Journal of pharmacological sciences最新文献_第4页

Rho kinase 2 promotes epithelial-mesenchymal transition and proliferation in human prostate cancer PC-3 cells Rho激酶2促进人前列腺癌PC-3细胞上皮间质转化和增殖

IF 2.9 3区医学 Q2 PHARMACOLOGY & PHARMACY

Journal of pharmacological sciences

Pub Date : 2025-09-20 DOI: 10.1016/j.jphs.2025.09.007

Alamgir Hossain , Aya Yamamura , Md Junayed Nayeem , Sivasundaram Karnan , Rie Takahashi , Hisaki Hayashi , Motohiko Sato

Prostate cancer is the second most common cancer in men. Although androgen deprivation therapy is initially effective, resistance inevitably develops. Most patients eventually progress to castration-resistant prostate cancer, a stage with limited treatment options and poor prognosis. Rho kinases (ROCK1 and ROCK2) have been implicated in cancer progression, but their therapeutic targeting remains limited. This study examined the pathological roles of ROCK1 and ROCK2 in epithelial-mesenchymal transition (EMT) and proliferation of prostate cancer cells. ROCK1 expression was comparable between human prostate epithelial cells (PrECs) and androgen-independent prostate cancer cells, PC-3 and DU145. In contrast, ROCK2 expression was higher in PC-3 cells than in PrECs and DU145 cells. EMT marker analysis revealed that PC-3 cells exhibited decreased E-cadherin and increased N-cadherin and Snail expression. ROCK2 knockdown reversed this EMT phenotype, reducing cell proliferation, migration, 3D tumor spheroid formation, and spheroid cell viability. Similar inhibitory effects were observed by the ROCK2-selective blocker KD025 (IC₅₀ = 422 nM). Furthermore, ROCK2 deficiency attenuated the tumor growth of PC-3 cells in a xenograft mouse model. These findings indicate that ROCK2 promotes EMT process and tumor progression in PC-3 cells. Targeting ROCK2 may represent a promising therapeutic strategy for androgen-independent prostate cancer.

前列腺癌是男性中第二常见的癌症。虽然雄激素剥夺疗法最初是有效的，但不可避免地会产生耐药性。大多数患者最终发展为去势抵抗性前列腺癌，这一阶段的治疗选择有限，预后较差。Rho激酶（ROCK1和ROCK2）与癌症进展有关，但其治疗靶点仍然有限。本研究探讨了ROCK1和ROCK2在前列腺癌细胞上皮-间质转化（epithelial-mesenchymal transition， EMT）和增殖中的病理作用。ROCK1的表达在人前列腺上皮细胞（PrECs）和雄激素非依赖性前列腺癌细胞PC-3和DU145之间具有可同性。ROCK2在PC-3细胞中的表达高于PrECs和DU145细胞。EMT标记分析显示PC-3细胞E-cadherin表达减少，N-cadherin和Snail表达增加。ROCK2敲低逆转了这种EMT表型，减少了细胞增殖、迁移、3D肿瘤球状体形成和球状细胞活力。rock2选择性阻断剂KD025也有类似的抑制作用（IC50 = 422 nM）。此外，在异种移植小鼠模型中，ROCK2缺乏可减弱PC-3细胞的肿瘤生长。这些发现表明ROCK2促进了PC-3细胞的EMT过程和肿瘤进展。靶向ROCK2可能是治疗雄激素非依赖性前列腺癌的一种有希望的治疗策略。

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引用次数: 0

Establishing a nanoluciferase-based assay as a high-throughput screening platform for therapeutics in congenital nephrotic syndrome 建立一种基于纳米荧光素的检测方法，作为先天性肾病综合征治疗方法的高通量筛选平台

IF 2.9 3区医学 Q2 PHARMACOLOGY & PHARMACY

Journal of pharmacological sciences

Pub Date : 2025-09-20 DOI: 10.1016/j.jphs.2025.09.006

Haruki Tsuhako , Mary Ann Suico , Haruka Kojima , Saki Takahashi , Shunsuke Tanigawa , Misato Kamura , Ryoichi Sato , Riko Kato , Aimi Owaki , Ryuichi Nishinakamura , Tsuyoshi Shuto , Hirofumi Kai

Nephrin is crucial for the formation of the glomerular slit diaphragm, which is the final filtration barrier in the kidney. A mutation in the NPHS1 gene that codes for nephrin causes congenital nephrotic syndrome of the Finnish type (CNF). Most missense mutations render nephrin non-functional due to the defective nephrin trafficking to the cell membrane. Pharmacological approaches that induce the expression of nephrin on the cell membrane are feasible, but therapeutic development is hampered by the lack of a high-throughput screening (HTS) system. Here, we developed a nanoluciferase HiBiT-based HTS platform to quantify the cell membrane expression of a nephrin mutant. This evaluation system reflected the previously reported results of various nephrin mutant localization. Using this system, we screened and identified 10 compounds that promoted the expression of the nephrin E725D mutant on the cell membrane. Moreover, the phosphorylation and N-glycosylation of nephrin, which are modifications that indicate its cell surface localization, correlated with the luminescence values of HiBiT-Nephrin in the compound screening. Consequently, this HiBiT-Nephrin evaluation system could be a new platform for predicting the pathogenicity of variants and searching for therapeutic agents for CNF.

肾素对肾小球狭缝隔膜的形成至关重要，这是肾脏的最终滤过屏障。编码肾素的NPHS1基因突变导致芬兰型先天性肾病综合征（CNF）。大多数错义突变使肾素失去功能，这是由于肾素运输到细胞膜的缺陷。诱导肾素在细胞膜上表达的药理学方法是可行的，但由于缺乏高通量筛选（HTS）系统，治疗发展受到阻碍。在这里，我们开发了一个基于纳米荧光素酶hibit的HTS平台来量化肾素突变体的细胞膜表达。该评价体系反映了先前报道的各种肾素突变定位的结果。利用该系统，我们筛选并鉴定了10种促进肾素E725D突变体在细胞膜上表达的化合物。此外，nephrin的磷酸化和n -糖基化修饰（表明其细胞表面定位）与HiBiT-Nephrin在化合物筛选中的发光值相关。因此，该HiBiT-Nephrin评价系统可作为预测变异致病性和寻找CNF治疗药物的新平台。

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引用次数: 0

Rosiridin reduces Idiopathic Pulmonary Fibrosis by inhibiting the STAT3/NFκB/SMAD3 signaling pathways 罗西瑞定通过抑制STAT3/NFκB/SMAD3信号通路减少特发性肺纤维化

IF 2.9 3区医学 Q2 PHARMACOLOGY & PHARMACY

Journal of pharmacological sciences

Pub Date : 2025-09-19 DOI: 10.1016/j.jphs.2025.09.004

Yuyao Li , Huili Qi , Haoyue Xu , Xuehai Jia , Wenyan Chen , Ruoliu Pan , Xinhui Pan , Hangyu Wang , Dahong Yao , Ke Zhang , Jinhui Wang

Idiopathic pulmonary fibrosis is a progressive, highly lethal disease with limited treatment options. It is characterized by fibroblast-to-myofibroblast transformation, excessive ECM proliferation and collagen deposition, leading to the destruction of normal lung architecture and function. As a constituent of Rhodiola rosea L., rosiridin is a monomer with significant structural compatibility, conferring strong therapeutic potential. This bioactive compound mitigates oxidative stress-driven pathology and reverses its resultant damage in various diseases. However, its potential protective effects against bleomycin-induced IPF and the underlying mechanisms remain unclear. This study aimed to investigate the role and mechanism of rosiridin in IPF. Rosiridin attenuated TGF-β1-induced oxidative stress and inflammatory responses in lung epithelial cells and suppressed apoptosis associated with pulmonary fibrosis. Hematoxylin and eosin (HE) staining and Masson's trichrome staining showed that rosiridin improved pathological lung changes, reduced oxidative stress, and alleviated pulmonary fibrosis in a dose-dependent manner. Transcriptomic analysis revealed that rosiridin inhibited JAK protein activation, reduced the transformation of fibroblasts into myofibroblasts, and suppressed the secretion of proinflammatory and profibrotic cytokines. These findings suggest that rosiridin mitigates pulmonary fibrosis through modulation of the STAT3/NF-κB/SMAD3 signaling pathways. Rosiridin may represent a promising therapeutic candidate for the treatment of IPF.

特发性肺纤维化是一种进行性、高致命性疾病，治疗方案有限。其特点是成纤维细胞向肌成纤维细胞转化，ECM过度增殖和胶原沉积，导致正常肺结构和功能的破坏。作为红景天的组成成分，红景天苷是一种具有显著结构相容性的单体，具有很强的治疗潜力。这种生物活性化合物减轻氧化应激驱动的病理，并逆转其在各种疾病中产生的损害。然而，其对博莱霉素诱导的IPF的潜在保护作用及其潜在机制尚不清楚。本研究旨在探讨罗什瑞定在IPF中的作用及其机制。罗西瑞定可减弱TGF-β1诱导的肺上皮细胞氧化应激和炎症反应，抑制与肺纤维化相关的细胞凋亡。苏木精和伊红（HE）染色和马松三色染色显示罗西瑞定改善病理性肺改变，降低氧化应激，减轻肺纤维化呈剂量依赖性。转录组学分析显示，罗西瑞定抑制JAK蛋白活化，减少成纤维细胞向肌成纤维细胞的转化，抑制促炎和促纤维化细胞因子的分泌。这些发现表明，罗西瑞定通过调节STAT3/NF-κB/SMAD3信号通路减轻肺纤维化。罗西瑞定可能是治疗IPF的一个有希望的候选药物。

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引用次数: 0

Histone deacetylase inhibitors suppress retinal angiogenesis by preventing endothelial cell proliferation and accelerating VEGF degradation 组蛋白去乙酰化酶抑制剂通过阻止内皮细胞增殖和加速VEGF降解抑制视网膜血管生成

IF 2.9 3区医学 Q2 PHARMACOLOGY & PHARMACY

Journal of pharmacological sciences

Pub Date : 2025-09-17 DOI: 10.1016/j.jphs.2025.09.005

Akane Morita, Kanako Takahashi, Naoto Iizuka, Tsutomu Nakahara

Inhibitors of histone deacetylases (HDACs) suppress retinal angiogenesis by interrupting the vascular endothelial growth factor (VEGF)-mammalian target of rapamycin complex 1 (mTORC1) pathway in proliferating endothelial cells. To investigate the underlying mechanisms, we examined the effects of valproic acid (VPA) and vorinostat on the distribution of VEGF protein and phosphorylated S6 protein, an indicator of mTORC1 activity, in the neonatal mouse retina, an experimental model of retinal angiogenesis. Newborn mice were subcutaneously injected with VPA, vorinostat, or vehicle once daily from postnatal day (P) 0 to P3. Their eyes were collected at P4. Compared to vehicle-treated mice, retinal vascularization was delayed, and the number of proliferating vascular cells was reduced in front of the retinal vasculature in VPA- and vorinostat-treated mice. In P4 mice, a single injection of VPA or vorinostat reduced VEGF expression on the retinal surface at 2 and 6 h after injection. Both drugs reduced mTORC1 activity in proliferating endothelial cells. The proteasome inhibitor, MG132, suppressed the VPA- and vorinostat-induced reduction in VEGF expression on the retinal surface. These results suggest that HDAC inhibitors suppress retinal angiogenesis by preventing endothelial cell proliferation and accelerating VEGF protein degradation in a proteasome-dependent manner.

组蛋白去乙酰化酶（hdac）抑制剂通过阻断内皮细胞增殖中的血管内皮生长因子(VEGF)-哺乳动物雷帕霉素复合物1 （mTORC1）通路抑制视网膜血管生成。为了研究其潜在的机制，我们研究了丙戊酸（VPA）和伏立诺他对新生小鼠视网膜（视网膜血管生成的实验模型）中VEGF蛋白和磷酸化S6蛋白（mTORC1活性的指标）分布的影响。新生小鼠从出生后(P) 0至P3，每天1次皮下注射VPA、伏立诺他或对照物。他们的眼睛集中在P4。VPA-和伏立诺他处理小鼠视网膜血管化延迟，视网膜血管前增殖血管细胞数量减少。在P4小鼠中，单次注射VPA或伏立诺他可在注射后2和6小时降低视网膜表面VEGF的表达。这两种药物都降低了增殖内皮细胞中mTORC1的活性。蛋白酶体抑制剂MG132抑制VPA-和伏立诺他诱导的视网膜表面VEGF表达的降低。这些结果表明，HDAC抑制剂通过蛋白酶体依赖的方式阻止内皮细胞增殖和加速VEGF蛋白降解来抑制视网膜血管生成。

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引用次数: 0

MicroRNA-3473b regulates corticosterone-induced microglial polarization and inflammation through TREM2 MicroRNA-3473b通过TREM2调控皮质酮诱导的小胶质细胞极化和炎症

IF 2.9 3区医学 Q2 PHARMACOLOGY & PHARMACY

Journal of pharmacological sciences

Pub Date : 2025-09-16 DOI: 10.1016/j.jphs.2025.09.002

Jingjing Shi , Caina Ma , Yuexi Liu , Chao Yang , Jinyu Wu , Xiaohong Wang

引用次数: 0

Endothelial NLRP3-mediated pyroptosis induces blood-brain barrier and neuronal damage in Huntington's disease models 内皮nlrp3介导的焦亡诱导亨廷顿病模型血脑屏障和神经元损伤

IF 2.9 3区医学 Q2 PHARMACOLOGY & PHARMACY

Journal of pharmacological sciences

Pub Date : 2025-09-14 DOI: 10.1016/j.jphs.2025.09.003

Jing Cai , Wenshuang Ji , Peng Liu , Libo Zou

The NLRP3 inflammasome is primarily expressed and activated in microglial and endothelial cells. Extensive research has been conducted on the activation of NLRP3 inflammasomes by microglial cells leading to pyroptosis. However, there have been no reports on the activation of NLRP3 inflammasomes in brain vascular endothelial cells in patients with Huntington's disease (HD) or HD animal models, leading to blood-brain barrier (BBB) disruption. We herein found that BBB leakage increased and the expression of tight junction proteins significantly decreased after transfecting the mutant Huntingtin protein (mHtt) Q74 plasmid into the mouse brain microvascular endothelial cell line bEnd.3. mHtt promoted the activation of NLRP3 by brain vascular endothelial cells, and increased the expression of the pyroptosis-related proteins. This resulted in a decrease in the expression of the NeuN in the brain of hHTT130 transgenic mice. Furthermore, by downregulating NLRP3 in Q74-transfected bEnd.3 cells or in hHTT130 mouse brain vascular endothelial cells, BBB disruption and endothelial cell pyroptosis were alleviated, the number of surviving neurons was significantly increased. In conclusion, mHtt can activate the NLRP3 inflammasome in brain microvascular endothelial cells to induce endothelial cell pyroptosis, thereby disrupting the function of the BBB, leading to neuronal damage.

NLRP3炎性小体主要在小胶质细胞和内皮细胞中表达和激活。关于小胶质细胞激活NLRP3炎性小体导致焦亡的研究已经进行了大量的研究。然而，在亨廷顿病（HD）患者或HD动物模型的脑血管内皮细胞中，NLRP3炎症小体激活导致血脑屏障（BBB）破坏的报道尚未见报道。本研究发现，将突变型亨廷顿蛋白（mHtt） Q74质粒转染小鼠脑微血管内皮细胞系bend后，血脑屏障渗漏增加，紧密连接蛋白表达显著降低。mHtt促进了NLRP3被脑血管内皮细胞激活，并增加了热解相关蛋白的表达。这导致了hHTT130转基因小鼠大脑中NeuN表达的减少。此外，通过下调NLRP3在q74转染的bEnd。3细胞或在hHTT130小鼠脑血管内皮细胞中，血脑屏障破坏和内皮细胞焦亡均得到缓解，存活神经元数量明显增加。综上所述，mHtt可激活脑微血管内皮细胞内NLRP3炎性体，诱导内皮细胞焦亡，从而破坏血脑屏障功能，导致神经元损伤。

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引用次数: 0

Microtubule-dependent regulation of TMEM16A-mediated Ca2+-activated Cl− currents in vascular smooth muscle cells 血管平滑肌细胞中tmem16a介导的Ca2+激活Cl -电流的微管依赖性调节

IF 2.9 3区医学 Q2 PHARMACOLOGY & PHARMACY

Journal of pharmacological sciences

Pub Date : 2025-09-06 DOI: 10.1016/j.jphs.2025.09.001

Ryosuke Hemmi , Akane Suzukawa , Moe Fujiwara , Rubii Kondo , Yoshiaki Suzuki , Aya Yamamura , Hisao Yamamura

TMEM16A channels mediate Ca²⁺-activated Cl⁻ (Cl_Ca) currents in vascular smooth muscle cells (VSMCs), and their activity is influenced by cytoskeletal dynamics. The present study examined the functional role of microtubules in TMEM16A regulation. Treatment with microtubule polymerization inhibitors, colchicine and nocodazole, reduced plasma membrane localization of TMEM16A protein and TMEM16A-mediated Cl_Ca currents. Similar effects were observed in TMEM16A-expressing HEK293 cells, with IC₅₀ values of 3.0 μM for colchicine and 0.6 μM for nocodazole. In contrast, acute application had no significant effect. These findings indicate that microtubules are required for maintaining the expression and functional activity of TMEM16A channels in VSMCs.

TMEM16A通道介导血管平滑肌细胞（VSMCs）中Ca2+激活的Cl - (ClCa)电流，其活性受细胞骨架动力学的影响。本研究探讨了微管在TMEM16A调控中的功能作用。微管聚合抑制剂、秋水仙碱和诺可达唑可降低TMEM16A蛋白的质膜定位和TMEM16A介导的ClCa电流。在表达tmem16a的HEK293细胞中也观察到类似的效果，秋水仙碱的IC50值为3.0 μM，诺可唑的IC50值为0.6 μM。急性应用无明显效果。这些发现表明，微管是维持vsmc中TMEM16A通道表达和功能活性所必需的。

引用次数: 0

Protective role of orphan G protein-coupled receptor GPR35 in the pathogenesis of colitis through regulating epithelial barrier function and immune responses 孤儿G蛋白偶联受体GPR35通过调节上皮屏障功能和免疫应答在结肠炎发病中的保护作用

IF 2.9 3区医学 Q2 PHARMACOLOGY & PHARMACY

Journal of pharmacological sciences

Pub Date : 2025-08-27 DOI: 10.1016/j.jphs.2025.08.009

Koga Tokuyama , Hiroyuki Yasuda , Michiko Saito , Shusaku Hayashi , Shinichi Kato

Background and objective

GPR35 is involved in the pathogenesis of colitis. However, because GPR35 is expressed in colonic epithelial and inflammatory/immune cells, its precise protective mechanisms remain unclear. We investigated the role of GPR35 in colitis, especially its relation to epithelial barrier function and inflammatory/immune responses.

Methods

We performed GPR35 knockout (KO) in a dextran sodium sulfate (DSS)-induced murine colitis model and elucidated the role of GPR35 through various experiments, including histological analysis, intestinal permeability, immunohistochemical staining, RT-qPCR, and western blotting.

Results

GPR35KO mice exhibited significantly exacerbated DSS-induced colitis, accompanied by upregulation of cytokines, compared with wild-type (WT) mice. An investigation using bone marrow (BM)-chimeric mice revealed that GPR35KO, which is expressed in both hematopoietic and non-hematopoietic cells, contributed to this exacerbation. GPR35KO mice showed significantly increased intestinal permeability compared with WT mice under normal conditions. Although no differences were observed in goblet cell number or epithelial proliferation between WT and GPR35KO mice, the expression levels of intercellular junction proteins were significantly lower in the normal colons of GPR35KO mice. Lipopolysaccharide-stimulated cytokine expression was significantly enhanced in BM-derived macrophages obtained from GPR35KO mice compared with WT mice.

Conclusions

GPR35 contributes to colonic protection by regulating epithelial barrier function and inflammatory/immune responses.

背景与目的vegpr35参与结肠炎的发病机制。然而，由于GPR35在结肠上皮细胞和炎症/免疫细胞中表达，其确切的保护机制尚不清楚。我们研究了GPR35在结肠炎中的作用，特别是它与上皮屏障功能和炎症/免疫反应的关系。方法对葡聚糖硫酸钠（DSS）诱导的小鼠结肠炎模型进行GPR35基因敲除（KO），并通过组织学分析、肠通透性、免疫组化染色、RT-qPCR和western blotting等实验来阐明GPR35的作用。结果与野生型（WT）小鼠相比，gpr35ko小鼠表现出明显加重的dss诱导的结肠炎，并伴有细胞因子上调。一项使用骨髓（BM）嵌合小鼠的研究表明，在造血细胞和非造血细胞中表达的GPR35KO导致了这种恶化。与正常情况下的WT小鼠相比，GPR35KO小鼠的肠通透性明显增加。虽然WT和GPR35KO小鼠在杯状细胞数量和上皮细胞增殖方面没有差异，但GPR35KO小鼠正常结肠中细胞间连接蛋白的表达水平明显降低。与WT小鼠相比，GPR35KO小鼠脑源性巨噬细胞中脂多糖刺激的细胞因子表达显著增强。结论sgpr35通过调节上皮屏障功能和炎症/免疫反应参与结肠保护。

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引用次数: 0

Aprepitant attenuates cutaneous mast cell migration in oxaliplatin-treated mice 阿瑞吡坦减轻奥沙利铂治疗小鼠皮肤肥大细胞的迁移

IF 2.9 3区医学 Q2 PHARMACOLOGY & PHARMACY

Journal of pharmacological sciences

Pub Date : 2025-08-25 DOI: 10.1016/j.jphs.2025.08.008

Tsugunobu Andoh

This study investigated whether tachykinin NK1 receptor antagonist aprepitant (APT) inhibits oxaliplatin (OXP)-induced cutaneous mast cell migration in mice. OXP-induced mast cell migration was inhibited by repeated oral administration of APT. OXP increased the expression of monocyte chemotactic protein-1 (MCP-1), stem cell factor (SCF), and interleukin-3 (IL-3), but not platelet-derived endothelial cell growth factor in the plantar skin. APT inhibited OXP-induced MCP-1, but not IL-3, expression. The expression of SCF tended to be inhibited by APT. These results suggest that APT attenuates OXP-induced cutaneous mast cell migration mainly by inhibiting the expression of MCP-1 and SCF.

本研究探讨速激肽NK1受体拮抗剂阿瑞匹坦（aprepitant， APT）是否抑制奥沙利铂（OXP）诱导的小鼠皮肤肥大细胞迁移。反复口服APT可抑制OXP诱导的肥大细胞迁移。OXP可增加足底皮肤单核细胞趋化蛋白-1 （MCP-1）、干细胞因子（SCF）和白细胞介素-3 （IL-3）的表达，但不影响血小板来源的内皮细胞生长因子的表达。APT抑制oxp诱导的MCP-1的表达，但不抑制IL-3的表达。这些结果表明，APT主要通过抑制MCP-1和SCF的表达来减弱oxp诱导的皮肤肥大细胞迁移。

引用次数: 0

TRPV1 antagonist AMG9810 suppresses focal epileptiform discharges and seizures by decreasing extracellular glutamate concentrations in mice TRPV1拮抗剂AMG9810通过降低小鼠细胞外谷氨酸浓度抑制局灶性癫痫样放电和癫痫发作

IF 2.9 3区医学 Q2 PHARMACOLOGY & PHARMACY

Journal of pharmacological sciences

Pub Date : 2025-08-22 DOI: 10.1016/j.jphs.2025.08.007

Hiroshi Moriyama , Hirochika Imoto , Sadahiro Nomura , Naomasa Mori , Yuichi Maruta , Natsumi Fujii , Shunsuke Fujitsuku , Hideyuki Ishihara

The development of targeted anti-epilepsy drugs is crucial, as 30 % of patients with epilepsy are resistant to current therapeutics. Transient receptor potential vanilloid 1 (TRPV1) channel antagonists have been demonstrated to suppress drug-induced epileptiform discharges (EDs) and seizures (ESs). Here, we investigated the correlation between the anti-epileptiform efficacy of AMG9810 and extracellular glutamate levels. The somatosensory cortices of male C57BL/6N mice were intracortically injected with penicillin G (PG: 200 IU, 1 μL/10 min), a seizure inducer that inhibits the GABA_A receptor. The mice were intracortically injected with AMG9810 (3 μM, 1 μL/10 min) either before or after PG administration. EDs, ESs, and glutamate levels were subsequently evaluated. The results of each experiment were compared between the vehicle and AMG9810-injected groups. AMG9810 injected after PG reduced glutamate levels and ED power, and there was a positive correlation between AMG9810 efficacy and these parameters. Injecting AMG9810 before PG injection decreased the increase in glutamate levels and development of EDs and ESs, with positive correlations observed among the three parameters. These findings suggest that TRPV1 antagonists suppress the development of EDs and ESs by decreasing extracellular glutamate levels, indicating that TRPV1 channels may represent a promising treatment option for epilepsy.

开发靶向抗癫痫药物至关重要，因为30%的癫痫患者对目前的治疗方法具有耐药性。瞬时受体电位香草样蛋白1 （TRPV1）通道拮抗剂已被证明可抑制药物诱导的癫痫样放电（EDs）和癫痫发作（ESs）。在此，我们研究了AMG9810抗癫痫疗效与细胞外谷氨酸水平的相关性。在雄性C57BL/6N小鼠体感觉皮质内注射抑制GABAA受体的癫痫诱变剂青霉素G （PG: 200 IU, 1 μL/10 min）。在给药前后分别向小鼠皮质内注射AMG9810 （3 μM, 1 μL/10 min）。随后评估EDs、ESs和谷氨酸水平。将各组实验结果与注射amg9810组进行比较。PG后注射AMG9810可降低谷氨酸水平和ED功率，且AMG9810疗效与上述参数呈正相关。PG注射前注射AMG9810降低了谷氨酸水平的升高和ed、ESs的发生，三者之间呈正相关。这些发现表明，TRPV1拮抗剂通过降低细胞外谷氨酸水平来抑制EDs和ESs的发展，表明TRPV1通道可能是一种有希望的癫痫治疗选择。

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引用次数: 0