175 results on '"Hisashi Shirakawa"'
Search Results
2. Amelioration of obsessive-compulsive disorder by intracellular acidification of cortical neurons with a proton pump inhibitor
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Hikari Hatakama, Nozomi Asaoka, Kazuki Nagayasu, Hisashi Shirakawa, and Shuji Kaneko
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Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Abstract Obsessive-compulsive disorder (OCD) is a highly prevalent neuropsychiatric disorder poorly controlled with pharmacological treatment because of the wide variation in symptom patterns. We analysed real-world data on adverse self-reports and insurance claims to identify a novel therapeutic target for OCD. We found that dopamine D2 receptor (D2R) agonists increased the incidence of OCD-like symptoms, which were suppressed by the concomitant use of proton pump inhibitors (PPIs). Further, OCD-like repetitive and habitual behaviours were observed in mice repeatedly injected with a D2R agonist, quinpirole. However, these abnormalities were suppressed by short-term PPI treatment. In quinpirole-treated mice, PPI inhibited pyramidal neuron hyperactivity in the lateral orbitofrontal cortex, a region where the P-type proton pump gene Atp4a is abundantly expressed. In primary cultured cortical neurons, short-term PPI treatment lowered intracellular pH and decreased firing activity, which was mimicked by Atp4a knockdown. Our findings show that inhibition of P-type proton pumps may be a novel therapeutic strategy for OCD.
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- 2024
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3. Large-scale animal model study uncovers altered brain pH and lactate levels as a transdiagnostic endophenotype of neuropsychiatric disorders involving cognitive impairment
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Hideo Hagihara, Hirotaka Shoji, Satoko Hattori, Giovanni Sala, Yoshihiro Takamiya, Mika Tanaka, Masafumi Ihara, Mihiro Shibutani, Izuho Hatada, Kei Hori, Mikio Hoshino, Akito Nakao, Yasuo Mori, Shigeo Okabe, Masayuki Matsushita, Anja Urbach, Yuta Katayama, Akinobu Matsumoto, Keiichi I Nakayama, Shota Katori, Takuya Sato, Takuji Iwasato, Haruko Nakamura, Yoshio Goshima, Matthieu Raveau, Tetsuya Tatsukawa, Kazuhiro Yamakawa, Noriko Takahashi, Haruo Kasai, Johji Inazawa, Ikuo Nobuhisa, Tetsushi Kagawa, Tetsuya Taga, Mohamed Darwish, Hirofumi Nishizono, Keizo Takao, Kiran Sapkota, Kazutoshi Nakazawa, Tsuyoshi Takagi, Haruki Fujisawa, Yoshihisa Sugimura, Kyosuke Yamanishi, Lakshmi Rajagopal, Nanette Deneen Hannah, Herbert Y Meltzer, Tohru Yamamoto, Shuji Wakatsuki, Toshiyuki Araki, Katsuhiko Tabuchi, Tadahiro Numakawa, Hiroshi Kunugi, Freesia L Huang, Atsuko Hayata-Takano, Hitoshi Hashimoto, Kota Tamada, Toru Takumi, Takaoki Kasahara, Tadafumi Kato, Isabella A Graef, Gerald R Crabtree, Nozomi Asaoka, Hikari Hatakama, Shuji Kaneko, Takao Kohno, Mitsuharu Hattori, Yoshio Hoshiba, Ryuhei Miyake, Kisho Obi-Nagata, Akiko Hayashi-Takagi, Léa J Becker, Ipek Yalcin, Yoko Hagino, Hiroko Kotajima-Murakami, Yuki Moriya, Kazutaka Ikeda, Hyopil Kim, Bong-Kiun Kaang, Hikari Otabi, Yuta Yoshida, Atsushi Toyoda, Noboru H Komiyama, Seth GN Grant, Michiru Ida-Eto, Masaaki Narita, Ken-ichi Matsumoto, Emiko Okuda-Ashitaka, Iori Ohmori, Tadayuki Shimada, Kanato Yamagata, Hiroshi Ageta, Kunihiro Tsuchida, Kaoru Inokuchi, Takayuki Sassa, Akio Kihara, Motoaki Fukasawa, Nobuteru Usuda, Tayo Katano, Teruyuki Tanaka, Yoshihiro Yoshihara, Michihiro Igarashi, Takashi Hayashi, Kaori Ishikawa, Satoshi Yamamoto, Naoya Nishimura, Kazuto Nakada, Shinji Hirotsune, Kiyoshi Egawa, Kazuma Higashisaka, Yasuo Tsutsumi, Shoko Nishihara, Noriyuki Sugo, Takeshi Yagi, Naoto Ueno, Tomomi Yamamoto, Yoshihiro Kubo, Rie Ohashi, Nobuyuki Shiina, Kimiko Shimizu, Sayaka Higo-Yamamoto, Katsutaka Oishi, Hisashi Mori, Tamio Furuse, Masaru Tamura, Hisashi Shirakawa, Daiki X Sato, Yukiko U Inoue, Takayoshi Inoue, Yuriko Komine, Tetsuo Yamamori, Kenji Sakimura, and Tsuyoshi Miyakawa
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brain pH ,lactate ,metabolism ,neuropsychiatric disorders ,animal models ,working memory ,Medicine ,Science ,Biology (General) ,QH301-705.5 - Abstract
Increased levels of lactate, an end-product of glycolysis, have been proposed as a potential surrogate marker for metabolic changes during neuronal excitation. These changes in lactate levels can result in decreased brain pH, which has been implicated in patients with various neuropsychiatric disorders. We previously demonstrated that such alterations are commonly observed in five mouse models of schizophrenia, bipolar disorder, and autism, suggesting a shared endophenotype among these disorders rather than mere artifacts due to medications or agonal state. However, there is still limited research on this phenomenon in animal models, leaving its generality across other disease animal models uncertain. Moreover, the association between changes in brain lactate levels and specific behavioral abnormalities remains unclear. To address these gaps, the International Brain pH Project Consortium investigated brain pH and lactate levels in 109 strains/conditions of 2294 animals with genetic and other experimental manipulations relevant to neuropsychiatric disorders. Systematic analysis revealed that decreased brain pH and increased lactate levels were common features observed in multiple models of depression, epilepsy, Alzheimer’s disease, and some additional schizophrenia models. While certain autism models also exhibited decreased pH and increased lactate levels, others showed the opposite pattern, potentially reflecting subpopulations within the autism spectrum. Furthermore, utilizing large-scale behavioral test battery, a multivariate cross-validated prediction analysis demonstrated that poor working memory performance was predominantly associated with increased brain lactate levels. Importantly, this association was confirmed in an independent cohort of animal models. Collectively, these findings suggest that altered brain pH and lactate levels, which could be attributed to dysregulated excitation/inhibition balance, may serve as transdiagnostic endophenotypes of debilitating neuropsychiatric disorders characterized by cognitive impairment, irrespective of their beneficial or detrimental nature.
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- 2024
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4. Acetaminophen improves tardive akathisia induced by dopamine D2 receptor antagonists
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Koki Nagaoka, Kazuki Nagayasu, Hisashi Shirakawa, and Shuji Kaneko
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Acetaminophen ,Clinical big data ,Dopamine D2 receptor ,Indirect-pathway medium spiny neurons ,Tardive akathisia ,Therapeutics. Pharmacology ,RM1-950 - Abstract
Tardive akathisia is a movement disorder characterized by internal restlessness with an uncontrollable urge to move, leading to repetitive movements. It is a common side effect of long-term treatment with dopamine D2 receptor antagonists. In the present study, we analyzed the FDA Adverse Event Reporting System and IBM MarketScan Research Database to find a drug that can be used concomitantly with dopamine D2 receptor antagonists and still reduce the risk of akathisia. Acetaminophen was determined to be the most effective akathisia-suppressing drug. In an experimental validation of the hypothesis, chronic treatment of rats with haloperidol caused akathisia symptoms, including increased stereotyped behavior and locomotor activity, and decreased immobility time. Acute treatment with acetaminophen significantly attenuated haloperidol-induced akathisia. In the ventral striata of these rats, acetaminophen prevented haloperidol-induced decrease in the number of c-Fos+ preproenkephalin+ neurons. These results suggest that acetaminophen is effective in suppressing tardive akathisia by activating indirect-pathway medium spiny neurons.
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- 2023
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5. Median raphe serotonergic neurons projecting to the interpeduncular nucleus control preference and aversion
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Hiroyuki Kawai, Youcef Bouchekioua, Naoya Nishitani, Kazuhei Niitani, Shoma Izumi, Hinako Morishita, Chihiro Andoh, Yuma Nagai, Masashi Koda, Masako Hagiwara, Koji Toda, Hisashi Shirakawa, Kazuki Nagayasu, Yu Ohmura, Makoto Kondo, Katsuyuki Kaneda, Mitsuhiro Yoshioka, and Shuji Kaneko
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Science - Abstract
Appropriate processing of value information is essential for survival. Here the authors show that in mice, serotonergic activations originating from the median raphe nucleus facilitated aversion in a pathway-dependent manner, while silencing this pathway was rewarding.
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- 2022
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6. Increased expression of glutathione peroxidase 3 prevents tendinopathy by suppressing oxidative stress
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Haruka Furuta, Mari Yamada, Takuya Nagashima, Shuichi Matsuda, Kazuki Nagayasu, Hisashi Shirakawa, and Shuji Kaneko
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real-world data ,tendinopathy ,fluoroquinolone ,aging ,dexamethasone ,GPX3 ,Therapeutics. Pharmacology ,RM1-950 - Abstract
Tendinopathy, a degenerative disease, is characterized by pain, loss of tendon strength, or rupture. Previous studies have identified multiple risk factors for tendinopathy, including aging and fluoroquinolone use; however, its therapeutic target remains unclear. We analyzed self-reported adverse events and the US commercial claims data and found that the short-term use of dexamethasone prevented both fluoroquinolone-induced and age-related tendinopathy. Rat tendons treated systemically with fluoroquinolone exhibited mechanical fragility, histological change, and DNA damage; co-treatment with dexamethasone attenuated these effects and increased the expression of the antioxidant enzyme glutathione peroxidase 3 (GPX3), as revealed via RNA-sequencing. The primary role of GPX3 was validated in primary cultured rat tenocytes treated with fluoroquinolone or H2O2, which accelerates senescence, in combination with dexamethasone or viral overexpression of GPX3. These results suggest that dexamethasone prevents tendinopathy by suppressing oxidative stress through the upregulation of GPX3. This steroid-free approach for upregulation or activation of GPX3 can serve as a novel therapeutic strategy for tendinopathy.
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- 2023
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7. Dorsal raphe serotonergic neurons preferentially reactivate dorsal dentate gyrus cell ensembles associated with positive experience
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Yuma Nagai, Yuri Kisaka, Kento Nomura, Naoya Nishitani, Chihiro Andoh, Masashi Koda, Hiroyuki Kawai, Kaoru Seiriki, Kazuki Nagayasu, Atsushi Kasai, Hisashi Shirakawa, Takanobu Nakazawa, Hitoshi Hashimoto, and Shuji Kaneko
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serotonin ,dentate gyrus ,neuronal ensembles ,stress ,Biology (General) ,QH301-705.5 - Abstract
Summary: Major depressive disorder (MDD) is among the most common mental illnesses. Serotonergic (5-HT) neurons are central to the pathophysiology and treatment of MDD. Repeatedly recalling positive episodes is effective for MDD. Stimulating 5-HT neurons of the dorsal raphe nucleus (DRN) or neuronal ensembles in the dorsal dentate gyrus (dDG) associated with positive memories reverses the stress-induced behavioral abnormalities. Despite this phenotypic similarity, their causal relationship is unclear. This study revealed that the DRN 5-HT neurons activate dDG neurons; surprisingly, this activation was specifically observed in positive memory ensembles rather than neutral or negative ensembles. Furthermore, we revealed that dopaminergic signaling induced by activation of DRN 5-HT neurons projecting to the ventral tegmental area mediates an increase in active coping behavior and positive dDG ensemble reactivation. Our study identifies a role of DRN 5-HT neurons as specific reactivators of positive memories and provides insights into how serotonin elicits antidepressive effects.
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- 2023
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8. Vitamin D supplementation is effective for olanzapine-induced dyslipidemia
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Zijian Zhou, Takuya Nagashima, Chihiro Toda, Mone Kobayashi, Takahide Suzuki, Kazuki Nagayasu, Hisashi Shirakawa, Satoshi Asai, and Shuji Kaneko
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olanzapine ,vitamin D ,C2C12 cells ,dyslipidemia ,clinical big data ,low-density lipoprotein ,Therapeutics. Pharmacology ,RM1-950 - Abstract
Olanzapine is an atypical antipsychotic drug that is clinically applied in patients with schizophrenia. It increases the risk of dyslipidemia, a disturbance of lipid metabolic homeostasis, usually characterized by increased low-density lipoprotein (LDL) cholesterol and triglycerides, and accompanied by decreased high-density lipoprotein (HDL) in the serum. In this study, analyzing the FDA Adverse Event Reporting System, JMDC insurance claims, and electronic medical records from Nihon University School of Medicine revealed that a co-treated drug, vitamin D, can reduce the incidence of olanzapine-induced dyslipidemia. In the following experimental validations of this hypothesis, short-term oral olanzapine administration in mice caused a simultaneous increase and decrease in the levels of LDL and HDL cholesterol, respectively, while the triglyceride level remained unaffected. Cholecalciferol supplementation attenuated these deteriorations in blood lipid profiles. RNA-seq analysis was conducted on three cell types that are closely related to maintaining cholesterol metabolic balance (hepatocytes, adipocytes, and C2C12) to verify the direct effects of olanzapine and the functional metabolites of cholecalciferol (calcifediol and calcitriol). Consequently, the expression of cholesterol-biosynthesis-related genes was reduced in calcifediol- and calcitriol-treated C2C12 cells, which was likely to be mediated by activating the vitamin D receptor that subsequently inhibited the cholesterol biosynthesis process via insulin-induced gene 2 regulation. This clinical big-data-based drug repurposing approach is effective in finding a novel treatment with high clinical predictability and a well-defined molecular mechanism.
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- 2023
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9. Enhancement of adenosine A2A signaling improves dopamine D2 receptor antagonist-induced dyskinesia via β-arrestin signaling
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Koki Nagaoka, Nozomi Asaoka, Kazuki Nagayasu, Hisashi Shirakawa, and Shuji Kaneko
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adenosine A2A receptor ,β-arrestin ,dopamine D2 receptor ,indirect pathway medium spiny neuron ,tardive dyskinesia ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Repeated administration of dopamine D2 receptor (D2R) antagonists, which is the treatment for psychosis, often causes tardive dyskinesia (TD). Despite notable clinical demand, effective treatment for TD has not been established yet. The neural mechanism involving the hyperinhibition of indirect pathway medium spiny neurons (iMSNs) in the striatum is considered one of the main causes of TD. In this study, we focused on adenosine A2A receptors (A2ARs) expressed in iMSNs and investigated whether pharmacological activation of A2ARs improves dyskinetic symptoms in a TD mouse model. A 21-day treatment with haloperidol increased the number of vacuous chewing movements (VCMs) and decreased the number of c-Fos+/ppENK+ iMSNs in the dorsal striatum. Haloperidol-induced VCMs were reduced by acute intraperitoneal administration of an A2AR agonist, CGS 21680A. Consistently, haloperidol-induced VCMs and decrease in the number of c-Fos+/ppENK+ iMSNs were also mitigated by intrastriatal injection of CGS 21680A. The effects of intrastriatal CGS 21680A were not observed when it was concomitantly administered with a β-arrestin inhibitor, barbadin. Finally, intrastriatal injection of an arrestin-biased D2R agonist, UNC9994, also inhibited haloperidol-induced VCMs. These results suggest that A2AR agonists mitigate TD symptoms by activating striatal iMSNs via β-arrestin signaling.
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- 2023
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10. Lisinopril prevents bullous pemphigoid induced by dipeptidyl peptidase 4 inhibitors via the Mas receptor pathway
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Keisuke Nozawa, Takahide Suzuki, Gen Kayanuma, Hiroki Yamamoto, Kazuki Nagayasu, Hisashi Shirakawa, and Shuji Kaneko
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bullous pemphigoid ,dipeptidyl peptidase 4 inhibitor ,lisinopril ,Mas receptor ,FDA Adverse Event Reporting System ,IBM® MarketScan® Research databases ,Immunologic diseases. Allergy ,RC581-607 - Abstract
Recent studies have suggested that dipeptidyl peptidase 4 (DPP4) inhibitors increase the risk of development of bullous pemphigoid (BP), which is the most common autoimmune blistering skin disease; however, the associated mechanisms remain unclear, and thus far, no therapeutic targets responsible for drug-induced BP have been identified. Therefore, we used clinical data mining to identify candidate drugs that can suppress DPP4 inhibitor-associated BP, and we experimentally examined the underlying molecular mechanisms using human peripheral blood mononuclear cells (hPBMCs). A search of the US Food and Drug Administration Adverse Event Reporting System and the IBM® MarketScan® Research databases indicated that DPP4 inhibitors increased the risk of BP, and that the concomitant use of lisinopril, an angiotensin-converting enzyme inhibitor, significantly decreased the incidence of BP in patients receiving DPP4 inhibitors. Additionally, in vitro experiments with hPBMCs showed that DPP4 inhibitors upregulated mRNA expression of MMP9 and ACE2, which are responsible for the pathophysiology of BP in monocytes/macrophages. Furthermore, lisinopril and Mas receptor (MasR) inhibitors suppressed DPP4 inhibitor-induced upregulation of MMP9. These findings suggest that the modulation of the renin-angiotensin system, especially the angiotensin1-7/MasR axis, is a therapeutic target in DPP4 inhibitor-associated BP.
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- 2023
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11. MrgprB4 in trigeminal neurons expressing TRPA1 modulates unpleasant sensations
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Shota Tobori, Haruka Hiyama, Takahito Miyake, Yuichi Yano, Kazuki Nagayasu, Hisashi Shirakawa, Takayuki Nakagawa, Yasuo Mori, and Shuji Kaneko
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Sensory behavior ,Hairy skin ,MrgprB4 ,TRPA1 ,Trigeminal ganglion ,Therapeutics. Pharmacology ,RM1-950 - Abstract
Gentle touch such as stroking of the skin produces a pleasant feeling, which is detected by a rare subset of sensory neurons that express Mas-related G protein-coupled receptor B4 (MrgprB4) in mice. We examined small populations of MrgprB4-positive neurons in the trigeminal ganglion and the dorsal root ganglion, and most of these were sensitive to transient receptor potential ankyrin 1 (TRPA1) agonist but not TRPV1, TRPM8, or TRPV4 agonists. Deficiency of MrgprB4 did not affect noxious pain or itch behaviors in the hairless plantar and hairy cheek. Although behavior related to acetone-induced cold sensing in the hind paw was not changed, unpleasant sensory behaviors in response to acetone application or sucrose splash to the cheek were significantly enhanced in Mrgprb4-knockout mice as well as in TRPA1-knockout mice. These results suggest that MrgprB4 in the trigeminal neurons produces pleasant sensations in cooperation with TRPA1, rather than noxious or cold sensations. Pleasant sensations may modulate unpleasant sensations on the cheek via MrgprB4.
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- 2021
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12. Prediction of pharmacological activities from chemical structures with graph convolutional neural networks
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Miyuki Sakai, Kazuki Nagayasu, Norihiro Shibui, Chihiro Andoh, Kaito Takayama, Hisashi Shirakawa, and Shuji Kaneko
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Medicine ,Science - Abstract
Abstract Many therapeutic drugs are compounds that can be represented by simple chemical structures, which contain important determinants of affinity at the site of action. Recently, graph convolutional neural network (GCN) models have exhibited excellent results in classifying the activity of such compounds. For models that make quantitative predictions of activity, more complex information has been utilized, such as the three-dimensional structures of compounds and the amino acid sequences of their respective target proteins. As another approach, we hypothesized that if sufficient experimental data were available and there were enough nodes in hidden layers, a simple compound representation would quantitatively predict activity with satisfactory accuracy. In this study, we report that GCN models constructed solely from the two-dimensional structural information of compounds demonstrated a high degree of activity predictability against 127 diverse targets from the ChEMBL database. Using the information entropy as a metric, we also show that the structural diversity had less effect on the prediction performance. Finally, we report that virtual screening using the constructed model identified a new serotonin transporter inhibitor with activity comparable to that of a marketed drug in vitro and exhibited antidepressant effects in behavioural studies.
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- 2021
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13. Peripheral Beta-2 Adrenergic Receptors Mediate the Sympathetic Efferent Activation from Central Nervous System to Splenocytes in a Mouse Model of Fibromyalgia
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Shiori Yamashita, Naoki Dozono, Shota Tobori, Kazuki Nagayasu, Shuji Kaneko, Hisashi Shirakawa, and Hiroshi Ueda
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fibromyalgia ,adrenergic receptors ,central nervous system ,AcGP model ,splenocytes ,sympathetic efferent ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Abnormalities in the peripheral immune system are involved in the pathophysiology of fibromyalgia, although their contribution to the painful symptoms remains unknown. Our previous study reported the ability of splenocytes to develop pain-like behavior and an association between the central nervous system (CNS) and splenocytes. Since the spleen is directly innervated by sympathetic nerves, this study aimed to examine whether adrenergic receptors are necessary for pain development or maintenance using an acid saline-induced generalized pain (AcGP) model (an experimental model of fibromyalgia) and whether the activation of these receptors is also essential for pain reproduction by the adoptive transfer of AcGP splenocytes. The administration of selective β2-blockers, including one with only peripheral action, prevented the development but did not reverse the maintenance of pain-like behavior in acid saline-treated C57BL/6J mice. Neither a selective α1-blocker nor an anticholinergic drug affects the development of pain-like behavior. Furthermore, β2-blockade in donor AcGP mice eliminated pain reproduction in recipient mice injected with AcGP splenocytes. These results suggest that peripheral β2-adrenergic receptors play an important role in the efferent pathway from the CNS to splenocytes in pain development.
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- 2023
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14. Striatal TRPV1 activation by acetaminophen ameliorates dopamine D2 receptor antagonist–induced orofacial dyskinesia
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Koki Nagaoka, Takuya Nagashima, Nozomi Asaoka, Hiroki Yamamoto, Chihiro Toda, Gen Kayanuma, Soni Siswanto, Yasuhiro Funahashi, Keisuke Kuroda, Kozo Kaibuchi, Yasuo Mori, Kazuki Nagayasu, Hisashi Shirakawa, and Shuji Kaneko
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Neuroscience ,Medicine - Abstract
Antipsychotics often cause tardive dyskinesia, an adverse symptom of involuntary hyperkinetic movements. Analysis of the US Food and Drug Administration Adverse Event Reporting System and JMDC insurance claims revealed that acetaminophen prevented the dyskinesia induced by dopamine D2 receptor antagonists. In vivo experiments further showed that a 21-day treatment with haloperidol increased the number of vacuous chewing movements (VCMs) in rats, an effect that was inhibited by oral acetaminophen treatment or intracerebroventricular injection of N-(4-hydroxyphenyl)-arachidonylamide (AM404), an acetaminophen metabolite that acts as an activator of the transient receptor potential vanilloid 1 (TRPV1). In mice, haloperidol-induced VCMs were also mitigated by treatment with AM404 applied to the dorsal striatum, an effect not seen in TRPV1-deficient mice. Acetaminophen prevented the haloperidol-induced decrease in the number of c-Fos+preproenkephalin+ striatal neurons in wild-type mice but not in TRPV1-deficient mice. Finally, chemogenetic stimulation of indirect pathway medium spiny neurons in the dorsal striatum decreased haloperidol-induced VCMs. These results suggest that acetaminophen activates the indirect pathway neurons by activating TRPV1 channels via AM404.
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- 2021
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15. Myelin Oligodendrocyte Glycoprotein 35-55 (MOG 35-55)-induced Experimental Autoimmune Encephalomyelitis: A Model of Chronic Multiple Sclerosis
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Sakie Miyamura, Nagisa Matsuo, Kazuki Nagayasu, Hisashi Shirakawa, and Shuji Kaneko
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Biology (General) ,QH301-705.5 - Abstract
Multiple sclerosis (MS) is the common demyelinating disease of human central nervous system. Among mouse models available to study MS, including the cuprizone application and lysolecithin-injection models, experimental autoimmune encephalomyelitis (EAE) model is widely used so that chronic EAE model of C57BL/6J can reflect the autoimmune pathogenesis of MS well. Here we introduce the EAE model based on C57BL/6J mice, which is generated by injection of myelin oligodendrocyte glycoprotein 35-55 (MOG 35-55) as an antigen. After immunization with complete Freund's adjuvant, clinical signs and changes in body weight are observed one or two weeks later. The EAE model will continue to be useful for development of therapeutics for MS.
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- 2019
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16. Cold sensitivity of TRPA1 is unveiled by the prolyl hydroxylation blockade-induced sensitization to ROS
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Takahito Miyake, Saki Nakamura, Meng Zhao, Kanako So, Keisuke Inoue, Tomohiro Numata, Nobuaki Takahashi, Hisashi Shirakawa, Yasuo Mori, Takayuki Nakagawa, and Shuji Kaneko
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Science - Abstract
The transient receptor potential ankyrin 1 (TRPA1) is a cation channel that is involved in nociceptive pain sensing. Here, the authors show that hydroxylation of a proline in the N terminus of TRPA1 renders it sensitive to reactive oxygen species resulting from noxious cold.
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- 2016
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17. The Role of Dorsal Raphe Serotonin Neurons in the Balance between Reward and Aversion
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Yuma Nagai, Kaito Takayama, Naoya Nishitani, Chihiro Andoh, Masashi Koda, Hisashi Shirakawa, Takayuki Nakagawa, Kazuki Nagayasu, Akihiro Yamanaka, and Shuji Kaneko
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serotonin ,optogenetics ,reward ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Background: Reward processing is fundamental for animals to survive and reproduce. Many studies have shown the importance of dorsal raphe nucleus (DRN) serotonin (5-HT) neurons in this process, but the strongly correlative link between the activity of DRN 5-HT neurons and rewarding/aversive potency is under debate. Our primary objective was to reveal this link using two different strategies to transduce DRN 5-HT neurons. Methods: For transduction of 5-HT neurons in wildtype mice, adeno-associated virus (AAV) bearing the mouse tryptophan hydroxylase 2 (TPH2) gene promoter was used. For transduction in Tph2-tTA transgenic mice, AAVs bearing the tTA-dependent TetO enhancer were used. To manipulate the activity of 5-HT neurons, optogenetic actuators (CheRiff, eArchT) were expressed by AAVs. For measurement of rewarding/aversive potency, we performed a nose-poke self-stimulation test and conditioned place preference (CPP) test. Results: We found that stimulation of DRN 5-HT neurons and their projections to the ventral tegmental area (VTA) increased the number of nose-pokes in self-stimulation test and CPP scores in both targeting methods. Concomitantly, CPP scores were decreased by inhibition of DRN 5-HT neurons and their projections to VTA. Conclusion: Our findings indicate that the activity of DRN 5-HT neurons projecting to the VTA is a key modulator of balance between reward and aversion.
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- 2020
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18. Distinct Mechanism of Cysteine Oxidation-Dependent Activation and Cold Sensitization of Human Transient Receptor Potential Ankyrin 1 Channel by High and Low Oxaliplatin
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Takahito Miyake, Saki Nakamura, Zhao Meng, Satoshi Hamano, Keisuke Inoue, Tomohiro Numata, Nobuaki Takahashi, Kazuki Nagayasu, Hisashi Shirakawa, Yasuo Mori, Takayuki Nakagawa, and Shuji Kaneko
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TRPA1 ,oxaliplatin ,reactive oxygen species ,cold hypersensitivity ,prolyl hydroxylase ,cysteine oxidation ,Physiology ,QP1-981 - Abstract
Oxaliplatin, a third-generation platinum-based chemotherapeutic agent, displays unique acute peripheral neuropathy triggered or enhanced by cold, and accumulating evidence suggests that transient receptor potential ankyrin 1 (TRPA1) is responsible. TRPA1 is activated by oxaliplatin via a glutathione-sensitive mechanism. However, oxaliplatin interrupts hydroxylation of a proline residue located in the N-terminal region of TRPA1 via inhibition of prolyl hydroxylase (PHD), which causes sensitization of TRPA1 to reactive oxygen species (ROS). Furthermore, PHD inhibition endows cold-insensitive human TRPA1 (hTRPA1) with ROS-dependent cold sensitivity. Since cysteine oxidation and proline hydroxylation regulate its activity, their association with oxaliplatin-induced TRPA1 activation and acquirement of cold sensitivity were investigated in the present study. A high concentration of oxaliplatin (1 mM) induced outward-rectifier whole-cell currents and increased the intracellular Ca2+ concentration in hTRPA1-expressing HEK293 cells, but did not increase the probability of hTRPA1 channel opening in the inside-out configuration. Oxaliplatin also induced the rapid generation of hydrogen peroxide, and the resultant Ca2+ influx was prevented in the presence of glutathione and in cysteine-mutated hTRPA1 (Cys641Ser)-expressing cells, whereas proline-mutated hTRPA1 (Pro394Ala)-expressing cells showed similar whole-cell currents and Ca2+ influx. By contrast, a lower concentration of oxaliplatin (100 μM) did not increase the intracellular Ca2+ concentration but did confer cold sensitivity on hTRPA1-expressing cells, and this was inhibited by PHD2 co-overexpression. Cold sensitivity was abolished by the mitochondria-targeting ROS scavenger mitoTEMPO and was minimal in cysteine-mutated hTRPA1 (Cys641Ser or Cys665Ser)-expressing cells. Thus, high oxaliplatin evokes ROS-mediated cysteine oxidation-dependent hTRPA1 activation independent of PHD activity, while a lower concentration induces cold-induced cysteine oxidation-dependent opening of hTRPA1 via PHD inhibition.
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- 2017
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19. Pathophysiological Role of Transient Receptor Potential Ankyrin 1 in a Mouse Long-Lasting Cystitis Model Induced by an Intravesical Injection of Hydrogen Peroxide
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Shohei Oyama, Koji Dogishi, Mizuki Kodera, Masashi Kakae, Kazuki Nagayasu, Hisashi Shirakawa, Takayuki Nakagawa, and Shuji Kaneko
- Subjects
TRPA1 ,cystitis ,hydrogen peroxide ,mouse model ,chronic inflammatory bladder ,gene knockout ,Physiology ,QP1-981 - Abstract
Chronic inflammatory bladder disorders, such as interstitial cystitis/bladder pain syndrome, are associated with poor quality of life. The exact pathological processes remain unclear, but accumulating evidence suggests that reactive oxidative species (ROS) are involved in urinary bladder disorders. Transient receptor potential ankyrin 1 (TRPA1), the most sensitive TRP channel to ROS, was shown to be responsible for urinary bladder abnormalities and hyperalgesia in an acute cystitis model. However, the roles of TRPA1 in chronic inflammatory bladder are not fully understood. We previously established a novel mouse cystitis model induced by intravesical injection of hydrogen peroxide (H2O2), resulting in long-lasting frequent urination, bladder inflammation, pain-related behavior, and histopathological changes. In the present study, we investigated the pathophysiological role of TRPA1 in the H2O2-induced long-lasting cystitis mouse model. Under anesthesia, 1.5% H2O2 solution was introduced transurethrally into the bladder of female wild-type (WT) and TRPA1-knockout mice and maintained for 30 min. This increased the number of voids in WT mice at 1 and 7 days after injection, but reduced the number in TRPA1-knockout mice at 1 day but not 7 days after injection. Spontaneous locomotor activities (increase in freezing time and decrease in distance moved) were reduced at 3 h after injection in WT mice, whereas the spontaneous visceral pain-related behaviors were attenuated in TRPA1-knockout mice. Furthermore, upregulation of c-fos mRNA in the spinal cord at 1 day after injection was observed in WT but not TRPA1-knockout mice. However, there was no difference in histopathological changes in the urinary bladder, such as edematous thickening in the submucosa, between WT and TRPA1-knockout mice at 1 or 7 days after injection. Finally, Trpa1 mRNA levels in the L5-S1 dorsal root ganglion were not altered, but levels in the urinary bladder were drastically increased at 1 and 7 days after injection. Taken together, these results suggest that TRPA1 contributes to acute bladder hyperactivity such as frequent urination and bladder pain, but does not appear to play a major role in the pathological processes of long-lasting cystitis.
- Published
- 2017
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20. Involvement of TRPM2 in a wide range of inflammatory and neuropathic pain mouse models
- Author
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Kanako So, Kayo Haraguchi, Kayoko Asakura, Koichi Isami, Shinya Sakimoto, Hisashi Shirakawa, Yasuo Mori, Takayuki Nakagawa, and Shuji Kaneko
- Subjects
TRPM2 ,Inflammatory pain ,Neuropathic pain ,Pain models ,Knockout mice ,Therapeutics. Pharmacology ,RM1-950 - Abstract
Recent evidence suggests a role of transient receptor potential melastatin 2 (TRPM2) in immune and inflammatory responses. We previously reported that TRPM2 deficiency attenuated inflammatory and neuropathic pain in some pain mouse models, including formalin- or carrageenan-induced inflammatory pain, and peripheral nerve injury-induced neuropathic pain models, while it had no effect on the basal mechanical and thermal nociceptive sensitivities. In this study, we further explored the involvement of TRPM2 in various pain models using TRPM2-knockout mice. There were no differences in the chemonociceptive behaviors evoked by intraplantar injection of capsaicin or hydrogen peroxide between wildtype and TRPM2-knockout mice, while acetic acid-induced writhing behavior was significantly attenuated in TRPM2-knockout mice. In the postoperative incisional pain model, no difference in mechanical allodynia was observed between the two genotypes. By contrast, mechanical allodynia in the monosodium iodoacetate-induced osteoarthritis pain model and the experimental autoimmune encephalomyelitis model were significantly attenuated in TRPM2-knockout mice. Furthermore, mechanical allodynia in paclitaxel-induced peripheral neuropathy and streptozotocin-induced painful diabetic neuropathy models were significantly attenuated in TRPM2-knockout mice. Taken together, these results suggest that TRPM2 plays roles in a wide range of pathological pain models based on peripheral and central neuroinflammation, rather than physiological nociceptive pain.
- Published
- 2015
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21. Long-lasting pain-related behaviors in mouse chronic cystitis model induced by a single intravesical injection of hydrogen peroxide
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Koji Dogishi, Mizuki Kodera, Shohei Oyama, Hisashi Shirakawa, Takayuki Nakagawa, and Shuji Kaneko
- Subjects
Chronic cystitis ,Hydrogen peroxide ,Painful bladder syndrome ,Therapeutics. Pharmacology ,RM1-950 - Abstract
We previously established a long-lasting cystitis model by an intravesical injection of hydrogen peroxide (H2O2) into mice. In this study, we assessed the pain-related behaviors in the cystitis model. An intravesical injection of 1.5% H2O2 transiently decreased spontaneous locomotor activity at 3 h after injection, indicative of acute spontaneous pain. In contrast, licking response to a bladder distention was slowly observed as licks to the lower abdomen at 7 and 14 days after injection, which was attenuated by amitriptyline and morphine, but not by oxybutynin. These results suggest that H2O2-induced chronic cystitis model shows delayed and long-lasting painful pathological condition.
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- 2015
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22. Pharmacological Characterization of Standard Analgesics on Oxaliplatin-Induced Acute Cold Hypersensitivity in Mice
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Meng Zhao, Saki Nakamura, Takahito Miyake, Kanako So, Hisashi Shirakawa, Shogo Tokuyama, Minoru Narita, Takayuki Nakagawa, and Shuji Kaneko
- Subjects
Therapeutics. Pharmacology ,RM1-950 - Abstract
Oxaliplatin, a platinum-based chemotherapeutic agent, causes an acute peripheral neuropathy triggered by cold in almost all patients during or within hours after its infusion. We recently reported that a single administration of oxaliplatin induced cold hypersensitivity 2 h after the administration in mice. In this study, we examined whether standard analgesics relieve the oxaliplatin-induced acute cold hypersensitivity. Gabapentin, tramadol, mexiletine, and calcium gluconate significantly inhibited and morphine and milnacipran decreased the acute cold hypersensitivity, while diclofenac and amitriptyline had no effects. These results suggest that gabapentin, tramadol, mexiletine, and calcium gluconate are effective against oxaliplatin-induced acute peripheral neuropathy. Keywords:: oxaliplatin, acute peripheral neuropathy, analgesic
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- 2014
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23. Preventive and Alleviative Effect of Tramadol on Neuropathic Pain in Rats: Roles of α2-Adrenoceptors and Spinal Astrocytes
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Minoru Sakakiyama, Sanae Maeda, Kouichi Isami, Kayoko Asakura, Kanako So, Hisashi Shirakawa, Takayuki Nakagawa, and Shuji Kaneko
- Subjects
Therapeutics. Pharmacology ,RM1-950 - Abstract
The acute analgesic effect of tramadol has been extensively investigated; however, its long-term effect on neuropathic pain has not been well clarified. In this study, we examined the effects of repeated administration of tramadol on partial sciatic nerve ligation–induced neuropathic pain in rats. Each drug was administered once daily from 0 – 6 days (preventive effect) or 7 – 14 days (alleviative effect) after the surgery. Mechanical allodynia was evaluated just before (preventive or alleviative effect) and 1 h after (analgesic effect) drug administration. Like morphine, first administration of tramadol (20 mg/kg) showed an acute analgesic effect on the developed mechanical allodynia, which was diminished by naloxone. Like amitriptyline, repeated administration of tramadol showed preventive and alleviative effects on the mechanical allodynia that was diminished by yohimbine, but not naloxone. The alleviative effects of tramadol lasted even after drug cessation or in the presence of yohimbine. Repeated administration of tramadol increased the dopamine β-hydroxylase immunoreactivity in the spinal cord. Furthermore, tramadol inhibited the nerve ligation–induced activation of spinal astrocytes, which was reduced by yohimbine. These results suggest that tramadol has both μ-opioid receptor–mediated acute analgesic and α2-adrenoceptor–mediated preventive and alleviative effects on neuropathic pain, and the latter is due to α2-adrenoceptor–mediated inhibition of astrocytic activation. Keywords:: tramadol, neuropathic pain, antidepressant, α2-adrenoceptor, astrocyte
- Published
- 2014
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24. A Novel Mouse Model of Chronic Inflammatory and Overactive Bladder by a Single Intravesical Injection of Hydrogen Peroxide
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Takashi Homan, Tetsunori Tsuzuki, Koji Dogishi, Hisashi Shirakawa, Tatsuya Oyama, Takayuki Nakagawa, and Shuji Kaneko
- Subjects
Therapeutics. Pharmacology ,RM1-950 - Abstract
Abstract.: There is so far no generally accepted animal model of chronic cystitis by which potential therapies can be evaluated. In this study, we aimed to establish a new mouse model of cystitis based on the proinflammatory effects of reactive oxygen species. A single intravesical injection of 1.5% hydrogen peroxide (H2O2) significantly increased the numbers of voids by 1 day after injection in female mice, which lasted up to 7 days. The H2O2 injection rapidly increased the bladder weight by 3 h in parallel with the histological damage and hyperpermeability of urothelial barrier. Although the urothelial dysfunction was recovered to normal by 7 days, increase in bladder weight, edematous thickening of the submucosa, and vascular hyperpermeability were apparent even 7 days after injection. During the time course, massive infiltration of neutrophils and increased expression of inflammatory cytokines were observed in the bladder. An intraperitoneal administration of oxybutynin, amitriptyline, indomethacin, or morphine attenuated the H2O2-induced frequent urination. These findings suggest that an intravesical injection of H2O2 induces relatively long-lasting inflammatory and overactive bladder, compared with existing cystitis models. The intravesical H2O2 injection model may be a simple and useful tool in the pathological study and drug discovery for chronic cystitis.[Supplementary Figure: available only at http://dx.doi.org/10.1254/jphs.12265FP] Keywords:: chronic cystitis, hydrogen peroxide, interstitial cystitis, overactive bladder, long-lasting
- Published
- 2013
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25. Sustained Exposure to 3,4-Methylenedioxymethamphetamine Induces the Augmentation of Exocytotic Serotonin Release in Rat Organotypic Raphe Slice Cultures
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Kazuki Nagayasu, Maiko Kitaichi, Hisashi Shirakawa, Takayuki Nakagawa, and Shuji Kaneko
- Subjects
Therapeutics. Pharmacology ,RM1-950 - Abstract
3,4-Methylenedioxymethamphetamine (MDMA) causes serotonin efflux via serotonin transporter. Recently, we have reported that sustained exposure to MDMA induced an augmentation of serotonin release in rat raphe serotonergic slice cultures. Here we investigated the mechanism of augmented serotonin release from the slice cultures. Sustained MDMA exposure had no effect on MDMA-induced serotonin efflux in the synaptosomal fraction, whereas either tetrodotoxin, calcium channel inhibitors, or AMPA-receptor antagonists significantly attenuated the augmented serotonin release. These results suggest that the increase in Ca2+-dependent exocytotic serotonin release is mediated through activation of AMPA receptors and responsible for the sustained MDMA-induced augmentation of serotonin release. Keywords:: serotonin (5-HT), 3,4-methylenedioxymethamphetamine (MDMA), slice culture
- Published
- 2010
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26. Involvement of TRPM2 in peripheral nerve injury-induced infiltration of peripheral immune cells into the spinal cord in mouse neuropathic pain model.
- Author
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Kouichi Isami, Kayo Haraguchi, Kanako So, Kayoko Asakura, Hisashi Shirakawa, Yasuo Mori, Takayuki Nakagawa, and Shuji Kaneko
- Subjects
Medicine ,Science - Abstract
Recent evidence suggests that transient receptor potential melastatin 2 (TRPM2) expressed in immune cells plays an important role in immune and inflammatory responses. We recently reported that TRPM2 expressed in macrophages and spinal microglia contributes to the pathogenesis of inflammatory and neuropathic pain aggravating peripheral and central pronociceptive inflammatory responses in mice. To further elucidate the contribution of TRPM2 expressed by peripheral immune cells to neuropathic pain, we examined the development of peripheral nerve injury-induced neuropathic pain and the infiltration of immune cells (particularly macrophages) into the injured nerve and spinal cord by using bone marrow (BM) chimeric mice by crossing wildtype (WT) and TRPM2-knockout (TRPM2-KO) mice. Four types of BM chimeric mice were prepared, in which irradiated WT or TRPM2-KO recipient mice were transplanted with either WT-or TRPM2-KO donor mouse-derived green fluorescence protein-positive (GFP(+)) BM cells (TRPM2(BM+/Rec+), TRPM2(BM-/Rec+), TRPM2(BM+/Rec-), and TRPM2(BM-/Rec-) mice). Mechanical allodynia induced by partial sciatic nerve ligation observed in TRPM2(BM+/Rec+) mice was attenuated in TRPM2(BM-/Rec+), TRPM2(BM+/Rec-), and TRPM2(BM-/Rec-) mice. The numbers of GFP(+) BM-derived cells and Iba1/GFP double-positive macrophages in the injured sciatic nerve did not differ among chimeric mice 14 days after the nerve injury. In the spinal cord, the number of GFP(+) BM-derived cells, particularly GFP/Iba1 double-positive macrophages, was significantly decreased in the three TRPM2-KO chimeric mouse groups compared with TRPM2(BM+/Rec+) mice. However, the numbers of GFP(-)/Iba1(+) resident microglia did not differ among chimeric mice. These results suggest that TRPM2 plays an important role in the infiltration of peripheral immune cells, particularly macrophages, into the spinal cord, rather than the infiltration of peripheral immune cells into the injured nerves and activation of spinal-resident microglia. The spinal infiltration of macrophages mediated by TRPM2 may contribute to the pathogenesis of neuropathic pain.
- Published
- 2013
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27. Repeated exposure to methamphetamine, cocaine or morphine induces augmentation of dopamine release in rat mesocorticolimbic slice co-cultures.
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Takayuki Nakagawa, Yuichi Suzuki, Kazuki Nagayasu, Maiko Kitaichi, Hisashi Shirakawa, and Shuji Kaneko
- Subjects
Medicine ,Science - Abstract
Repeated intermittent exposure to psychostimulants and morphine leads to progressive augmentation of its locomotor activating effects in rodents. Accumulating evidence suggests the critical involvement of the mesocorticolimbic dopaminergic neurons, which project from the ventral tegmental area to the nucleus accumbens and the medial prefrontal cortex, in the behavioral sensitization. Here, we examined the acute and chronic effects of psychostimulants and morphine on dopamine release in a reconstructed mesocorticolimbic system comprised of a rat triple organotypic slice co-culture of the ventral tegmental area, nucleus accumbens and medial prefrontal cortex regions. Tyrosine hydroxylase-positive cell bodies were localized in the ventral tegmental area, and their neurites projected to the nucleus accumbens and medial prefrontal cortex regions. Acute treatment with methamphetamine (0.1-1000 µM), cocaine (0.1-300 µM) or morphine (0.1-100 µM) for 30 min increased extracellular dopamine levels in a concentration-dependent manner, while 3,4-methylenedioxyamphetamine (0.1-1000 µM) had little effect. Following repeated exposure to methamphetamine (10 µM) for 30 min every day for 6 days, the dopamine release gradually increased during the 30-min treatment. The augmentation of dopamine release was maintained even after the withdrawal of methamphetamine for 7 days. Similar augmentation was observed by repeated exposure to cocaine (1-300 µM) or morphine (10 and 100 µM). Furthermore, methamphetamine-induced augmentation of dopamine release was prevented by an NMDA receptor antagonist, MK-801 (10 µM), and was not observed in double slice co-cultures that excluded the medial prefrontal cortex slice. These results suggest that repeated psychostimulant- or morphine-induced augmentation of dopamine release, i.e. dopaminergic sensitization, was reproduced in a rat triple organotypic slice co-cultures. In addition, the slice co-culture system revealed that the NMDA receptors and the medial prefrontal cortex play an essential role in the dopaminergic sensitization. This in vitro sensitization model provides a unique approach for studying mechanisms underlying behavioral sensitization to drugs of abuse.
- Published
- 2011
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28. Specific Cellular Effects of Low Bortezomib Concentrations on Purified Cultures of Schwann Cells, Satellite Glial Cells, Macrophages, and Dorsal Root Ganglion Neurons
- Author
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Zijian, Zhou, Kazuki, Nagayasu, Hisashi, Shirakawa, and Shuji, Kaneko
- Subjects
Bortezomib ,Neurons ,Pharmacology ,Ganglia, Spinal ,Macrophages ,Humans ,Peripheral Nervous System Diseases ,Pharmaceutical Science ,Schwann Cells ,General Medicine ,Neuroglia ,Ion Channels - Abstract
Peripheral neuropathy is one of the major adverse effects that limit the clinical application of bortezomib (BTZ). However, the underlying mechanisms of BTZ-induced peripheral neuropathy (BIPN) remain elusive. To examine cell types potentially involved in the development of BIPN, we used four purified cultures of cells of the peripheral nervous system: Schwann cells (SCs), satellite glial cells (SGCs), macrophages, and dorsal root ganglion (DRG) neurons. Administration of a low BTZ concentration (5 nM; similar to concentrations in clinical use) caused dedifferentiation of cultured SCs, returning mature SCs to an immature state. In cultured SGCs, BTZ increased glial fibrillary acidic protein (GFAP) levels without inducing the release of inflammatory cytokines or chemokines. In macrophages, BTZ caused little inflammatory response. Finally, in DRG neurons, BTZ strongly suppressed the expression levels of sensor and transducer ion channels without affecting cell morphology. Taken together, low concentrations of BTZ can cause SC dedifferentiation (i.e., demyelination), increased GFAP level in SGC, and decreased expression levels of sensor and transducer ion channels in DRG neurons (i.e., numbness feeling). Thus, we have reported, for the first time, specific effects of BTZ on peripheral nervous system cells, thereby contributing to a better understanding of the initiating mechanism of BIPN.
- Published
- 2023
29. Diff-ATAC-STARR-Seq: A Method for Genome-Wide Functional Screening of Enhancer Activity in Vivo
- Author
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Kazuki Nagayasu, Chihiro Andoh, Hisashi Shirakawa, and Shuji Kaneko
- Subjects
Pharmacology ,Pharmaceutical Science ,General Medicine - Published
- 2022
30. Autism Spectrum Disorder Model Mice Induced by Prenatal Exposure to Valproic Acid Exhibit Enhanced Empathy-Like Behavior via Oxytocinergic Signaling
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Kaito Takayama, Shota Tobori, Chihiro Andoh, Masashi Kakae, Masako Hagiwara, Kazuki Nagayasu, Hisashi Shirakawa, Yukio Ago, and Shuji Kaneko
- Subjects
Pharmacology ,Behavior, Animal ,Autism Spectrum Disorder ,Valproic Acid ,Pharmaceutical Science ,General Medicine ,Disease Models, Animal ,Mice ,Pregnancy ,Prenatal Exposure Delayed Effects ,Animals ,Humans ,Female ,Empathy ,Social Behavior - Abstract
Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by core symptoms, including impairments in social behavior and repetitive interests. Recent studies have revealed that individuals with ASD also display decreased empathy, ultimately leading to difficulties in social relationships; however, another report indicated that individuals with ASD have enhanced emotional empathy. Nonetheless, the neurobiological mechanisms underlying altered empathy in individuals with ASD remain unclear. In this study, we assessed empathy-like behaviors in valproic acid (VPA)-treated mice-a mouse model of ASD with observational fear learning. We then investigated the brain regions and signaling systems responsible for the altered empathy-like behaviors in VPA-treated mice. As a result, mice prenatally exposed to VPA displayed increased empathy-like behaviors, which were not attributed to altered sensitivity to auditory stimuli or enhanced memory for pain-related contexts. Immunohistochemical analysis revealed that the number of c-Fos positive oxytocinergic neurons in the paraventricular nucleus of the hypothalamus (PVN) was significantly higher in VPA-treated mice after observational fear learning. Finally, we found that pretreatment with L-368899, an antagonist of the oxytocin receptor, repressed the empathetic behavior in VPA-treated mice. These results suggest that VPA-treated ASD model animals showed increased emotional empathy-like behaviors through the hyperactivation of PVN oxytocinergic neurons for the first time. Further investigation of this hyperactivity will help to identify extrinsic stimuli and the condition which are capable of activation of PVN oxytocinergic neurons and to identify novel approach to enhance oxytocin signaling, which ultimately pave the way to development of novel therapy for ASD.
- Published
- 2022
31. Orai2 channel regulates prostaglandin <scp> E 2 </scp> production in <scp>TNFα</scp> / <scp>IL1α</scp> ‐stimulated astrocytes
- Author
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Hiroki Nakajima, Sayaka Fujita, Masashi Kakae, Kazuki Nagayasu, Masatsugu Oh‐hora, Hisashi Shirakawa, and Shuji Kaneko
- Subjects
Cellular and Molecular Neuroscience ,Neurology - Published
- 2022
32. MrgprB4 in trigeminal neurons expressing TRPA1 modulates unpleasant sensations
- Author
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Shuji Kaneko, Shota Tobori, Haruka Hiyama, Hisashi Shirakawa, Takayuki Nakagawa, Takahito Miyake, Kazuki Nagayasu, Yuichi Yano, and Yasuo Mori
- Subjects
Male ,0301 basic medicine ,TRPV4 ,Agonist ,Sensory Receptor Cells ,medicine.drug_class ,Sensation ,TRPV1 ,Gene Expression ,Sensory system ,RM1-950 ,TRPA1 ,Receptors, G-Protein-Coupled ,03 medical and health sciences ,Trigeminal ganglion ,Transient receptor potential channel ,0302 clinical medicine ,Dorsal root ganglion ,Skin Physiological Phenomena ,TRPM8 ,Animals ,Medicine ,TRPA1 Cation Channel ,Mice, Knockout ,Pharmacology ,business.industry ,Hairy skin ,Mice, Inbred C57BL ,030104 developmental biology ,medicine.anatomical_structure ,Sensory behavior ,MrgprB4 ,Molecular Medicine ,Female ,Therapeutics. Pharmacology ,business ,Neuroscience ,030217 neurology & neurosurgery ,psychological phenomena and processes - Abstract
Gentle touch such as stroking of the skin produces a pleasant feeling, which is detected by a rare subset of sensory neurons that express Mas-related G protein-coupled receptor B4 (MrgprB4) in mice. We examined small populations of MrgprB4-positive neurons in the trigeminal ganglion and the dorsal root ganglion, and most of these were sensitive to transient receptor potential ankyrin 1 (TRPA1) agonist but not TRPV1, TRPM8, or TRPV4 agonists. Deficiency of MrgprB4 did not affect noxious pain or itch behaviors in the hairless plantar and hairy cheek. Although behavior related to acetone-induced cold sensing in the hind paw was not changed, unpleasant sensory behaviors in response to acetone application or sucrose splash to the cheek were significantly enhanced in Mrgprb4-knockout mice as well as in TRPA1-knockout mice. These results suggest that MrgprB4 in the trigeminal neurons produces pleasant sensations in cooperation with TRPA1, rather than noxious or cold sensations. Pleasant sensations may modulate unpleasant sensations on the cheek via MrgprB4.
- Published
- 2021
33. Acetaminophen improves tardive akathisia induced by dopamine D
- Author
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Koki, Nagaoka, Kazuki, Nagayasu, Hisashi, Shirakawa, and Shuji, Kaneko
- Abstract
Tardive akathisia is a movement disorder characterized by internal restlessness with an uncontrollable urge to move, leading to repetitive movements. It is a common side effect of long-term treatment with dopamine D
- Published
- 2022
34. Characterization of Radioiodinated Diaryl Oxadiazole Derivatives as SPECT Probes for Detection of Myelin in Multiple Sclerosis
- Author
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Hiroyuki Watanabe, Rinka Maekawa, Shimpei Iikuni, Masashi Kakae, Nagisa Matsuo, Hisashi Shirakawa, Shuji Kaneko, and Masahiro Ono
- Subjects
Tomography, Emission-Computed, Single-Photon ,Mice ,Oxadiazoles ,Encephalomyelitis, Autoimmune, Experimental ,Multiple Sclerosis ,Physiology ,Cognitive Neuroscience ,Animals ,Cell Biology ,General Medicine ,Biochemistry ,Myelin Sheath - Abstract
Multiple sclerosis (MS) is an intractable disease of the central nervous system that results from destruction of the myelin sheath. Direct measurement of de- and remyelination is required for monitoring the disease stage of MS, but no useful method has been established. In this study, we characterized four diaryl oxadiazole derivatives as novel myelin-imaging probes for single photon emission computed tomography (SPECT). All the diaryl oxadiazole derivatives penetrated the blood-brain barrier in normal mice. Among them, the highest ratio of radioactivity accumulation in the white matter (myelin-rich region) against the gray matter (myelin-deficient region) was observed at 60 min postinjection of [
- Published
- 2022
35. Increased Expression of Glutathione Peroxidase 3 Prevents Tendinopathy Induced Commonly by Fluoroquinolones and Aging
- Author
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Haruka Furuta, Mari Yamada, Takuya Nagashima, Shuichi Matsuda, Kazuki Nagayasu, Hisashi Shirakawa, and Shuji Kaneko
- Subjects
History ,Polymers and Plastics ,Business and International Management ,Industrial and Manufacturing Engineering - Published
- 2022
36. Enhancement of adenosine A2A signaling improves dopamine D2 receptor antagonist-induced dyskinesia via β-arrestin signaling.
- Author
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Koki Nagaoka, Nozomi Asaoka, Kazuki Nagayasu, Hisashi Shirakawa, and Shuji Kaneko
- Abstract
Repeated administration of dopamine D
2 receptor (D2R) antagonists, which is the treatment for psychosis, often causes tardive dyskinesia (TD). Despite notable clinical demand, effective treatment for TD has not been established yet. The neural mechanism involving the hyperinhibition of indirect pathway medium spiny neurons (iMSNs) in the striatum is considered one of the main causes of TD. In this study, we focused on adenosine A2A receptors (A2ARs) expressed in iMSNs and investigated whether pharmacological activation of A2ARs improves dyskinetic symptoms in a TD mouse model. A 21-day treatment with haloperidol increased the number of vacuous chewing movements (VCMs) and decreased the number of c-Fos+ /ppENK+ iMSNs in the dorsal striatum. Haloperidol-induced VCMs were reduced by acute intraperitoneal administration of an A2AR agonist, CGS 21680A. Consistently, haloperidol-induced VCMs and decrease in the number of c-Fos+ /ppENK+ iMSNs were also mitigated by intrastriatal injection of CGS 21680A. The effects of intrastriatal CGS 21680A were not observed when it was concomitantly administered with a β-arrestin inhibitor, barbadin. Finally, intrastriatal injection of an arrestin-biased D2R agonist, UNC9994, also inhibited haloperidol-induced VCMs. These results suggest that A2AR agonists mitigate TD symptoms by activating striatal iMSNs via β-arrestin signaling. [ABSTRACT FROM AUTHOR]- Published
- 2023
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37. Striatal TRPV1 activation by acetaminophen ameliorates dopamine D2 receptor antagonist–induced orofacial dyskinesia
- Author
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Kozo Kaibuchi, Yasuo Mori, Koki Nagaoka, Keisuke Kuroda, Gen Kayanuma, Nozomi Asaoka, Kazuki Nagayasu, Takuya Nagashima, Soni Siswanto, Chihiro Toda, Hisashi Shirakawa, Hiroki Yamamoto, Yasuhiro Funahashi, and Shuji Kaneko
- Subjects
Male ,0301 basic medicine ,Dyskinesia, Drug-Induced ,TRPV1 ,TRPV Cation Channels ,Striatum ,Pharmacology ,Tardive dyskinesia ,Indirect pathway of movement ,Medium spiny neuron ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Dopamine receptor D2 ,Haloperidol ,Animals ,Medicine ,Rats, Wistar ,Acetaminophen ,business.industry ,digestive, oral, and skin physiology ,General Medicine ,medicine.disease ,Rats ,Mice, Inbred C57BL ,Disease Models, Animal ,Dopamine D2 Receptor Antagonists ,030104 developmental biology ,nervous system ,Dyskinesia ,030220 oncology & carcinogenesis ,Drug therapy ,medicine.symptom ,business ,Research Article ,Neuroscience ,medicine.drug - Abstract
Antipsychotics often cause tardive dyskinesia, an adverse symptom of involuntary hyperkinetic movements. Analysis of the US Food and Drug Administration Adverse Event Reporting System and JMDC insurance claims revealed that acetaminophen prevented the dyskinesia induced by dopamine D2 receptor antagonists. In vivo experiments further showed that a 21-day treatment with haloperidol increased the number of vacuous chewing movements (VCMs) in rats, an effect that was inhibited by oral acetaminophen treatment or intracerebroventricular injection of N-(4-hydroxyphenyl)-arachidonylamide (AM404), an acetaminophen metabolite that acts as an activator of the transient receptor potential vanilloid 1 (TRPV1). In mice, haloperidol-induced VCMs were also mitigated by treatment with AM404 applied to the dorsal striatum, an effect not seen in TRPV1-deficient mice. Acetaminophen prevented the haloperidol-induced decrease in the number of c-Fos+preproenkephalin+ striatal neurons in wild-type mice but not in TRPV1-deficient mice. Finally, chemogenetic stimulation of indirect pathway medium spiny neurons in the dorsal striatum decreased haloperidol-induced VCMs. These results suggest that acetaminophen activates the indirect pathway neurons by activating TRPV1 channels via AM404.
- Published
- 2021
38. Depletion of microglia ameliorates white matter injury and cognitive impairment in a mouse chronic cerebral hypoperfusion model
- Author
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Masashi Kakae, Hisashi Shirakawa, Misa Morishima, Shuji Kaneko, Shota Tobori, and Kazuki Nagayasu
- Subjects
Male ,0301 basic medicine ,Central nervous system ,Biophysics ,Biochemistry ,Neuroprotection ,Proinflammatory cytokine ,Mice ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Animals ,Cognitive Dysfunction ,Interleukin 6 ,Molecular Biology ,White matter injury ,Microglia ,biology ,Colony-stimulating factor 1 ,business.industry ,Chronic cerebral hypoperfusion ,Neurotoxicity ,Cell Biology ,medicine.disease ,White Matter ,Mice, Inbred C57BL ,Cerebrovascular Disorders ,Disease Models, Animal ,Cognitive impairment ,030104 developmental biology ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Chronic Disease ,Immunology ,biology.protein ,Cytokines ,Tumor necrosis factor alpha ,business ,Homeostasis - Abstract
Microglia are immune cells in the central nervous system (CNS) and essential for homeostasis that are important for both neuroprotection and neurotoxicity, and are activated in a variety of CNS diseases. Microglia aggravate cognitive impairment induced by chronic cerebral hypoperfusion, but their precise roles under these conditions remain unknown. Here, we used PLX3397, a colony-stimulating factor 1 receptor inhibitor, to deplete microglia in mice with chronic cerebral hypoperfusion induced by bilateral common carotid artery stenosis (BCAS). Cognitive impairment induced 28 days after BCAS was significantly improved in mice fed a diet containing PLX3397. In PLX3397-fed mice, microglia were depleted and white matter injury induced by BCAS was suppressed. In addition, the expression of proinflammatory cytokines, interleukin 6 and tumor necrosis factor alpha, was suppressed in PLX3397-fed mice. Taken together, these findings suggest that microglia play destructive roles in the development of cognitive impairment and white matter injury induced by chronic cerebral hypoperfusion. Thus, microglia represent a potential therapeutic target for chronic cerebral hypoperfusion-related diseases.
- Published
- 2019
39. Pathophysiological Role of TRPM2 in Age-Related Cognitive Impairment in Mice
- Author
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Kazuki Nagayasu, Masashi Kakae, Misa Morishima, Shuji Kaneko, Jun Miyanohara, Hisashi Shirakawa, and Yasuo Mori
- Subjects
0301 basic medicine ,Aging ,medicine.medical_specialty ,Memory Dysfunction ,TRPM Cation Channels ,Inflammation ,Hippocampal formation ,Hippocampus ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Internal medicine ,medicine ,Animals ,Cognitive Dysfunction ,TRPM2 ,cognitive impairment ,Spatial Memory ,Mice, Knockout ,Microglia ,business.industry ,General Neuroscience ,Calcium-Binding Proteins ,Microfilament Proteins ,Recognition, Psychology ,Cognition ,White Matter ,Pathophysiology ,030104 developmental biology ,medicine.anatomical_structure ,Endocrinology ,white matter injury ,Cytokines ,medicine.symptom ,business ,030217 neurology & neurosurgery - Abstract
Aging causes various functional changes, including cognitive impairment and inflammatory responses in the brain. Transient receptor potential melastatin 2 (TRPM2), a Ca2+-permeable channel expressed abundantly in immune cells, exacerbates inflammatory responses. Previously, we reported that TRPM2 on resident microglia plays a critical role in exacerbating inflammation, white matter injury, and cognitive impairment during chronic cerebral hypoperfusion; however, the physiological or pathophysiological role of TRPM2 during age-associated inflammatory responses remains unclear. Therefore, we examined the effects of TRPM2 deletion in young (2–3 months) and older (12–24 months) mice. Compared with young wild-type (WT) mice, middle-aged (12–16 months) WT mice showed working and cognitive memory dysfunction and aged (20–24 months) WT mice exhibited impaired spatial memory. However, these characteristics were not seen in TRPM2 knockout (TRPM2-KO) mice. Consistent with the finding of cognitive impairment, aged WT mice exhibited white matter injury and hippocampal damage and an increase in the number of Iba1-positive cells and amounts of pro-inflammatory cytokines in the brain; these characteristics were not seen in TRPM2-KO mice. These findings suggest that TRPM2 plays a critical role in exacerbating inflammatory responses and cognitive dysfunction during aging.
- Published
- 2019
40. TRPM2 confers susceptibility to social stress but is essential for behavioral flexibility
- Author
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Yuma Nagai, Tsuyoshi Miyakawa, Kazuki Nagayasu, Shuji Kaneko, Takayuki Nakagawa, Keizo Takao, Yasuo Mori, Naoya Nishitani, Emina Hashimoto, Hisashi Shirakawa, and Chihiro Andoh
- Subjects
0301 basic medicine ,Elevated plus maze ,General Mathematics ,TRPM Cation Channels ,Reversal Learning ,Behavioral inflexibility ,Biology ,Motor Activity ,Choice Behavior ,Social defeat ,03 medical and health sciences ,Transient receptor potential channel ,Mice ,0302 clinical medicine ,Stress resiliency ,Animals ,TRPM2 ,Social Behavior ,Molecular Biology ,Prepulse inhibition ,Social stress ,Mice, Knockout ,Behavior, Animal ,Prepulse Inhibition ,Applied Mathematics ,General Neuroscience ,Tail suspension test ,030104 developmental biology ,Neurology (clinical) ,Neuroscience ,030217 neurology & neurosurgery ,Stress, Psychological ,Developmental Biology ,Behavioural despair test - Abstract
Transient receptor potential melastatin 2 (TRPM2) is a Ca2+-permeable, nonselective cation channel and a member of the TRP channel superfamily that acts as a sensor of intracellular redox states. TRPM2 is widely distributed in many tissues and highly expressed in the brain, but the physiological roles of TRPM2 in the central nervous system remain unclear. In this study, TRPM2-deficient mice were examined in a series of behavioral tests. TRPM2-deficient mice did not significantly differ from wild-type littermates in muscle strength, light/dark transition test, rotarod, elevated plus maze, social interaction, prepulse inhibition, Y-maze, forced swim test, cued and contextual fear conditioning, and tail suspension test. In the Barnes circular maze, TRPM2-deficient mice learned the fixed escape box position at similar extent to wild-type littermates, suggesting normal reference memory. However, performance of the first reversal trial and probe test were significantly impaired in TRPM2-deficient mice. In the T-maze delayed alternation task, TRPM2 deficiency significantly reduced choice accuracy. These results indicate that TRPM2-deficient mice shows behavioral inflexibility. Meanwhile, social avoidance induced by repeated social defeat stress was significantly attenuated in TRPM2-deficient mice, suggesting that TRPM2 deficiency confers stress resiliency. Our findings indicate that TRPM2 plays an essential role in maintaining behavioral flexibility but it increases susceptibility to stress.
- Published
- 2019
41. The impact of mouse strain-specific spatial and temporal immune responses on the progression of neuropathic pain
- Author
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Satoshi Imai, Hisashi Shirakawa, Shuji Kaneko, Takayuki Nakagawa, Asami Sukeishi, Kazuki Nagayasu, and Koichi Isami
- Subjects
Male ,0301 basic medicine ,Immunology ,Mice, Inbred Strains ,Mice, Transgenic ,Biology ,CCL2 ,Mice ,03 medical and health sciences ,Behavioral Neuroscience ,0302 clinical medicine ,Immune system ,Peripheral Nerve Injuries ,Ganglia, Spinal ,medicine ,Animals ,Mice, Inbred C3H ,Microglia ,Endocrine and Autonomic Systems ,Macrophages ,Spinal cord ,Sciatic Nerve ,Mice, Inbred C57BL ,Disease Models, Animal ,Immunity, Active ,030104 developmental biology ,medicine.anatomical_structure ,Spinal Cord ,Hyperalgesia ,Mice, Inbred DBA ,Neuropathic pain ,Neuralgia ,Female ,Tumor necrosis factor alpha ,Sciatic nerve ,Bone marrow ,030217 neurology & neurosurgery - Abstract
The present study was designed to investigate the correlation between the spatial and temporal aspects of immune responses and genetic heterogeneity in the progression of peripheral neuropathic pain. To address this issue, we first screened four inbred mouse strains (C57BL/6J, C3H/He, DBA/2, and A/J mice) to identify high- and low-responder strains to mechanical hypersensitivity induced by partial sciatic nerve ligation (pSNL). Among these strains, the C57BL/6J strain showed the highest vulnerability to pSNL-induced mechanical hypersensitivity, whereas the C3H/HeSlc strain was most resistant. C3H/HeSlc mice exhibited a significant increase in CD206-immunoreactivity (anti-inflammatory macrophages) in the dorsal root ganglia (DRG) at 3 and 7 days, and lower Iba1-immunoreactivity (microglia) in the spinal cord from 3 to 14 days after pSNL than C57BL/6J mice. These phenomena might be associated with a decrease in the production of inflammatory factors (interleukin-1β, interleukin-6, and CX3CL1) in the DRG and the poor responsiveness of spinal microglia (i.e. microglial production of IL1β, CCL2, and TNFα) against CX3CL1 in C3H/HeSlc mice. Behavioral experiments using bone marrow (BM) chimeric mice derived by crossing C3H/HeSlc and C57BL/6J strains showed that the strength of mechanical hypersensitivity 3 days following pSNL was inversely correlated with the increase in the ratio of anti-inflammatory/pro-inflammatory DRG macrophages, which was based on the BM-derived hematopoietic cells from donor mice. By contrast, the intensity of Iba1-immunoreactivity (microglia) in the spinal cord was dependent on the phenotypes of recipient mice, but not affected by the phenotypes of BM-derived donor hematopoietic cells. These findings suggest that the strain-specific aspects of DRG macrophages and spinal microglia might be related to the early and late phases of pSNL-induced mechanical hypersensitivity, respectively. This study presents a greater understanding of the differences in neuropathic pain among genetically heterogeneous inbred mouse strains, and provides further insights into the spatial and temporal roles of the immune system in the pathogenesis of neuropathic pain.
- Published
- 2018
42. Manipulation of dorsal raphe serotonergic neurons modulates active coping to inescapable stress and anxiety-related behaviors in mice and rats
- Author
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Takayuki Nakagawa, Hisashi Shirakawa, Haruko Kinoshita, Hitoshi Hashimoto, Sergey Kasparov, Norihiro Shibui, Nozomi Asaoka, Mayumi Yamashiro, Hiroyuki Kawai, James Hewinson, Shuji Kaneko, Beihui Liu, Chihiro Andoh, Kazuki Nagayasu, Naoya Nishitani, and Yuma Nagai
- Subjects
Dorsal Raphe Nucleus ,Male ,Genetic Vectors ,Optogenetics ,Biology ,Anxiety ,Serotonergic ,Article ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Dorsal raphe nucleus ,Adaptation, Psychological ,medicine ,Animals ,Rats, Wistar ,Pharmacology ,Behavior, Animal ,Lentivirus ,Tryptophan hydroxylase ,Pathophysiology ,030227 psychiatry ,Electrophysiological Phenomena ,Rats ,Mice, Inbred C57BL ,Psychiatry and Mental health ,Electrophysiology ,Disease Models, Animal ,Immunohistochemistry ,medicine.symptom ,Neuroscience ,030217 neurology & neurosurgery ,Serotonergic Neurons - Abstract
Major depression and anxiety disorders are a social and economic burden worldwide. Serotonergic signaling has been implicated in the pathophysiology of these disorders and thus has been a crucial target for pharmacotherapy. However, the precise mechanisms underlying these disorders are still unclear. Here, we used species-optimized lentiviral vectors that were capable of efficient and specific transduction of serotonergic neurons in mice and rats for elucidation of serotonergic roles in anxiety-like behaviors and active coping behavior in both species. Immunohistochemical analyses revealed that lentiviral vectors with an upstream sequence of tryptophan hydroxylase 2 gene efficiently transduced serotonergic neurons with a specificity of approximately 95% in both mice and rats. Electrophysiological recordings showed that these lentiviral vectors induced sufficient expression of optogenetic tools for precise control of serotonergic neurons. Using these vectors, we demonstrate that acute activation of serotonergic neurons in the dorsal raphe nucleus increases active coping with inescapable stress in rats and mice in a time-locked manner, and that acute inhibition of these neurons increases anxiety-like behaviors specifically in rats. These findings further our understanding of the pathophysiological role of dorsal raphe serotonergic neurons in different species and the role of these neurons as therapeutic targets in major depression and anxiety disorders.
- Published
- 2018
43. Transient Receptor Potential Melastatin 3 Is Functionally Expressed in Oligodendrocyte Precursor Cells and Is Upregulated in Ischemic Demyelinated Lesions
- Author
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Shuji Kaneko, Hisashi Shirakawa, Kazuki Nagayasu, Koji Shibasaki, Ryotaro Kunimasa, Kana Ohashi, and Hayaki Nakazawa
- Subjects
0301 basic medicine ,Receptor, Platelet-Derived Growth Factor alpha ,Primary Cell Culture ,Pharmaceutical Science ,TRPM Cation Channels ,Stimulation ,In situ hybridization ,Corpus Callosum ,03 medical and health sciences ,chemistry.chemical_compound ,Transient receptor potential channel ,0302 clinical medicine ,Downregulation and upregulation ,medicine ,TRPM3 ,Animals ,Humans ,Cells, Cultured ,Pharmacology ,Cerebral Cortex ,Oligodendrocyte Precursor Cells ,General Medicine ,Cell biology ,Rats ,Up-Regulation ,stomatognathic diseases ,Disease Models, Animal ,030104 developmental biology ,medicine.anatomical_structure ,nervous system ,chemistry ,Cerebral cortex ,030220 oncology & carcinogenesis ,Pregnenolone ,Stroke, Lacunar ,Tumor necrosis factor alpha ,Pregnenolone sulfate ,Demyelinating Diseases - Abstract
Oligodendrocyte precursor cells (OPCs) are glial cells that differentiate into oligodendrocytes and myelinate axons. The number of OPCs is reportedly increased in brain lesions in some demyelinating diseases and during ischemia; however, these cells also secrete cytokines and elicit both protective and deleterious effects in response to brain injury. The mechanism regulating the behaviors of OPCs in physiological and pathological conditions must be elucidated to control these cells and to treat demyelinating diseases. Here, we focused on transient receptor potential melastatin 3 (TRPM3), a Ca2+-permeable channel that is activated by the neurosteroid pregnenolone sulfate (PS) and body temperature. Trpm3+/Pdgfra+ OPCs were detected in the cerebral cortex (CTX) and corpus callosum (CC) of P4 and adult rats by in situ hybridization. Trpm3 expression was detected in primary cultured rat OPCs and was increased by treatment with tumor necrosis factor α (TNFα). Application of PS (30-100 µM) increased the Ca2+ concentration in OPCs and this effect was inhibited by co-treatment with the TRP channel blocker Gd3+ (100 µM) or the TRPM3 inhibitor isosakuranetin (10 µM). Stimulation of TRPM3 with PS (50 µM) did not affect the differentiation or migration of OPCs. The number of Trpm3+ OPCs was markedly increased in demyelinated lesions in an endothelin-1 (ET-1)-induced ischemic rat model. In conclusion, TRPM3 is functionally expressed in OPCs in vivo and in vitro and is upregulated in inflammatory conditions such as ischemic insults and TNFα treatment, implying that TRPM3 is involved in the regulation of specific behaviors of OPCs in pathological conditions.
- Published
- 2021
44. Prediction of pharmacological activities from chemical structures with graph convolutional neural networks
- Author
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Hisashi Shirakawa, Miyuki Sakai, Kaito Takayama, Shuji Kaneko, Kazuki Nagayasu, Chihiro Andoh, and Norihiro Shibui
- Subjects
0301 basic medicine ,Computer science ,High-throughput screening ,Science ,Drug Evaluation, Preclinical ,Molecular Conformation ,Computational biology ,Toxicology ,Virtual drug screening ,01 natural sciences ,Convolutional neural network ,Article ,03 medical and health sciences ,Machine learning ,Humans ,Amino Acid Sequence ,Representation (mathematics) ,Drug safety ,Transporters in the nervous system ,Data mining ,chemistry.chemical_classification ,Pharmacology ,Virtual screening ,Multidisciplinary ,Degree (graph theory) ,Pharmaceutics ,chEMBL ,Antidepressive Agents ,0104 chemical sciences ,Amino acid ,010404 medicinal & biomolecular chemistry ,030104 developmental biology ,chemistry ,Pharmaceutical Preparations ,Drug screening ,Metric (mathematics) ,Graph (abstract data type) ,Medicine ,Neural Networks, Computer ,Selective Serotonin Reuptake Inhibitors ,Neuroscience - Abstract
Many therapeutic drugs are compounds that can be represented by simple chemical structures, which contain important determinants of affinity at the site of action. Recently, graph convolutional neural network (GCN) models have exhibited excellent results in classifying the activity of such compounds. For models that make quantitative predictions of activity, more complex information has been utilized, such as the three-dimensional structures of compounds and the amino acid sequences of their respective target proteins. As another approach, we hypothesized that if sufficient experimental data were available and there were enough nodes in hidden layers, a simple compound representation would quantitatively predict activity with satisfactory accuracy. In this study, we report that GCN models constructed solely from the two-dimensional structural information of compounds demonstrated a high degree of activity predictability against 127 diverse targets from the ChEMBL database. Using the information entropy as a metric, we also show that the structural diversity had less effect on the prediction performance. Finally, we report that virtual screening using the constructed model identified a new serotonin transporter inhibitor with activity comparable to that of a marketed drug in vitro and exhibited antidepressant effects in behavioural studies., 化合物の薬理作用を予測する技術を開発 --薬理作用ビッグデータを用いて--. 京都大学プレスリリース. 2021-01-13.
- Published
- 2021
45. A selective serotonin reuptake inhibitor ameliorates obsessive–compulsive disorder-like perseverative behavior by attenuating 5-HT2C receptor signaling in the orbitofrontal cortex
- Author
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Hikari Hatakama, Nozomi Asaoka, Kazuki Nagayasu, Hisashi Shirakawa, and Shuji Kaneko
- Subjects
Pharmacology ,Cellular and Molecular Neuroscience - Published
- 2022
46. Effectiveness of proton pump inhibitors on obsessive-compulsive disease discovered in real-world data and the molecular mechanism
- Author
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Hikari Hatakama, Nozomi Asaoka, Kazuki Nagayasu, Hisashi Shirakawa, and Shuji Kaneko
- Subjects
Applied Mathematics ,General Mathematics - Published
- 2022
47. Two-sidedness of reactive oxygen species-sensitive TRP channels in vascular cognitive impairment induced by chronic cerebral hypoperfusion
- Author
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Hisashi Shirakawa
- Subjects
Applied Mathematics ,General Mathematics - Published
- 2022
48. The astrocytic TRPA1 channel plays a protective role in vascular cognitive impairment
- Author
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Masashi Kakae, Hiroki Nakajima, Shota Tobori, Ayaka Kawashita, Jun Miyanohara, Misa Morishima, Kazuki Nagayasu, Eiji Shigetomi, Schuichi Koizumi, Yasuo Mori, Hisashi Shirakawa, and Shuji Kaneko
- Subjects
Applied Mathematics ,General Mathematics - Published
- 2022
49. Contribution of oligodendrocyte precursor cells to disease severity in a mouse model of multiple sclerosis
- Author
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Kana Ohashi, Nagisa Matsuo, Kazuki Nagayasu, Hisashi Shirakawa, and Shuji Kaneko
- Subjects
Applied Mathematics ,General Mathematics - Published
- 2022
50. Identification of the therapeutic target for tendinopathy through the combination of real world data analysis and pharmacological experiments
- Author
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Haruka Furuta, Mari Yamada, Takuya Nagashima, Shuichi Matsuda, Kazuki Nagayasu, Hisashi Shirakawa, and Shuji Kaneko
- Subjects
Applied Mathematics ,General Mathematics - Published
- 2022
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