Soichiro Sato

Time-Dependent Changes in Neurotrophic Factor mRNA Expression after Kindling and Long-Term Potentiation in Rats

We compared the time-dependent changes in messenger ribonucleic acid (mRNA) levels for two neurotrophic factors after amygdala-kindled seizures and hippocampal long-term potentiation (LTP) in rats in vivo. The brain-derived neurotrophic factor (BDNF) mRNA levels in the bilateral granule cell layer of the dentate gyrus, increased significantly 1-4 h after stage 5 kindled seizures. Nerve growth factor (NGF) mRNA levels increased throughout the bilateral limbic regions more gradually than those of BDNF mRNA. The maximum levels in the dentate gyrus ipsilateral to stimulation (BDNF mRNA: 493%, NGF mRNA: 199% of control levels) occurred 2 h after seizures. As observed with kindling, BDNF and NGF mRNA expression increased in the dentate gyrus ipsilateral to stimulation also increased following LTP induced by the perforant path stimulation, with maximum levels occurring 2 h and 4 h, respectively, after stimulation, when they reached 284% and 189% of the control levels, respectively. These results suggest that BDNF and NGF are involved in enhancement of synaptic efficacy in the granule cells of the dentate gyrus in the hippocampus in kindling, not related to the neuronal excitability associated with seizure activity.

Time-dependent and regional expression of GABA transporter mRNAs following amygdala-kindled seizures in rats

To investigate the role played by GABA transporters in epileptic seizures, we examined time-dependent and regional changes in expression of GAT-1 and GAT-3 GABA transporter mRNA in amygdala-kindled rat brain using an in situ hybridization method. GAT-1 mRNA was significantly increased bilaterally in the hippocampal dentate gyrus (111-116%) at 1 h after kindled generalized seizures. GAT-1 mRNA was also significantly increased bilaterally in the hippocampal subfields (CA1-4 and dentate gyrus [110-117%]) at 4 h after kindled seizures. There were no significant changes in GAT-1 mRNA level in the amygdalar nuclei, pyriform cortex or cerebral cortex either ipsilaterally or contralaterally at any time after kindled seizures. In contrast, GAT-3 mRNA was significantly increased bilaterally in the amygdalar nuclei and in the contralateral pyriform cortex and cerebral cortex 1 h after seizures. Since all these changes returned to control levels by 8 or 24 h after kindled seizures, the increases in GABA transporter mRNA appeared to be transient responses to seizure activity. These findings indicate that GAT-1 subtype transporter is specifically involved in seizure activity in the hippocampus, while GAT-3 subtype transporter is mainly involved in seizure activity in the amygdalar nuclei and pyriform cortex following amygdala-kindled generalized seizures.

Anti-inflammatory and bronchodilator properties of KF19514, a phosphodiesterase 4 and 1 inhibitor.

We investigated the effects of KF19514 (5-phenyl-3-(3-pyridyl)methyl-3H-imidazo[4,5-c][1,8]naphthyridin-4 (5H)-one) on bronchoconstriction and allergic inflammation in guinea pigs and on tumor necrosis factor-alpha production in mice. KF19514 inhibited phosphodiesterase 4 (IC50 = 0.40 microM) and phosphodiesterase 1 (IC50 = 0.27 microM) derived from canine tracheal smooth muscles. KF19514 relaxed contracted tracheal smooth muscle and had a potent inhibitory effect on antigen-induced bronchoconstriction (EC50 = 0.058 microM) in vitro. Intravenous administration of KF19514 inhibited histamine-induced bronchoconstriction (ID50 = 2.8 microg/kg i.v.). Moreover, oral administration of KF19514 inhibited anaphylactic bronchoconstriction (ID50 = 0.2 mg/kg p.o.), and eosinophil infiltration in airway stimulated with platelet-activating factor (PAF) or antigen. KF19514 also produced a significant inhibition of tumor necrosis factor-alpha production in mice (ID50 = 0.023 mg/kg p.o.). Finally, KF19514 completely inhibited antigen-induced hyperreactivity at 0.1 mg/kg p.o. These results demonstrate that KF19514 may have efficacy in the treatment of asthma.

BW1003C87, phenytoin and carbamazepine elevate seizure threshold in the rat amygdala-kindling model of epilepsy

We examined the anticonvulsant effects of BW1003C87 (5-(2,3,5-trichlorophenyl)-2,4-diaminopyrimidine ethane sulphonic acid), which is structurally related to the new antiepileptic drug, lamotrigine, and compared its effects to those of the conventional antiepileptic drugs, phenytoin and carbamazopine, using the rat amygdala-kindling model of epilepsy. BW1003C87 (2.5-10 mg/kg, i.p.) had potent and long-lasting (48 h after single administration) effects on amygdala-kindled seizures. The effects of BW1003C87 were completely reversed when the stimulus intensity was increased to 2 or 3 times the threshold determined. Since the same effects on seizure threshold were obtained for phenytoin and carbamazepine in the present study and for lamotrigine in our previous study, we propose that the principal mechanism of these antiepileptic drugs, which act primarily on voltage-sensitive Na+ channels, is significant elevation of the seizure threshold in epileptogenic foci and that BW1003C87 has a profile similar to that of these drugs.

Quality of life for patients with schizophrenia in a Japanese psychiatric hospital

Providing a good quality of life (QOL) has recently been recognized as a central purpose of health care in psychiatry. In this study, we performed a detailed evaluation of the subjective QOL of schizophrenic inpatients and examined the relationship of QOL to various patient characteristics. This study was conducted on schizophrenic inpatients and nursing staff members in a Japanese private psychiatric hospital. As a result, only depression showed a weak, but significant, relationship with subjective QOL. Other characteristics showed no meaningful correlation to subjective QOL. Comparison between the schizophrenic group and the nursing staff group revealed that schizophrenic inpatients showed a lower QOL in the domains of physical health and social relationships. Schizophrenia itself and/or accompanying disabilities might induce lower subjective QOL. It is difficult to determine what the important factors are, except for depression, for subjective QOL of schizophrenic inpatients. However, depression should receive more attention for the QOL in the physical health and psychological health domains.

Time-dependent changes in rat hippocampal synapsin I mRNA expression during long-term potentiation.

We studied the time-dependent changes in synapsin I mRNA levels after hippocampal long-term potentiation (LTP) in rats in vivo. Following LTP induction by stimulating the perforant path, synapsin I mRNA expression in the granule cell layer of the dentate gyrus ipsilateral to stimulation increased significantly in a time-dependent manner. From 2 to 8 h after stimulation, the synapsin I mRNA levels in the ipsilateral dentate gyrus were significantly higher than those of controls subjected to a sham procedure. The synapsin I mRNA level (157.4+/-7.1% of the control level, mean+/-SEM) was at a maximum 8 h after stimulation. The synapsin I mRNA level of animals that received only test pulses did not increase significantly, compared with the control level. These results suggest that the increased level of synapsin I mRNA is related to persistent enhancement of synaptic activity within the neural networks in which dentate granule cells participate in LTP.

Efficacy of second-generation antipsychotics in patients at ultra-high risk and those with first-episode or multi-episode schizophrenia

Aim The aim of this study was to examine the speed of response, doses, and safety of treatment with second-generation antipsychotics (SGAs) in patients at ultra-high risk (UHR) compared to those with schizophrenia. Methods A 12-week open-label, prospective study of SGAs was performed in UHR patients and those with first-episode schizophrenia (FES) and multi-episode schizophrenia (MES). The subjects were 14–30 years old and were recruited at Zikei Hospital, Okayama, Japan from December 1, 2006 to December 1, 2011. Treatment was carried out in a natural setting in an open-label format, but clinical evaluation was performed blind. The clinical rating scales include the Global Assessment of Functioning (GAF), the Positive and Negative Syndrome Scale (PANSS), and the Clinical Global Impression-Severity scale (CGI-S). Results UHR (n = 17), FES (n = 23), and MES (n = 21) patients all showed significant improvements on the GAF, PANSS, and CGI-S. However, the UHR patients showed significantly greater improvement on the GAF at weeks 4, 8, and 12 compared to the other groups, and a significantly lower modal dose of SGAs (chlorpromazine equivalent: 183 [201.1] mg/day, mean [SD]) was needed for improvement in the UHR group. Each group was also prescribed anticholinergic agents during the study period and the UHR group had significantly fewer extrapyramidal symptoms (only 6%) compared with the FES group. Conclusion Our findings suggest that UHR patients have a better response to SGAs compared to patients with schizophrenia, and that these drugs can be given safely by minimizing the dosage of SGAs and using anticholinergic agents.

Effects of Antiepileptie Drugs on Seizure Thresholds in the Rat Kindling Model of Temporal Lobe Epilepsy

Purpose: To determine the antiepileptic profiles of antiepileptic drugs (AEDs), we compared the effects of various AEDs, including phenytoin (PHT), carbamazepine (CBZ), valproate (VPA), and diazepam (DZP), on seizure thresholds in the rat kindling model of temporal lobe epilepsy.

Increment of Synapsin I Protein in the Hippocampus of Kindled Rats

Introduction: Synapsin is a vesiele‐associated protein considered to be involved in synaptogenesis and neurotransmitter release. Previously, we havc reported that synapsin I mRNA is significantly increased in the bilalcral dentate gyrus after amygdala‐kindled scizures. In this study, we investigated amygdala kindling‐induced changes i n synapsin I protein using immunohistochemistry. Quantitativc densitomctry (Mathern ct al., Ncurosciene, 1997) was performed to evaluatc changes i n synapsin I protein i n the hippocampus.