Journal of pharmacological sciences最新文献

{"title":"Modulation of netrin-1/DCC signaling pathway by Jiawei Kongsheng Zhenzhong Pill improves synaptic structural plasticity in PSD rats","authors":"Yue Zhao ,&nbsp;Aizhen Song ,&nbsp;Guowei Liu ,&nbsp;Qiuyue Chen ,&nbsp;Qiaolan Wu ,&nbsp;Zu Gao ,&nbsp;Zifa Li ,&nbsp;Huayun Yu ,&nbsp;Zhichun Wu","doi":"10.1016/j.jphs.2025.02.004","DOIUrl":"10.1016/j.jphs.2025.02.004","url":null,"abstract":"<div><div>Jiawei Kongsheng Zhenzhong Pill(JKZP) is based on Kongsheng Zhenzhong Pill contained in the Tang Dynasty's “<em>Thousand Golden Prescriptions</em>,” which exhibited good anti-ischemic and antidepressant effects in the previous study. However, its specific effects on post-stroke depression (PSD) and the mechanism are not clear. This study aimed to investigate the effects of JKZP in the treatment of PSD and related mechanisms. The decoction of JKZP was first analyzed for its medicinal chemical composition and screened for representative components of JKZP. The Middle cerebral artery occlusion (MCAO) method combined with solitary rearing and chronic unpredictable mild stress (CUMS) was used to establish a rat model of PSD, and to observe the effects of JKZP on the behavior and synaptic plasticity of PSD rats, and to investigate the mechanism of JKZP in the treatment of PSD by detecting the mRNA level, protein expression and activity of Netrin-1/DCC signaling pathway-related proteins. The results showed that the JKZP decoction contained loganin, β-asarone and other pharmaceutical ingredients, which have been reported to protect against cerebral ischemic injury and antidepressant effects. JKZP significantly improved the depression-like behavior of PSD rats and improved the damage to pyramidal neurons in the medial prefrontal cortex (mPFC) of PSD rats. Moreover, JKZP increased the density of dendritic spines in the mPFC of PSD rats, improved synaptic gap width and thickness of the post-synaptic density, and increased the number of synaptic vesicles. The results of Real-Time quantitative reverse transcription PCR (qRT-PCR), Western blotting, and pull-down assays revealed that JKZP increased netrin-1, deleted in colorectal cancer (DCC), and focal adhesion kinase (FAK) mRNA and protein expression, elevated the <em>p</em>-FAK/FAK ratio, and decreased myosin II protein expression and Ras homolog gene family member A (RhoA-GTP) activity in the mPFC of PSD rats. Taken together, JKZP can affect synaptic structural remodeling and improve depressive manifestations and neuronal damage in PSD rats by regulating the expression and activity of signaling molecules related to the netrin-1/DCC signaling pathway.</div></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"157 4","pages":"Pages 242-252"},"PeriodicalIF":3.0,"publicationDate":"2025-02-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143511865","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"YAP activation in Müller cells alleviates oxidative stress in the rat retina after intravitreal injection with methylglyoxal","authors":"Toshihide Kashihara,&nbsp;Mayuko Yasaki,&nbsp;Yumi Okuyama,&nbsp;Aki Murayama,&nbsp;Akane Morita,&nbsp;Tsutomu Nakahara","doi":"10.1016/j.jphs.2025.02.005","DOIUrl":"10.1016/j.jphs.2025.02.005","url":null,"abstract":"<div><div>Methylglyoxal (MGO), a highly reactive dicarbonyl compound produced via the glycolytic pathway, plays a key role in the pathogenesis of various diabetic complications, such as diabetic retinopathy. Müller cells provide neurotrophic support and maintain retinal homeostasis, including the redox balance. This dysfunction leads to retinal disease. Yes-associated protein (YAP), a major downstream effector of the Hippo pathway, plays a crucial role in regulating cell survival. In this study, we investigated the roles of Müller cell YAP during MGO-induced retinal injury using normal rats intravitreally injected with MGO and a rat Müller cell line (rMC-1). Immunohistochemistry revealed that MGO injection increased the glial fibrillary acidic protein immunoreactivity in Müller cells. The alignment of Müller cell nuclei was disrupted in MGO-treated retinas. YAP increased and activated in Müller cells two days after MGO injection. This increase in YAP levels was independent of the Hippo pathway and partially attributed to the upregulation of <em>YAP</em> mRNA levels. YAP inhibition by verteporfin exacerbated MGO-induced cell damage and decreased Bcl-xL levels in rMC-1 cells. Intravitreal verteporfin injection also enhanced MGO-induced retinal oxidative stress. Overall, our findings suggest that YAP activation in Müller cells alleviates oxidative stress in the retina following MGO-induced retinal injury.</div></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"157 4","pages":"Pages 219-228"},"PeriodicalIF":3.0,"publicationDate":"2025-02-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143487186","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Spinal dorsal horn neurons involved in the alleviating effects of cannabinoid receptor agonists on neuropathic allodynia-like behaviors in rats","authors":"Daichi Sueto ,&nbsp;Eriko I ,&nbsp;Akihisa Onishi ,&nbsp;Makoto Tsuda","doi":"10.1016/j.jphs.2025.02.008","DOIUrl":"10.1016/j.jphs.2025.02.008","url":null,"abstract":"<div><div>Mechanical allodynia, the pain caused by innocuous tactile stimuli, is a hallmark symptom of neuropathic pain that is often resistant to currently available treatments. Cannabinoids are widely used for pain management; however, their therapeutic mechanisms for neuropathic mechanical allodynia remain unclear. Using transgenic rats that enable to optogenetically stimulate touch-sensing Aβ fibers in the skin, we found that the intrathecal administration of the synthetic cannabinoid, WIN 55,212-2, alleviated the Aβ fiber-derived neuropathic allodynia. Furthermore, we injected adeno-associated virus vectors incorporating the rat cannabinoid receptor 1 (CB₁ receptor) (encoded by <em>Cnr1</em>) promoter and tdTomato or short hairpin RNA targeting the CB₁ receptor into the spinal dorsal horn (SDH) and demonstrated that the conditional knockdown of CB₁ receptors in <em>Cnr1</em>⁺ SDH neurons attenuates the anti-allodynic effects of intrathecally administered WIN 55,212-2. Electrophysiological analysis revealed that <em>Cnr1</em>⁺ SDH neurons received excitatory synaptic inputs from the primary afferent Aβ fibers. Collectively, our results suggest that the CB₁ receptors in <em>Cnr1</em>⁺ SDH neurons are molecular and cellular targets of intrathecal WIN 55,212-2 to alleviate neuropathic allodynia.</div></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"157 4","pages":"Pages 253-260"},"PeriodicalIF":3.0,"publicationDate":"2025-02-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143511866","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Japanese black vinegar Kurozu promotes lifespan and healthspan extension in Caenorhabditis elegans","authors":"Yutaro Fukushima ,&nbsp;Asuka Kagami ,&nbsp;Hirotaka Sonoda ,&nbsp;Kotomi Shimokawa ,&nbsp;Sota Nishikawa ,&nbsp;Mary Ann Suico ,&nbsp;Hirofumi Kai ,&nbsp;Marina Miyazaki ,&nbsp;Kanta Torigoe ,&nbsp;Yuki Yoshinaga ,&nbsp;Yoshiyuki Matsumoto ,&nbsp;Tsuyoshi Shuto","doi":"10.1016/j.jphs.2025.02.003","DOIUrl":"10.1016/j.jphs.2025.02.003","url":null,"abstract":"<div><div>Kurozu, a traditional Japanese black vinegar (JBV), is produced from steamed unpolished rice, koji, and water through saccharification, alcoholic fermentation, and acetic fermentation. These processes result in a vinegar rich in amino acids, vitamins, organic acids, and proteins. While Kurozu has demonstrated benefits, including anti-oxidative and anti-adipogenic activities, its effects on health at the organismal level remain poorly understood. This study aimed to evaluate the impact of Kurozu on healthspan of <em>Caenorhabditis elegans</em> (<em>C. elegans</em>) using the <em>C. elegans</em> Health lifespan Auto-monitoring System (C-HAS). Kurozu concentrated liquid (KCL) was tested at concentrations ranging from 0.005% to 0.5%. Results showed that 0.5% KCL significantly extended lifespan and healthspan, particularly when heat-killed (HK) <em>E. coli</em> OP50 was provided as the food source. In contrast, the lifespan- and healthspan-extending effects at 0.5% KCL were abolished when live <em>E. coli</em> was used as the food source. This suggests that active components in KCL may be metabolized by live bacteria, diminishing their beneficial effects. Further reproducibility tests at 0.5% and 1% KCL concentrations confirmed the healthspan-extending effects under conditions of dead bacterial feeding. This study highlights the health-promoting impact of KCL and provides new insights into its role as a functional food ingredient.</div></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"157 4","pages":"Pages 233-241"},"PeriodicalIF":3.0,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143508143","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neuroprotective effects of compounds interacting with carrier-mediated amantadine transport across the blood–retinal barrier in rats","authors":"Yusuke Shinozaki,&nbsp;Shin-ichi Akanuma,&nbsp;Yuma Tega,&nbsp;Ken-ichi Hosoya","doi":"10.1016/j.jphs.2025.02.002","DOIUrl":"10.1016/j.jphs.2025.02.002","url":null,"abstract":"<div><div>Retinal drug delivery via peripheral administration enhances the safety and efficacy of retinal pharmacotherapy. As retinal drug distribution from the circulating blood is limited by the blood–retinal barrier (BRB), BRB-permeable retinal drugs with potent pharmacological effects are needed for peripheral administration. Our previous research indicated carrier-mediated retinal transport of amantadine, which has neuroprotective effects by inhibiting N-methyl-<span>d</span>-aspartate receptors, across the BRB. As several amantadine derivatives are also suggestive to strongly interact with the carrier-mediated amantadine transport at the BRB, these compounds are proposed as candidates for the treatment of retinal diseases after peripheral administration. To find the appropriate retinal drug candidate, neuroprotective effects of compounds interacting with carrier-mediated amantadine transport across the BRB were firstly evaluated using primary-cultured rat cortical neurons. As a result, N'-(1-adamantyl)ethane-1,2-diamine (test compound) exerted the most potent neuroprotective effects. In addition, this test compound indicated neuroprotective effects against retinal damage after intraperitoneal administration in retinal damage rats. Our findings suggest the test compound, which interacts with carrier-mediated amantadine transport across the BRB and protected neurons from excitotoxicity <em>in vitro</em>, is a key agent to develop the pharmacotherapy with peripheral administration of medicines for retinal diseases.</div></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"157 4","pages":"Pages 212-218"},"PeriodicalIF":3.0,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143419897","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Intraoral treatment of persimmon tannin, a polyphenol extracted from persimmon, significantly ameliorates gingivitis, plaque and halitosis via directly influence the periodontal bacteria Porphyromonas gulae","authors":"Megu Toyooka ,&nbsp;Mao Kaneki ,&nbsp;Chiharu Ohira ,&nbsp;Azusa Hachiya ,&nbsp;Tomoki Fukuyama","doi":"10.1016/j.jphs.2025.02.001","DOIUrl":"10.1016/j.jphs.2025.02.001","url":null,"abstract":"<div><h3>Background</h3><div>As periodontal disease (PD) is an irreversible disorder, preventive dentistry in human and veterinary medicine has become pertinent. This study focused on <em>persimmon tannin</em> (PT) and examined its bactericidal, anti-halitosis, and anti-inflammatory effects by focusing on <em>Porphyromonas gulae</em> (<em>P. gulae</em>).</div></div><div><h3>Methods</h3><div>The direct effects of PT on <em>P. gulae</em> were evaluated <em>in vitro.</em> Pro-inflammatory cytokines secretion induced by <em>P. gulae</em> in the macrophage cell lines were determined. A clinical study in dogs with <em>P. gulae</em>-associated PD was performed by one-month intraoral treatment with 0.1% PT-containing gel.</div></div><div><h3>Results</h3><div>PT exhibited a significant bactericidal effect to <em>P. gulae</em>. The biofilm formation and methyl mercaptan generated by <em>P. gulae</em> was significantly decreased by PT even after a short exposure period. <em>P. gulae</em>-induced proinflammatory cytokine production in macrophage cell lines was inhibited by PT treatment in a dose-dependent manner. In a clinical study of dogs, intraoral treatment with 0.1% PT did not significantly influence the gingivitis and plaque scores, however, the concentrations of hydrogen sulfide and methyl mercaptan were also significantly decreased by the PT treatment. Although there was no anti-bacterial <em>in vitro</em>, <em>P. gulae</em> activity and DNA detection decreased with PT treatment.</div></div><div><h3>Conclusions</h3><div>These findings suggest that intraoral administration of PT can prevent PD.</div></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"157 4","pages":"Pages 203-211"},"PeriodicalIF":3.0,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143419896","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"C57BL/6J and C57BL/6N mice show distinct aging-associated behavioral alterations","authors":"Rui Yamada ,&nbsp;Hirotaka Nagai ,&nbsp;Io Horikawa ,&nbsp;Wenran Qiu ,&nbsp;Yunhui Zhu ,&nbsp;Kohei Ota ,&nbsp;Tomoyuki Furuyashiki","doi":"10.1016/j.jphs.2025.01.002","DOIUrl":"10.1016/j.jphs.2025.01.002","url":null,"abstract":"<div><div>Aging affects emotional, cognitive, and social functions, increasing susceptibility to neuropsychiatric conditions. C57BL/6 mice are commonly used to study aging mechanisms, yet differences between C57BL/6J and C57BL/6N substrains remain underexplored. This study compared aging-related behavioral changes in these substrains. Aging reduced exploratory activity and heightened anxiety in C57BL/6J, but not C57BL/6N, mice. Conversely, aging reduced social novelty preference in C57BL/6N, but not C57BL/6J, mice. Male mice of both substrains exhibited increased female urine sniffing with age. These findings highlight substrain-specific aging effects, underscoring the importance of substrain selection in behavioral studies of aged mice for drug development.</div></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"157 2","pages":"Pages 124-129"},"PeriodicalIF":3.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143007287","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Goreisan suppresses cardiac remodeling and dysfunction in a new mouse model with diabetic cardiomyopathy","authors":"Masafumi Funamoto ,&nbsp;Shunji Hirose ,&nbsp;Mizuho Yamamoto ,&nbsp;Hai Du Ly-Nguyen ,&nbsp;Masaki Imanishi ,&nbsp;Fuka Ebi ,&nbsp;Mai Ito ,&nbsp;Hirokazu Ohminami ,&nbsp;Koichiro Tsuchiya ,&nbsp;Yasumasa Ikeda","doi":"10.1016/j.jphs.2025.01.003","DOIUrl":"10.1016/j.jphs.2025.01.003","url":null,"abstract":"<div><h3>Background</h3><div>The global increase in diabetes, driven by aging populations and lifestyle changes, has led to an increase in the incidence of diabetic cardiomyopathy (DCM). DCM is characterized by metabolic abnormalities, oxidative stress, and inflammation, leading to cardiac remodeling and dysfunction. Goreisan (GRS), a traditional Japanese Kampo medicine, is commonly used to treat fluid control such as edema, due to its diuretic effect. In this study, we examined the effects of GRS on DCM.</div></div><div><h3>Methods</h3><div>We first established a new mouse model of DCM and then evaluated the effects of GRS on DCM using a recently developed model.</div></div><div><h3>Results</h3><div>The DCM mouse model developed cardiac hypertrophy, fibrosis, and dysfunction by nine weeks, which was ameliorated by GRS administration. GRS suppressed apoptosis and protein degradation by inhibiting Akt dephosphorylation and oxidative stress in DCM mice. In contrast, no differences in inflammatory cytokine levels were observed, regardless of GRS administration.</div></div><div><h3>Conclusion</h3><div>GRS has potential efficacy in preventing DCM onset and development.</div></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"157 2","pages":"Pages 104-112"},"PeriodicalIF":3.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143007292","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Research on the protective effect of Rhizoma of Anemarrhena asphodeloides on TMT induced AD mice model based on network pharmacology combined with in vitro and in vivo experimental validation","authors":"Qi Huang ,&nbsp;Yingli Zhang ,&nbsp;Li Huang ,&nbsp;Zhijun Guo ,&nbsp;Deling Wu","doi":"10.1016/j.jphs.2024.12.005","DOIUrl":"10.1016/j.jphs.2024.12.005","url":null,"abstract":"<div><h3>Background</h3><div>Alzheimer's disease (AD) is a neurodegenerative disease, and neuroprotection is an important approach to improving AD outcomes. Rhizoma of <em>Anemarrhena asphodeloides</em> (RAA) is a commonly used Traditional Chinese Medicine (TCM) with demonstrated neuroprotective effects, but its anti-AD mechanism requires further exploration.</div></div><div><h3>Aim of the study</h3><div>To elucidate the neuroprotective mechanism of RAA on TMT-induced AD mice.</div></div><div><h3>Materials and methods</h3><div>The AD mice model was established via intraperitoneal injection of TMT. The effect of RAA on ameliorating learning and memory was assessed using the Morris Water Maze (MWM) and Y-maze tests. Haematoxylin-Eosin (HE), Nissl, and TUNEL staining were used to observe the neuroprotective effect of RAA. The components in serum containing RAA (RAA-S) were detected using UPLC-Q-Orbitrap MS. Potential targets were predicted through network pharmacology and molecular docking. Serum levels of reactive oxygen species (ROS), malondialdehyde (MDA), superoxide dismutase (SOD), glutathione (GSH), and glutathione peroxidase (GPx) were measured with ELISA kits. The HT22 hippocampal neuronal cell line injured by <span>l</span>-glutamate (L-Glu) was used to further elucidate the mechanism of RAA. ROS levels in HT22 cells were detected with the 2′-7′-dichlorodihydrofluorescein diacetate (DCFH-DA) fluorescent probe and flow cytometry. Apoptosis in HT22 cells was measured by flow cytometry. The proteins MAP2, GAP-43, Nrf2, Keap1, HO-1, Bax, and Bcl-2 were detected by Western blotting. Immunofluorescence staining was employed to observe Nrf2 nuclear translocation.</div></div><div><h3>Results</h3><div>RAA significantly increased the residence time of mice in the W zone and enhanced the correct alternation rate in TMT-treated mice. RAA preserved the integrity and orderly arrangement of nerve cells. A total of 12 components were detected in RAA-S. AKT1, PPARG, CASP3, STAT3, HSP90AA1, and NFE2L2 (Nrf2) were involved in the RAA-S target pathway network. Molecular docking revealed that Nrf2 exhibited the highest average binding energy with all components in RAA-S. <em>In vivo</em>, RAA elevated MAP2, GAP-43, Nrf2, and HO-1 levels, along with GPx, GSH, and SOD activity, which had been reduced by TMT. Additionally, RAA reduced serum levels of MDA and ROS, which had been elevated by TMT. <em>In vitro</em>, RAA-S reduced HT22 cell apoptosis and ROS accumulation caused by TMT. Furthermore, RAA-S promoted the expression of N-Nrf2 and HO-1 in L-Glu-injured HT22 cells.</div></div><div><h3>Conclusion</h3><div>RAA attenuated oxidative stress induced by TMT and L-Glu in AD model mice. The underlying mechanism was associated with the activation of the Nrf2/Keap1-HO-1 pathway.</div></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"157 2","pages":"Pages 75-87"},"PeriodicalIF":3.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143007310","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Thrombin-induced kynurenine 3-monooxygenase causes variations in the kynurenine pathway, leading to neurological deficits in a murine intracerebral hemorrhage model","authors":"Masatoshi Ohnishi ,&nbsp;Kengo Banshoya ,&nbsp;Aoi Machida ,&nbsp;Takao Kai ,&nbsp;Yuki Shimizu ,&nbsp;Yukino Yano ,&nbsp;Yuui Urabe ,&nbsp;Shumpei Tasaka ,&nbsp;Mana Furutaguchi ,&nbsp;Takuya Shigemasa ,&nbsp;Marina Akagi ,&nbsp;Shoji Maehara ,&nbsp;Toshiyuki Hata","doi":"10.1016/j.jphs.2024.12.003","DOIUrl":"10.1016/j.jphs.2024.12.003","url":null,"abstract":"<div><div>The purpose of the present study is to investigate changes in the kynurenine pathway after intracerebral hemorrhage (ICH) and its effects on ICH-induced injury. The exposure of a primary rat microglial culture to thrombin increased the mRNA level of kynurenine 3-monooxygenase (KMO), and this increase was attenuated by a p38 MAPK inhibitor. Thrombin also increased the protein level of KMO. In the cultured medium, the ratio of quinolinic acid (QUIN), an N-methyl-<span>d</span>-aspartate receptor (NMDAR) agonist, to kynurenic acid (KYNA), its antagonist, increased. The increase in the QUIN/KYNA ratio was blocked by Ro61-8048, a KMO inhibitor. The mRNA expression of KMO increased in an <em>in vivo</em> murine ICH model. Immunohistochemical staining showed that increased KMO co-localized with neurons, microglia, and astrocytes. The QUIN/KYNA ratio increased after ICH but was blocked by Ro61-8048 or clodronate, a microglia toxin. Ro61-8048 ameliorated brain edema; however, this effect was masked by MK-801, an NMDAR antagonist. Ro61-8048 protected against neuron loss in the perihematomal region and repaired neurological deficits assessed using the corner turn and pole tests. In conclusion, thrombin-induced changes in KMO in microglia mainly and intermediary metabolites of the kynurenine pathway appear to play crucial roles in neuronal injury after ICH.</div></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"157 2","pages":"Pages 65-74"},"PeriodicalIF":3.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143055743","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}