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Akashi, Japan

Doe N.,Kouiken Co. | Doe N.,Hyogo College of Medicine | Takahashi T.,Kwansei Gakuin University | Kiriyama M.,Kouiken Co.
Experimental Animals | Year: 2010

In the case of mice, when the difficulty of a water maze learning task is increased, some animals gradually cease to swim, abandon adaptive learning, and become immobile. We trained 99 male C57BL/6N mice in a pool containing a hidden platform. The pool was surrounded by white featureless walls, and almost all external cues were removed. On the eighth day of escape training, 36 inferior-learners exhibited behavioral despair. The predictive validity of the inferior-learners as a depression model was verified by testing their sensitivity to clinically efficacious antidepressants. The inferior-learners treated with a selective serotonin reuptake inhibitor (SSRI), fluvoxamine, or a serotonin noradrenaline reuptake inhibitor (SNRI), milnacipran, resumed swimming and adaptive learning. Because of facial similarities between inferior-learners and depressive patients and their sensitivity to antidepressant drugs, our experimental method is expected to be an effective tool in basic research on depression. Source


Nakama-Kitamura M.,Kwansei Gakuin University | Kitamura Y.,Kouiken Co.
Brain Research | Year: 2011

Chronic pain tends to be intractable, regardless of whether the etiology has improved or is persistent. This intractability may be due, in part, to conditioning factors, but studies of the underlying mechanism are limited. We predicted that the body might learn pain sensation during sustained pain. In the present study, we sought to examine the prediction that nociceptive pain could be a conditioned response. After pre-exposing mice to the context box, we assessed hind-paw licking responses(s), an unconditioned nociceptive response (UCR), in the training phase for 30 min following each of two injections (24 h apart) of formalin into the hind paws. Forty-eight hours later, in the test phase, we tested for a conditioned nociceptive response (CR) from paw injections of saline, with mice placed in either the same or a different visual context box. The results showed that the CR elicited in the same context box was significantly larger than one elicited in the different box. An audiovisual context, which is used in prototypical Pavlovian conditioning, augmented the CR. The CR diminished to baseline levels during repeated extinction procedures, in which saline alone was given in the same context box. However, the CR in animals injected with saline in their home cages was unchanged. Treatment with scopolamine, which has an antimuscarinic action, and thus induces an amnestic effect, did not affect the UCR, but reduced the CR. These results indicated that repeated nociceptive stimuli were sufficient to produce a CR. © 2011 Elsevier B.V. All rights reserved. Source


Tsuruoka N.,Cerebos Pacific Ltd | Beppu Y.,Suntory Business Expert Ltd | Koda H.,Suntory Business Expert Ltd | Doe N.,Kouiken Co. | And 3 more authors.
PLoS ONE | Year: 2012

Diketopiperazines (DKPs) are naturally-occurring cyclic dipeptides with a small structure and are found in many organisms and in large amounts in some foods and beverages. We found that a chicken essence beverage, which is popular among Southeast Asians as a traditional remedy and a rich source of DKPs, inhibited the serotonin transporter (SERT) and suppressed serotonin uptake from rat brain synaptosomes, which prompted us to isolate and identify the active substance(s). We purified a SERT inhibitor from the chicken essence beverage and identified it as the DKP cyclo(L-Phe-L-Phe). Interestingly, it was a naturally occurring dual inhibitor that inhibited both SERT and acetylcholinesterase (AChE) in vitro. The DKP increased extracellular levels of the cerebral monoamines serotonin, norepinephrine, and dopamine in the medial prefrontal cortex and acetylcholine in the ventral hippocampus of freely moving rats when administered orally. Moreover, cyclo(L-Phe-L-Phe) significantly shortened escape latency in the water maze test in depressed mice previously subjected to a repeated open-space swimming task, which induces a depression-like state. Cyclo(L-Phe-L-Phe) also significantly improved accuracy rates in a radial maze test in rats and increased step-through latencies in a passive avoidance test in mice with scopolamine-induced amnesia. These animal test results suggest that cyclo(L-Phe-L-Phe), which is present abundantly in some foods such as chicken essence, may abrogate the onset of depression and, thus, contribute to preventing the development of Alzheimer's disease and other dementia, because senile depression is a risk factor for dementia. © 2012 Tsuruoka et al. Source


Nakamura T.,Himeji Dokkyo University | Kitamura Y.,Kouiken Co. | Doe N.,Kouiken Co. | Hattori S.,Kurume National College of Technology | Honda G.,Himeji Dokkyo University
Genes and Environment | Year: 2011

The anti-genotoxicity effect of aqueous extracts of Connarus ruber cortex was studied in cultured human cells and mice. Connarus extract decreased bi-nuclei cells with micronuclei (MNBNC) significantly in NER-proficient WTK1 cells that were exposed to MNU, MMC, or UVC and in NER-deficient XPL3KA cells (that is, in XP-C) that were exposed to MNU or MMC, but not UVC. The genotoxicitysuppressing effect was further studied by the comet assay. Connarus extract decreased DNA migration signi ficantly inWTK1 cells that were exposed to MNU or UVC and in XPL3KA cells that were exposed to MNU but not UVC. In WTK1 cells, in contrast, DNA migration increased with the extract in the presence of DNA repair inhibitors (araC and HU), suggesting that the anti-genotoxic potential is due to an enhanced incision step of global genome repair (GGR) subpathways in NER. Chemical analysis revealed that the extract contains epicatechine, one of the anti-mutagenic components contained in green tea. Connarus extract fractions that decreased UVC-induced DNA migration were those not to contain epicatechine and they were different from those that decreased MNU-induced DNA migration, suggesting that some anti-mutagenic components other than epicatechine might be contained in Connarus extract and that a number of anti-genotoxic components with different modes of anti-genotoxicity are contained inConnarus extract. The anti-clastogenic effect of Connarus extracts was examined in mice using a micronucleus assay. When mice received ?2000 mg/kg Connarus extract by oral gavage at the same time as intraperitoneal injection of MMC, a decrease in the frequency of micronucleated reticulocytes was observed. This decrease was not due to a delay in the maturation of micronucleated reticulocytes. © The Japanese Environmental Mutagen Society. Source


Yamanishi K.,Hyogo College of Medicine | Doe N.,Hyogo College of Medicine | Doe N.,Kouiken Co. | Sumida M.,Kouiken Co. | And 8 more authors.
PLoS ONE | Year: 2015

Major depressive disorder (MDD) is a common psychiatric disorder that involves marked disabilities in global functioning, anorexia, and severe medical comorbidities. MDD is associated with not only psychological and sociocultural problems, but also pervasive physical dysfunctions such as metabolic, neurobiological and immunological abnormalities. Nevertheless, the mechanisms underlying the interactions between these factors have yet to be determined in detail. The aim of the present study was to identify the molecular mechanisms responsible for the interactions between MDD and dysregulation of physiological homeostasis, including immunological function as well as lipid metabolism, coagulation, and hormonal activity in the brain. We generated depression-like behavior in mice using chronic mild stress (CMS) as a model of depression. We compared the gene expression profiles in the prefrontal cortex (PFC) of CMS and control mice using microarrays. We subsequently categorized genes using two web-based bioinformatics applications: Ingenuity Pathway Analysis and The Database for Annotation, Visualization, and Integrated Discovery. We then confirmed significant group-differences by analyzing mRNA and protein expression levels not only in the PFC, but also in the thalamus and hippocampus. These web tools revealed that hepatocyte nuclear factor 4 alpha (Hnf4a) may exert direct effects on various genes specifically associated with amine synthesis, such as genes involved in serotonin metabolism and related immunological functions. Moreover, these genes may influence lipid metabolism, coagulation, and hormonal activity. We also confirmed the significant effects of Hnf4a on both mRNA and protein expression levels in the brain. These results suggest that Hnf4a may have a critical influence on physiological homeostasis under depressive states, and may be associated with the mechanisms responsible for the interactions between MDD and the dysregulation of physiological homeostasis in humans. © 2015 Signorelli et al. Source

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