Journal of pharmacological sciences最新文献_第4页

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

Subacute intranasal oxytocin improves neurological recovery after ischemic stroke 亚急性鼻内催产素促进缺血性脑卒中后神经系统恢复

IF 2.9 3区医学 Q2 PHARMACOLOGY & PHARMACY

Journal of pharmacological sciences

Pub Date : 2025-08-22 DOI: 10.1016/j.jphs.2025.08.006

Yusuke Morishita , Youichirou Higashi , Daichi Tani , Mio Togo , Takahiro Shimizu , Mikiya Fujieda , Motoaki Saito

Oxytocin (OXT) is a neuropeptide known for its anti-inflammatory and neuroprotective properties; however, its role in post-stroke recovery remains poorly defined. In this study, we investigated whether intranasal OXT administration during the subacute phase of stroke improves neurological outcomes and modulates microglial responses. Male mice underwent permanent middle cerebral artery occlusion and received intranasal OXT (300 ng/g) or saline on days 3 and 5 post-stroke. Neurological function was assessed using the modified neurological severity score; infarct volume was evaluated through hematoxylin-eosin (HE) staining, and survival rates were monitored until day 7. Immunofluorescence was used to assess microglial polarization in the peri-infarct region. OXT-treated mice showed significantly greater functional improvement and higher survival rates than saline-treated controls. Infarct volume was significantly reduced, and microglial polarization was altered by OXT, with a decrease in pro-inflammatory M1-type markers and an increase in anti-inflammatory M2-type markers. These findings demonstrate that OXT promotes neurological recovery through anti-inflammatory and neuroprotective mechanisms. Given its feasibility as a non-invasive delivery method, intranasal OXT may offer a promising therapeutic approach to enhance post-stroke neurorepair.

催产素（OXT）是一种神经肽，以其抗炎和神经保护特性而闻名；然而，其在中风后恢复中的作用仍不明确。在这项研究中，我们调查了在中风亚急性期鼻内给予OXT是否能改善神经预后并调节小胶质细胞反应。雄性小鼠在脑卒中后第3天和第5天接受永久性大脑中动脉闭塞，并鼻内注射OXT （300 ng/g）或生理盐水。采用改良的神经功能严重程度评分评估神经功能；通过苏木精-伊红（HE）染色评估梗死体积，并监测生存率至第7天。免疫荧光法用于评估梗死周围区域的小胶质细胞极化。与盐水处理的对照组相比，oxt处理的小鼠表现出更大的功能改善和更高的存活率。OXT显著减少梗死体积，改变小胶质细胞极化，促炎m1型标记物减少，抗炎m2型标记物增加。这些发现表明，OXT通过抗炎和神经保护机制促进神经恢复。鉴于其作为非侵入性给药方法的可行性，鼻内OXT可能为增强脑卒中后神经修复提供一种有希望的治疗方法。

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引用次数: 0

Sulfasalazine disrupts the interaction between TNFα and TNFR1 thus inhibiting NF-kB signaling activation to promote bone fracture healing 磺胺吡啶破坏TNFα和TNFR1之间的相互作用，从而抑制NF-kB信号激活，促进骨折愈合

IF 2.9 3区医学 Q2 PHARMACOLOGY & PHARMACY

Journal of pharmacological sciences

Pub Date : 2025-08-21 DOI: 10.1016/j.jphs.2025.08.005

Jingwei Liu , Cheng Qiu , Xiaoxiong Wang , Ziqian Xiang , Junyuan Sun , Mingzheng Chang , Qingliang Ma , Yan Zhuang , Yunpeng Zhao , Qiang Yang , Lianlei Wang , Xinyu Liu

Fracture is a common type of traumas and alternative therapies to boost bone fracture healing is necessary. The aim of this study is to elucidate the role of sulfasalazine in bone fracture healing by using MC3T3-E1 cells in vitro and murine femoral fracture model in vivo. Western blotting, flow cytometry, RNA sequencing, Calcein AM/PI staining, Alizarin-Red-S staining, ALP activity assay, transmission electron microscope, histological staining, immunohistochemistry, immunofluorescence and Surface plasmon resonance analysis were performed in this study. Sulfasalazine failed to elicit ferroptosis in osteoblasts within acceptable dose manner while promoted osteogenic differentiation. Furthermore, sulfasalazine was identified to inhibit inflammation by declination of inflammatory biomarkers. Besides, TNFα was verified as a potential downstream target for sulfasalazine and the adverse effect of TNFα on osteogenic differentiation could be largely salvaged by sulfasalazine due to direct binding between these two molecules. RNA-seq further implied decreased transcription of genes related to NF-κB pathway. Murine study showed sulfasalazine promotes fracture healing as evidenced by increased bone remodeling both histologically and radiologically. Overall, sulfasalazine accelerates osteogenic differentiation and promotes bone healing by direct binding to and thus inhibiting TNFα, which subsequently suppresses NF-κB signaling. Therefore, sulfasalazine shows a promising outcome for the treatment of bone fracture.

骨折是一种常见的创伤类型，促进骨折愈合的替代疗法是必要的。本研究的目的是通过体外培养MC3T3-E1细胞和小鼠股骨骨折模型来阐明磺胺氮嗪在骨折愈合中的作用。Western blotting、流式细胞术、RNA测序、Calcein AM/PI染色、茜素红- s染色、ALP活性测定、透射电镜、组织学染色、免疫组织化学、免疫荧光和表面等离子体共振分析。在可接受的剂量范围内，柳氮磺胺吡啶不能诱导成骨细胞铁下垂，但能促进成骨分化。此外，磺胺吡啶通过降低炎症生物标志物来抑制炎症。此外，tnf - α被证实是磺胺氮嗪的潜在下游靶点，由于tnf - α与磺胺氮嗪之间的直接结合，tnf - α对成骨分化的不利影响可以在很大程度上被磺胺氮嗪挽救。RNA-seq进一步提示NF-κB通路相关基因的转录减少。小鼠研究表明，柳氮磺胺吡啶促进骨折愈合，这在组织学和放射学上都证明了骨重塑的增加。总体而言，磺胺氮嗪通过直接结合并抑制TNFα，从而抑制NF-κB信号传导，从而加速成骨分化并促进骨愈合。因此，柳氮磺胺吡啶显示出治疗骨折的良好结果。

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引用次数: 0

Protocatechuic aldehyde restrains NLRP3 inflammasome activation to alleviate inflammatory response in sepsis 原儿茶醛抑制NLRP3炎性体激活以减轻脓毒症的炎症反应

IF 2.9 3区医学 Q2 PHARMACOLOGY & PHARMACY

Journal of pharmacological sciences

Pub Date : 2025-08-21 DOI: 10.1016/j.jphs.2025.08.003

Yu-fei Li , Ao Sun , Yang Miao , Hong-xia Wang , Lin-lin Zhang

Sepsis, a life-threatening organ dysfunction syndrome triggered by infection, is characterized by complex pathophysiology involving dysregulated inflammation, coagulation abnormalities, and mitochondrial dysfunction. Excessive activation of the NLRP3 inflammasome plays a pivotal role in sepsis progression. This study investigated the therapeutic effects and underlying mechanisms of protocatechuic aldehyde (PCA) in sepsis. Seventy-five potential PCA targets for sepsis were identified, with KEGG enrichment highlighting involvement in inflammatory and apoptotic pathways. PPI network analysis pinpointed TNF, IL-6, and IL-1β as key inflammatory targets. PCA dose-dependently suppressed IL-1β and TNF-α release in LPS/ATP-stimulated macrophages, reduced ASC speck formation and NLRP3-ASC interaction, and decreased mt-ROS production and TXNIP-NLRP3 co-localization. PCA also preserved mitochondrial network integrity by interacting with mitochondrial dynamics proteins DRP1 and MFN2, improving mitochondrial membrane potential and morphology. In LPS-induced septic mice, PCA significantly reduced serum IL-1β and TNF-α levels, improved survival rates, and downregulated NLRP3, pro-IL-1β, and cleaved-IL-1β expression in peritoneal macrophages. PCA alleviates inflammatory responses and organ damage in septic mice by inhibiting the mt-ROS/TXNIP/NLRP3 signaling axis and maintaining mitochondrial function, offering a promising natural therapeutic candidate for sepsis.

脓毒症是一种由感染引发的危及生命的器官功能障碍综合征，其特点是复杂的病理生理，包括炎症失调、凝血异常和线粒体功能障碍。NLRP3炎性小体的过度激活在脓毒症的进展中起关键作用。本研究探讨了原儿茶醛（PCA）对脓毒症的治疗作用及其机制。鉴定出75个潜在的脓毒症PCA靶点，其中KEGG富集突出了炎症和凋亡途径的参与。PPI网络分析确定TNF， IL-6和IL-1β是关键的炎症靶点。PCA剂量依赖性地抑制LPS/ atp刺激的巨噬细胞IL-1β和TNF-α释放，减少ASC斑点形成和NLRP3-ASC相互作用，减少mt-ROS产生和TXNIP-NLRP3共定位。PCA还通过与线粒体动力学蛋白DRP1和MFN2相互作用，改善线粒体膜电位和形态，从而保持线粒体网络的完整性。在lps诱导的脓毒症小鼠中，PCA显著降低血清IL-1β和TNF-α水平，提高存活率，下调腹腔巨噬细胞中NLRP3、pro-IL-1β和cleaved-IL-1β的表达。PCA通过抑制mt-ROS/TXNIP/NLRP3信号轴和维持线粒体功能，减轻脓毒症小鼠的炎症反应和器官损伤，为脓毒症提供了一种有前景的天然治疗候选药物。

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引用次数: 0

(2R,6R)-hydroxynorketamine reverses mechanical and thermal pain hypersensitivity produced by the chemotherapeutic agent oxaliplatin in rats （2R,6R）-羟诺氯胺酮逆转大鼠化疗药物奥沙利铂产生的机械和热痛超敏反应

IF 2.9 3区医学 Q2 PHARMACOLOGY & PHARMACY

Journal of pharmacological sciences

Pub Date : 2025-08-20 DOI: 10.1016/j.jphs.2025.08.004

Maria Campanile , Kaitlin Castell , Justin O. Pampalone , Bruno Carabelli , Irwin Lucki , Caroline A. Browne

Chemotherapy-induced peripheral neuropathy (CIPN) is a common and debilitating side effect of a number of anticancer drugs, like oxaliplatin, leading to chronic sensory hypersensitivity and neuropathic pain. This study investigated the efficacy of (2R,6R)-hydroxynorketamine ((2R,6R)-HNK), a metabolite of ketamine, in a rat model of CIPN induced by oxaliplatin. Rats treated with oxaliplatin developed long-lasting mechanical and thermal hypersensitivity, as assessed by the Von Frey test and the hot plate test, respectively. A single injection of (2R,6R)-HNK (30 mg/kg, s.c.) significantly reversed both mechanical and thermal hypersensitivity for up to 24 h. Furthermore, repeated treatment with (2R,6R)-HNK (30 mg/kg/day) for 7 days produced sustained analgesia on mechanical hypersensitivity that persisted up to 14 days after treatment cessation. In comparison, repeated duloxetine (15 mg/kg/day, s.c.) showed only a short-lasting reduction of thermal hypersensitivity and no effect on mechanical hypersensitivity. Locomotor activity was not affected by (2R,6R)-HNK treatment, although duloxetine caused a transient decrease. This is the first demonstration that (2R,6R)-HNK produced analgesia in a rat model of CIPN. The persistence of analgesia with repeated treatment and sustained effects following treatment cessation suggests that (2R,6R)-HNK may represent a promising new therapeutic strategy for the rapid and sustained relief of pain associated with CIPN.

化疗引起的周围神经病变（CIPN）是许多抗癌药物（如奥沙利铂）的常见和衰弱的副作用，导致慢性感觉超敏反应和神经性疼痛。本研究探讨氯胺酮代谢物(2R,6R)-羟诺氯胺酮（(2R,6R)-HNK）在奥沙利铂诱导的大鼠CIPN模型中的作用。Von Frey试验和热板试验分别评估了奥沙利铂治疗大鼠出现持久的机械和热超敏反应。单次注射(2R,6R)-HNK （30 mg/kg, s.c）可显著逆转机械和热超敏反应长达24小时。此外，(2R,6R)-HNK （30 mg/kg/天）重复治疗7天，对机械超敏反应产生持续镇痛，持续到治疗停止后14天。相比之下，重复使用度洛西汀（15mg /kg/天，s.c）仅能短期减轻热过敏，对机械过敏没有影响。运动活动不受(2R,6R)-HNK治疗的影响，尽管度洛西汀引起短暂性下降。这是首次证明(2R,6R)-HNK在大鼠CIPN模型中产生镇痛作用。反复治疗后镇痛的持续性和停止治疗后的持续效果表明(2R,6R)-HNK可能是一种有希望的快速和持续缓解CIPN相关疼痛的新治疗策略。

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引用次数: 0