Journal of pharmacological sciences最新文献_第8页

Additive effects of mirabegron on muscarinic receptor binding and on relaxation of cholinergic detrusor muscle contraction by antimuscarinics mirabegron对毒蕈碱受体结合和抗毒蕈碱剂对胆碱能逼尿肌收缩松弛的加性作用

IF 3 3区医学

Journal of pharmacological sciences Pub Date : 2025-08-01 Epub Date: 2025-05-27 DOI: 10.1016/j.jphs.2025.05.018

Shizuo Yamada , Masae Mochizuki , Kana Maruyama-Fumoto , Satomi Kagota , Kazumasa Shinozuka

{"title":"Additive effects of mirabegron on muscarinic receptor binding and on relaxation of cholinergic detrusor muscle contraction by antimuscarinics","authors":"Shizuo Yamada , Masae Mochizuki , Kana Maruyama-Fumoto , Satomi Kagota , Kazumasa Shinozuka","doi":"10.1016/j.jphs.2025.05.018","DOIUrl":"10.1016/j.jphs.2025.05.018","url":null,"abstract":"<div><div>Mirabegron is the first selective β<sub>3</sub>-adrenoceptor agonist, to be developed as an alternative to antimuscarinic therapy for patients with overactive bladder (OAB). This agent exerts off-target effects on muscarinic receptors. Its combination with solifenacin results in a higher incidence of anticholinergic effects, such as dry mouth, than solifenacin alone. The present study investigated whether the combination of mirabegron and antimuscarinics exerted additive effects on muscarinic receptors and cholinergic contraction in rat tissues. Muscarinic receptor binding activity and inhibitory effect on carbachol-induced contraction in rat tissues were evaluated by radioreceptor assays using [N-methyl-<sup>3</sup>H]scopolamine chloride (3HNMS) and the organ-bath procedure, respectively. The muscarinic receptor binding activities of solifenacin and imidafenacin in the rat brain increased when administered in combination with mirabegron. Moreover, the inhibitory effects of solifenacin and imidafenacin on carbachol-induced contractions in rat isolated bladder strips were increased by mirabegron, particularly at lower concentrations of solifenacin and imidafenacin. This is the first study to suggest that mirabegron in combination with antimuscarinics exerts additive effects for muscarinic receptor binding and inhibitory effects on cholinergic contractions in bladder strips. The results obtained also showed that these additive effects may contribute to enhanced therapeutic effects on OAB, but also cholinergic adverse effects.</div></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"158 4","pages":"Pages 363-367"},"PeriodicalIF":3.0,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144279414","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

HIF-1α stabilization in osteoclasts induces the expression of aerobic glycolysis-related proteins GLUT1, LDHA, and MCT4 破骨细胞中HIF-1α的稳定诱导了有氧糖酵解相关蛋白GLUT1、LDHA和MCT4的表达

IF 3 3区医学

Journal of pharmacological sciences Pub Date : 2025-08-01 Epub Date: 2025-05-26 DOI: 10.1016/j.jphs.2025.05.017

Tsuyoshi Nishioku, Sae Nakao, Rumi Anzai, Sami Hiramatsu, Akiko Momono, Miyu Moriyama, Mamiko Nakao, Ayaka Terazono

{"title":"HIF-1α stabilization in osteoclasts induces the expression of aerobic glycolysis-related proteins GLUT1, LDHA, and MCT4","authors":"Tsuyoshi Nishioku, Sae Nakao, Rumi Anzai, Sami Hiramatsu, Akiko Momono, Miyu Moriyama, Mamiko Nakao, Ayaka Terazono","doi":"10.1016/j.jphs.2025.05.017","DOIUrl":"10.1016/j.jphs.2025.05.017","url":null,"abstract":"<div><div>Hypoxia-inducible factor (HIF)-1α is a master transcription factor regulating hypoxic adaptation and activates the transcription of genes involved in various steps of energy metabolism. However, some subsets of cancer cells exhibit high HIF-1α levels regardless of the oxygen concentration. Even under normoxic and normoglycemic conditions, HIF-1α regulates basal expression of its target genes. Osteoclasts are giant multinucleated cells derived from the monocyte/macrophage lineage and are specialized in bone resorption. Excessive osteoclast resorbing activities is involved in destructive bone diseases. There are few data regarding how HIF-1α affects osteoclast differentiation. In this study, we investigated whether echinomycin, a HIF-1α inhibitor, reduced the expression of proteins of aerobic glycolysis, such as glucose transporter 1 (GLUT1), lactate dehydrogenase A (LDHA), and monocarboxylate transporter 4 (MCT4), and whether HIF-1α stabilization is involved in osteoclast differentiation. HIF-1α was stabilized earlier than the upregulation of GLUT1, LDHA, and MCT4 expression during osteoclast differentiation. Echinomycin inhibited GLUT1, LDHA, and MCT4 expression. It also inhibited osteoclast differentiation and suppressed osteoclast bone-resorbing activity. We propose that HIF-1α inhibition suppresses excessive osteoclast differentiation and may represent a novel therapeutic strategy for controlling excessive bone resorption in osteoporosis and rheumatoid arthritis.</div></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"158 4","pages":"Pages 336-342"},"PeriodicalIF":3.0,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144178600","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Oral administration of undenatured type II collagen significantly inhibits arthritis-associated pain signal in a mouse model of collagen antibody-induced arthritis and meniscus removal 在胶原抗体诱导的关节炎和半月板切除小鼠模型中，口服未变性的II型胶原可显著抑制关节炎相关的疼痛信号

IF 3 3区医学

Journal of pharmacological sciences Pub Date : 2025-08-01 Epub Date: 2025-06-12 DOI: 10.1016/j.jphs.2025.06.001

Ibuki Yasuda , Mao Kaneki , Chiharu Ohira , Mana Ichikawa , Eiji Iwazaki , Hirohito Tsuruwaka , Tomoki Fukuyama

引用次数: 0

Erratum to “A novel lysophosphatidic acid receptor 1 antagonist with high brain penetrability has a curative effect in the empathic pain-related fibromyalgia model” [J Pharmacol Sci (2025) 139-142] “一种新型高脑穿透性溶血磷脂酸受体1拮抗剂在共情性疼痛相关纤维肌痛模型中的疗效”[J].药理杂志，2025,139-142。

IF 3 3区医学

Journal of pharmacological sciences Pub Date : 2025-08-01 Epub Date: 2025-04-29 DOI: 10.1016/j.jphs.2025.04.009

Hiroyuki Neyama , Naoki Dozono , Yasuka Sahara , Kenji Nishikawa , Hiroshi Ueda

引用次数: 0

Tomatidine attenuates post-stroke cognitive impairment by reducing neuroinflammation through prevention of M1 microglial polarization via NF-κB signaling 番茄碱通过NF-κB信号传导预防M1小胶质细胞极化，减轻神经炎症，从而减轻脑卒中后认知障碍

IF 3 3区医学

Journal of pharmacological sciences Pub Date : 2025-08-01 Epub Date: 2025-05-15 DOI: 10.1016/j.jphs.2025.05.011

Ayami Kita, Yuka Kawade, Haruyoshi Murakami, Rei Ikeda, Ryota Araki, Takeshi Yabe

{"title":"Tomatidine attenuates post-stroke cognitive impairment by reducing neuroinflammation through prevention of M1 microglial polarization via NF-κB signaling","authors":"Ayami Kita, Yuka Kawade, Haruyoshi Murakami, Rei Ikeda, Ryota Araki, Takeshi Yabe","doi":"10.1016/j.jphs.2025.05.011","DOIUrl":"10.1016/j.jphs.2025.05.011","url":null,"abstract":"<div><div>Post-stroke cognitive impairment (PSCI) is a clinical disorder that commonly occurs after a stroke and may persist long-term in most stroke survivors. Neuroinflammation involving proinflammatory M1 microglia, an activated microglial phenotype after stroke injury, is a major risk factor for PSCI. Tomatidine is a steroidal alkaloid of immature green tomatoes that has anti-inflammatory properties. To investigate the effects of tomatidine on cognitive impairment and microglial-associated neuroinflammation after stroke, we performed behavioral experiments and analyses on activated microglia in a transient bilateral common carotid arteries occlusion (tBCCAO) mouse model. Tomatidine attenuated cognitive impairment and neurodegeneration in the CA1 and CA3 hippocampal regions and reduced microglial activation and polarization into an M1 phenotype in the hippocampus in tBCCAO mice. The direct effect of tomatidine on polarization into the M1 phenotype was examined using LPS-stimulated BV2 microglia, as an M1 microglia model. Tomatidine reduced expression of M1 microglial markers and inflammatory mediators and inhibited nuclear translocation and phosphorylation of NF-κB in LPS-treated BV2 microglia. These results suggest that tomatidine suppresses microglial polarization into an M1 phenotype via modulation of NF-κB signaling, resulting in attenuation of neuroinflammation and reduction of PSCI.</div></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"158 4","pages":"Pages 294-302"},"PeriodicalIF":3.0,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144105737","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Comparative analysis of the single-molecule transport kinetics of OATP1B1 genetic variants OATP1B1基因变异的单分子转运动力学比较分析

IF 3 3区医学

Journal of pharmacological sciences Pub Date : 2025-07-01 Epub Date: 2025-04-15 DOI: 10.1016/j.jphs.2025.04.005

Kazunari Tsujii , Kodai Yajima , Takeshi Akiyoshi , Kazuho Sakamoto , Yoshiaki Suzuki , Takayuki Oka , Ayuko Imaoka , Hisao Yamamura , Junko Kurokawa , Hisakazu Ohtani

{"title":"Comparative analysis of the single-molecule transport kinetics of OATP1B1 genetic variants","authors":"Kazunari Tsujii , Kodai Yajima , Takeshi Akiyoshi , Kazuho Sakamoto , Yoshiaki Suzuki , Takayuki Oka , Ayuko Imaoka , Hisao Yamamura , Junko Kurokawa , Hisakazu Ohtani","doi":"10.1016/j.jphs.2025.04.005","DOIUrl":"10.1016/j.jphs.2025.04.005","url":null,"abstract":"<div><div>Several genetic variants of OATP1B1, a hepatic uptake transporter, increase the blood concentrations of substrate drugs, e.g., ∗15 carriers exhibit higher blood substrate concentrations than ∗1b carriers. It remains unclear whether these differences are due to changes in expression or intrinsic activity (transport activity per OATP1B1 molecule). This study compared the intrinsic activity of four OATP1B1 variants, ∗1a, ∗1b, ∗5, and ∗15, using HEK293 cell lines that co-expressed large-conductance Ca<sup>2+</sup>-activated K<sup>+</sup> (BK) channels and one of the OATP1B1 variants. To estimate the kinetic parameters <em>K</em><sub>m</sub> and <em>V</em><sub>max</sub>, 2′, 7′-dichlorofluorescein uptake was evaluated. The number of OATP molecules per cell (Q<sub>T</sub>) was calculated from BK channel-mediated whole-cell conductance and the OATP1B1/BK channel expression ratio (ρ) (determined by LC-MS/MS). <em>V</em><sub>max,int</sub> (maximum intrinsic transport velocity) was obtained by dividing <em>V</em><sub>max</sub> by Q<sub>T</sub>, and intrinsic clearance (<em>CL</em><sub>int</sub>) was calculated as <em>V</em><sub>max,int</sub>/<em>K</em><sub>m</sub>. The <em>K</em><sub>m</sub> values of ∗1a, ∗1b, ∗5, and ∗15 were 12.5, 9.19, 7.53, and 10.4 μM, and their <em>V</em><sub>max,int</sub> values were 3.0, 7.0, 1.5, and 1.2 × 10<sup>−21</sup> mol/OATP molecule/min, respectively. Accordingly, the <em>CL</em><sub>int</sub> value for OATP1B1∗15 was 15 % lower than that for OATP1B1∗1b, suggesting that the increased blood substrate concentrations observed in OATP1B1∗15 carriers may be due to the decreased intrinsic activity of OATP1B1∗15.</div></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"158 3","pages":"Pages 166-171"},"PeriodicalIF":3.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143864009","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Centrally administered prostaglandin E2 suppresses the micturition reflex in rats 中央给药前列腺素E2抑制大鼠排尿反射

IF 3 3区医学

Journal of pharmacological sciences Pub Date : 2025-07-01 Epub Date: 2025-05-07 DOI: 10.1016/j.jphs.2025.05.005

Takahiro Shimizu , Nobutaka Shimizu , Shun Tsubouchi , Mio Togo , Youichirou Higashi , Motoaki Saito

{"title":"Centrally administered prostaglandin E2 suppresses the micturition reflex in rats","authors":"Takahiro Shimizu , Nobutaka Shimizu , Shun Tsubouchi , Mio Togo , Youichirou Higashi , Motoaki Saito","doi":"10.1016/j.jphs.2025.05.005","DOIUrl":"10.1016/j.jphs.2025.05.005","url":null,"abstract":"<div><div>Prostaglandin E<sub>2</sub> (PGE<sub>2</sub>) facilitates the micturition reflex at the lower urinary tract and spinal cord levels. However, the roles of brain PGE<sub>2</sub> in reflex regulation remain unclear. Therefore, we aimed to investigate the effects of intracerebroventricularly administered PGE<sub>2</sub> on the micturition reflex. We further investigated whether the PGE<sub>2</sub>-induced responses were dependent on the sympathetic nervous system (SNS) and identified the brain E-prostanoid receptor subtypes (EP<sub>1</sub>–EP<sub>4</sub>) involved in PGE<sub>2</sub>-induced effects. Intracerebroventricularly administered PGE<sub>2</sub> (0.1, 0.3, or 1 nmol/rat) dose-dependently increased the intercontraction intervals (ICI) and threshold pressure required to induce micturition (TP) without altering maximal voiding pressure in urethane-anesthetized (0.8 g/kg, ip) male rats. PGE<sub>2</sub> (1 nmol/rat) significantly increased the mean blood pressure; 6-hydroxydopamine-induced chemical sympathectomy ameliorated this increase. In contrast, chemical sympathectomy had no significant effect on the PGE<sub>2</sub>-induced increases in ICI and TP. Intracerebroventricularly pretreated SC51322 (EP<sub>1</sub> receptor antagonist, 100 nmol/rat) and PF04418948 (EP<sub>2</sub> receptor antagonist, 100 nmol/rat), but not L-798106 (EP<sub>3</sub> receptor antagonist, 100 nmol/rat) or L-161982 (EP<sub>4</sub> receptor antagonist, 100 nmol/rat), significantly attenuated the PGE<sub>2</sub> (1 nmol/rat)-induced changes in ICI and TP. These results suggest that centrally administered PGE<sub>2</sub> suppresses the rat micturition reflex through brain EP<sub>1</sub> and EP<sub>2</sub> receptors, independent of SNS activation.</div></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"158 3","pages":"Pages 231-237"},"PeriodicalIF":3.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143931633","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Pedunculoside regulates the differentiation of neural stem cells into neurons via the PI3K/AKT/GSK-3β pathway pedculloside通过PI3K/AKT/GSK-3β通路调控神经干细胞向神经元的分化

IF 3 3区医学

Journal of pharmacological sciences Pub Date : 2025-07-01 Epub Date: 2025-05-02 DOI: 10.1016/j.jphs.2025.05.002

Ruichen Jiang , Yuming Wang , Yanzhu Shen , Jiancheng Tang , Xiangsheng Tang , Haoning Ma , Ping Yi

{"title":"Pedunculoside regulates the differentiation of neural stem cells into neurons via the PI3K/AKT/GSK-3β pathway","authors":"Ruichen Jiang , Yuming Wang , Yanzhu Shen , Jiancheng Tang , Xiangsheng Tang , Haoning Ma , Ping Yi","doi":"10.1016/j.jphs.2025.05.002","DOIUrl":"10.1016/j.jphs.2025.05.002","url":null,"abstract":"<div><div>The aging population has increased neurodegenerative diseases, yet current therapies mostly relieve symptoms rather than halt disease progression. Neural stem cells (NSCs) are crucial in nervous system development and repair, and research on their proliferation and differentiation regulation is vital. This study aimed to explore the effect of pedunculoside (PE) on primary NSCs and its mechanism. NSCs from pregnant rats (E13 - E14) were cultured and studied using CCK - 8, EDU incorporation, immunofluorescence, Western blot, and molecular docking. Results showed PE significantly promoted NSC proliferation at 10 μM and 20 μM dose - dependently. It also enhanced neuronal differentiation, with increased TUJ - 1 and decreased GFAP. Molecular docking and Western blot revealed PE binds to PI3K, activates the PI3K/AKT/GSK-3β pathway, and promotes protein phosphorylation. The PI3K inhibitor experiment confirmed PE's effect on NSC differentiation is mediated by this pathway. This study provides evidence for PE's role in NSC research and advances nervous system disease treatment research.</div></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"158 3","pages":"Pages 276-282"},"PeriodicalIF":3.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143948132","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Unravelling the effects of specific ingredients of kamishoyosan in reducing aggressive biting behavior in chronically isolated mice to inanimate objects 揭示神生糖特定成分在减少长期隔离小鼠对无生命物体的攻击性咬伤行为中的作用

IF 3 3区医学

Journal of pharmacological sciences Pub Date : 2025-07-01 Epub Date: 2025-05-02 DOI: 10.1016/j.jphs.2025.05.001

Kento Igarashi , Satoshi Kuchiiwa , Toshiko Kuchiiwa , Tomoaki Sato

{"title":"Unravelling the effects of specific ingredients of kamishoyosan in reducing aggressive biting behavior in chronically isolated mice to inanimate objects","authors":"Kento Igarashi , Satoshi Kuchiiwa , Toshiko Kuchiiwa , Tomoaki Sato","doi":"10.1016/j.jphs.2025.05.001","DOIUrl":"10.1016/j.jphs.2025.05.001","url":null,"abstract":"<div><div>Kamishoyosan (KSS) is a well-known traditional Japanese herbal medicine used to treat psychiatric symptoms, such as irritation. We previously reported that KSS decreases mouse aggressive biting behavior (ABB) to inanimate objects using the Aggression Response Meter, however, it was not revealed which ingredient of KSS is effective. In this study, we used real-time reverse transcriptase (RT) PCR to investigate the mRNA expression of 5-HT-related genes in SH-SY5Y cells cultured in a medium containing the ten individual herbal medicines in KSS. The cells treated with shakuyaku showed increase of tryptophan hydroxylase mRNA expression, whereas those cultured in a medium containing botanpi showed decreased monoamine oxidase A and B mRNA levels. We investigated the ABB of mice administered with <em>Paeonia lactiflora</em> (shakuyaku) or <em>Paeonia suffruticosa</em> (botanpi). We also examined the gene expression in cells treated with paeoniflorin (PF), a main active component in shakuyaku, and the ABB of PF-treated mice. We found that shakuyaku or PF administration reduced ABB in male and female mice, whereas botanpi treatment mitigated ABB only in males. WAY-100635, a 5-HT1A receptor antagonist, abolished ABB-reducing effect of shakuyaku and botanpi. These results suggest that shakuyaku and botanpi are activate ingredient to reduce ABB through activation on serotoninergic neurotransmission.</div></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"158 3","pages":"Pages 259-269"},"PeriodicalIF":3.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143936647","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Early neuromyelitis optica antibody-induced molecular changes in aquaporin 4 and associated proteins at astrocyte endfeet in murine brain tissues 早期视神经脊髓炎抗体诱导小鼠脑组织星形胶质细胞终足水通道蛋白4及相关蛋白的分子变化

IF 3 3区医学

Journal of pharmacological sciences Pub Date : 2025-07-01 Epub Date: 2025-05-07 DOI: 10.1016/j.jphs.2025.05.007

Yumi Yoshikawa , Masaki Tomioka , Yoichiro Abe , Masato Yasui , Mutsuo Nuriya

{"title":"Early neuromyelitis optica antibody-induced molecular changes in aquaporin 4 and associated proteins at astrocyte endfeet in murine brain tissues","authors":"Yumi Yoshikawa , Masaki Tomioka , Yoichiro Abe , Masato Yasui , Mutsuo Nuriya","doi":"10.1016/j.jphs.2025.05.007","DOIUrl":"10.1016/j.jphs.2025.05.007","url":null,"abstract":"<div><div>Neuromyelitis optica spectrum disorder (NMOSD) is characterized by the production of autoantibodies against aquaporin 4 (AQP4). Because NMOSD progressively causes irreversible and severe neurological damages, understanding the initial molecular changes induced by anti-AQP4 antibody binding is crucial for designing early interventions. However, knowledge about the effects of the antibodies before AQP4 loss in brain tissues is limited. Using acutely prepared mouse brain slices, we aimed to investigate the initial molecular impact of NMO model antibodies on AQP4 and its associated proteins. We employed two different types of NMO model antibodies, E5415A and E5415B; E5415A recognizes both M1 and M23 isoforms, whereas E5415B exclusively binds to M23. We found that E5415A but not E5415B disrupted the uniform perivascular localization of AQP4, leading to fragmentation. We further addressed the impact of these changes on AQP4-associated proteins and found that strong colocalizations between AQP4 and dystrophin-glycoprotein complex (DGC) components were preserved, even after AQP4 localization pattern became fragmented. Thus, our study reveals the initial molecular changes in the AQP4 channel at the astrocytic endfeet in response to NMO model antibodies and highlights the early pathological events occurring in NMOSD.</div></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"158 3","pages":"Pages 212-218"},"PeriodicalIF":3.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143929572","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0