducible nitric oxide synthase (iNOS) protein related to redox regulation were measured in the hippocampus of rats after 14 days of administration of LEV at a dose of 54 mg/day i.p. The half-life of PCAM was statistically shortened after LEV perfusion compared with the results of the control experiment. While the expression of the pro-oxidant protein iNOS was decreased, that of the antioxidant protein xCT was statistically increased by the administration of LEV. The role of xCT is to transport cystine, the internal material of glutathione, into the cell. The shortened half-life of the nitroxide radical by co-perfusion of LEV with increased xCT and decreased iNOS expression revealed the enhancement of the endogenous antioxidant effect or free-radical scavenging activity. The results of this study suggest that LEV synergistically enhances the basal endogenous antioxidant effect in the hippocampus with ascorbic acid and alpha-tocopherol. Our findings further suggest that LEV exerts a neuroprotective role by 1) modifying the expression of xCT and iNOS in connection with lipid peroxidation, 2) synergistically enhancing the increased basal endogenous antioxidant ability in the hippocampus, and 3) decreasing the basal concentration of glutamate followed by up-regulation of the intake of cystine, an internal material of GSH.

Role of glutamate and GABA transporters in development of pentylenetetrazol-kindling.

Kindling is a form of epileptogenesis that can be induced with pentylenetetrazol (PTZ). We undertook this study to evaluate the contribution of glutamate and GABA transporters to the process of PTZ kindling. Rats were injected i.p. three times per week with PTZ (40 mg/kg) until they were fully kindled. In rats who achieved full kindling, measurement of hippocampal glutamate and GABA transporters within 24 h by western blot showed that GLAST, GLT-1, and EAAC1 were elevated significantly. However, fully kindled rats at 30 days after their last seizure had no change in either glutamate or GABA transporters proteins. These sequential observations suggest that glutamate transporters may contribute to the occurrence of seizures, but were not associated with maintenance of epileptogenesis. During this experiment, we collected data from animals that had kindled easily and animals who were resistant to kindling. Easily-kindled rats reached full kindling with less than five injections of PTZ. Kindling resistant animals failed to achieve full kindling even after administration of 12 consecutive injections of PTZ. Levels of EAAC1 and GAT-1 in easily-kindled rats were decreased by 30% when compared to kindling resistant animals at 30 days after the last PTZ injection. Since decreased EAAC1 and GAT-1 would diminish GABA function, less quantity of these proteins would appear to be associated with the convulsive threshold at the beginning of kindling development. We wonder if glutamate and GABA transporters might be operant in a convulsion threshold set factor or as a pace factor for kindling.

Molecular regulation of antioxidant ability in the hippocampus of EL mice.

We recently found that the antioxidant ability was remarkably decreased in the hippocampus (Hipp) of EL at 8 weeks of age utilizing ESR spectroscopy. In this study, in addition to evaluating the extracellular glutamate concentration, we tried to determine whether or not changes in the expression of cystine/glutamate exchanger (xCT) and glutamate transporter take place in the Hipp of EL. EL mice and DDY mice at 5, 10, and 20 weeks of age were used for Exp. I and II, respectively. Exp. I: During the interictal state, dialysate was collected from the ventral Hipp using a microdialysis technique, and an extracellular concentration of glutamate ([Glu](o)) was measured with HPLC-ECD. Exp. II: The hippocampal expression of the glutamate transporter and xCT was estimated by Western blots. Exp. I: The level of [Glu](o) at 10 weeks of age was remarkably higher at other ages of EL mice, while [Glu](o) of DDY was unchanged as a result of age. Exp. II: The excitatory amino acid carrier-1 (EAAC-1) and xCT of EL mice at 10 weeks of age decreased more than those of DDY. GLAST and GLT-1 of EL mice at 5 weeks of age decreased more than those of DDY at the same age. No differences were found between EL and DDY for GLAST and GLT-1 at other ages. According to previous studies, the decreased endogenous antioxidant potential observed at 10 weeks of age is a very likely explanation for ictogenesis. The decreased xCT expression at 10 weeks of age could provide the molecular mechanism to explain the depletion of the endogenous antioxidant ability of EL mice during ictogenesis. In addition to the depletion of antioxidant ability, decreased EAAC-1 at this period could be one reason for the collapse of the molecular action of inhibition. These molecular findings support the idea that the elevation of [Glu](o) at 10 weeks of age triggers ictogenesis.

In vivo activation of N-methyl-D-aspartate receptors generates free radicals and reduces antioxidant ability in the rat hippocampus: experimental protocol of in vivo ESR spectroscopy and microdialysis for redox status evaluation.

The pathological mechanisms of various CNS diseases are closely related to glutamate neuronal excitotoxicity following NMDA receptor activation. To verify this relationship, in vivo microdialysis in the hippocampus of rats was applied to ESR spectroscopy during NMDA perfusion. Microdialysis co-perfusion of 0.1 mM NMDA dissolved in 150 mM POBN for 60 min revealed six-line carbon-centered radical ESR spectra. The hfc values were aN=15.7 G and aHbeta=2.5 G, corresponding to the values produced from the generation of lipid radicals. The antioxidant activity during the freely moving state was examined utilizing the principle that systemically applied nitroxide radicals are reduced and lose their paramagnetism by antioxidant activity in the brain. ESR analysis of sequential changes in the signal amplitude of nitroxide radicals in both the NMDA group and the control group revealed an exponential decay. The half-life of the nitroxide radical was significantly longer in the NMDA group than in the control group. The homeostasis of a steady redox balance was destroyed by acute NMDA infusion, which resulted in the generation of lipid radicals and the reduction of antioxidant ability in the hippocampus. The redox imbalance induced by the activation of NMDA-R was recovered by the inhibition of PLA2 and NOS. These results indicated that NMDA-R activation caused the shift to oxidized condition of the redox state, which subsequently leads to neuron death in the hippocampus in the model of glutamate-associated neuronal disease.

In vivo EPR estimation of bilateral hippocampal antioxidant ability of rats with epileptogenesis induced by amygdalar FeCl3 microinjection.

PURPOSE: To measure the neural antioxidant function in the hippocampus of rats with epileptogenesis induced by microinjection of FeCl3 into the amygdala using the decay rate of the nitroxide radical as estimated by L-band electron paramagnetic resonance (EPR) spectroscopy. MATERIALS AND METHODS: Region-selected intensity determination (RSID) was used for the estimation of the nitroxide decay ratio. It is possible to estimate the in vivo hippocampal antioxidant ability using the half-life of the EPR signal of the blood-brain barrier-permeable nitroxide radical. Rats were microinjected with aqueous FeCl3 into the right amygdaloid body. Recording from chronically implanted depth electrodes showed the development of spike discharges with recurrent seizures arising from amygdalar regions with propagation into both hippocampi. Rats with unilateral aqueous FeCl3 lesions were injected systemically with the nitroxide radical and then had EPR for RSID estimation at 5, 15, and 30 days after the iron salt injection. RESULTS: The in vivo antioxidant ability of the dorsal hippocampus was significantly decreased bilaterally in animals with FeCl3-induced seizures when compared to the control. CONCLUSION: Neural antioxidant function in the hippocampi of rats with chronic seizures induced by amygdalar FeCl3 was decreased early and both ipsilaterally and bilaterally.

Age-dependent changes in the hippocampal antioxidant ability of EL mice.

Electron spin resonance (ESR) spectroscopy combined with in vivo microdialysis was used to analyze the antioxidant ability in the hippocampus of mice in an interictal state of EL mice utilizing decay ratio of an exogenously applied nitroxide radical (3-methoxycarbonyl-2,2,5,5-tetramethylpyrrolidine-1-oxyl (PCAM)). In EL mice with a history of frequent seizures, the half-life of the electron paramagnetism of PCAM in the hippocampus was prolonged. These results revealed decreased antioxidant ability, suggesting vulnerability against oxidative stress. Our data suggest that epileptogenesis in EL mice with chronic seizures is associated with functional failure due to the oxidized redox state and revealed that the decreased hippocampal antioxidant ability is related to the regional vulnerability to oxidative stress in the limbic system of EL mice during epileptogenesis.

Functional role for redox in the epileptogenesis: molecular regulation of glutamate in the hippocampus of FeCl3-induced limbic epilepsy model.

We used western blotting to measure the quantity of glutamate and gamma-aminobutyric acid (GABA) transporters proteins within hippocampal tissue obtained from rats who had undergone epileptogenesis. Chronic seizures were induced by amygdalar injection of FeCl(3). We found that the glial glutamate transporters GLAST and GLT-1 were down-regulated at 60 days after initiation of chronic and recurrent seizures. However, the neuronal glutamate transporter EAAC-1 and the GABA transporter GAT-3 were increased. We performed in vivo microdialysis in freely moving animals to estimate in vivo redox state. We found that the hippocampal tissues were oxidized, resulting in even further impairment of glutamate transport. Our data show that epileptogenesis in rats resulting in chronic and recurrent seizures is associated with collapse of glutamate regulation caused by both the molecular down-regulation of glial glutamate transporters combined with the functional failure due to oxidation.

Effect of levetiracetam on molecular regulation of hippocampal glutamate and GABA transporters in rats with chronic seizures induced by amygdalar FeCl3 injection.

Enhancement of the glutamatergic excitatory synaptic transmission efficacy in the FeCl3 induced epilepsy model is associated with changes in the levels of glutamate and GABA transporter proteins. This study examined the effect of levetiracetam (LEV) on glutamate overflow and glutamate/GABA transporters expression in rats with epileptogenesis induced by the amygdalar injection of 1.0 microl of 100 mM FeCl3 (epileptic rat) and in control rats receiving amygdalar acidic saline injection (non-epileptic rat). In amygdalar acidic saline injected rats, 40 mM KCl-evoked glutamate overflow was significantly suppressed by both 32 and 100 microM LEV co-perfusion. In unilateral amygdalar FeCl3 injected rats, 32 microM LEV was ineffective, but the 100 microM LEV statistically suppressed glutamate overflow. Western blotting was employed to determine the hippocampal expression of glutamate/GABA transporters in epileptic or non-epileptic rats. The rats were treated for 14 days with 54 mg/kg LEV or vehicle intraperitoneally injection. Following 14 days of treatment, the ipsilateral hippocampus was removed for a Western blot analysis. In non-epileptic rats, the expression increased for all of the glutamate and GABA transporters (GLAST, GLT-1, EAAC-1, GAT-1 and GAT-3) while the glutamate transporter regulating protein (GTRAP3-18) decreased in comparison to those of normal rats that were treated with the vehicle. In epileptic rats receiving LEV, the EAAC-1 and GAT-3 levels increased while GTRAP3-18 (89%) decreased in comparison to those of the epileptic rats treated with the vehicle. GTRAP3-18 inhibitor regulates glutamate-binding affinity to EAAC-1. The anti-epileptic action of LEV may be partially due to a reduction of glutamate-induced excitotoxicity and an enhancement of the GABAergic inhibition as observed with the inhibitory effect on the 40 mM KCl-evoked glutamate overflow. These conclusions are supported by the increase in the expression of glial glutamate transporters (GLAST and GLT-1), and the increase in the expression of EAAC-1 and GAT-3 associated with a decrease in GTRAP3-18. The increased expression of EAAC-1 and the decreased expression of GTRAP3-18 in association with the up-regulation of GAT-3 due to such continual LEV administration was thus found to enhance GABA synthesis and reverse the transport of GABA both in non-epileptic and epileptic rats. The suppression of glutamate excitation and the enhancement of GABA inhibition in the rats with continual LEV administration is a result of the up-regulation of glutamate and GABA transporters with the down-regulation of GTRAP3-18. These observations together demonstrated the critical molecular mechanism of the anti-epileptic activity of LEV.

Protective role of pentobarbital pretreatment for NMDA-R activated lipid peroxidation is derived from the synergistic effect on endogenous anti-oxidant in the hippocampus of rats.

We have attempted to explore the neuroprotective effectiveness of PBT by measuring anti-oxidant ability in the hippocampus of rats in a freely moving state. Anti-oxidant ability was examined utilizing the principle that blood-brain barrier-permeable nitroxide radicals (PCAM) injected i.p. lose their paramagnetism in an exponential decay correlated with anti-oxidant ability in the brain. The half-life of PCAM was used as the indicator of the hippocampal anti-oxidant ability. While the half-life was statistically prolonged when infused with 0.1mM NMDA without PBT, the half-life was almost the same as in the control when infused with NMDA under anesthesia with PBT. In addition, the half-life under only PBT anesthesia was the shortest of all the groups. Our findings, therefore, suggested that PBT anesthesia not only suppresses NMDA-R activated free radical generation but also synergistically enhances the increased basal endogenous anti-oxidant ability in the hippocampus.

An acute dysfunction of the glutamate transport activity has been shown to generate free radicals and suppress the anti-oxidant ability in the hippocampus of rats.

In this study, we attempted to elucidate whether or not an acute inhibition of glutamate transports activity with l-trans-pyrrolidine-2,4-dicarboxylic acid (l-trans PDC) would cause neuroexcitoxicity in the hippocampus. We used in vivo microdialysis and X-band electron spin resonance (ESR) spectroscopy to measure the changes in the redox state during the perfusion of l-trans PDC. ESR signals from rats using l-trans PDC were characteristically a six-line spectra, for which the hfc was a(N)=1.57mT and a(H)=0.25mT; these hfc's were obtained from the lipoxygenase/linoleic acid system that was used for the generation of lipid radicals. The antioxidant effect was measured using an ESR analysis to monitor sequential changes in the signal amplitude of nitroxide radical in the dialysate of both l-trans PDC and control animals. The pattern showed exponential decay with median half-life of the nitroxide radical took significantly longer in the l-trans PDC group. Acute changes in the glutamate transport resulted in the generation of a lipid radical and a depletion in the anti-oxidant effect in the hippocampus. Our data indicate that a dysfunction of a glutamate transport resulted in the collapse of the redox state, which thus eventually led to neuronal necrosis in the hippocampus. This study provides clear evidence for the mechanisms associated with neuronal disorder in relation to glutamate.

Functional role of GABA transporters for kindling development in GLAST KO mice.

Kindling-induced after discharge in electroencephalograms depends on the protein associated with glutamatergic and/or GABAergic neuronal transmission. In glutamate transporter knockout (GLAST KO) mice, the kindling phenomena in GLAST KO developed more slowly while the after discharge duration (ADD) was briefer than that of the control C57BL-6J mice. These findings indicate that either the excitatory function was suppressed or the inhibitory function was enhanced in GLAST KO kindling. To explain these phenomena, we used Western blotting to evaluate the alterations in the expression of hippocampal GABA transporter proteins, and the estimation of the effect on the process of epileptogenesis. Although no alterations were observed in the GAT-3 expression, the hippocampal GAT-1 expression was significantly suppressed in comparison to that of C57BL-6J mice. A decreased GAT-1 level in the hippocampus, which might be associated with the increased extracellular GABA level, may therefore inhibit both ADD and seizure propagation as shown by the amygdaloid kindling phenomenon observed in GLAST KO mice.