Journal of pharmacological sciences最新文献

英文中文

Clonidine-induced tension changes in guinea pig thoracic aorta: roles of α1L-adrenoceptors, L-type voltage-dependent Ca2+ channels, and K+ channels 可乐定诱导的豚鼠胸主动脉张力变化：α 1l肾上腺素受体、l型电压依赖性Ca2+通道和K+通道的作用

IF 2.9 3区医学 Q2 PHARMACOLOGY & PHARMACY

Journal of pharmacological sciences

Pub Date : 2025-11-10 DOI: 10.1016/j.jphs.2025.11.002

Keisuke Obara, Ryusei Ono, Daiki Kato, Minori Gohara, Qianghaodi Hong, Yusuke Matsuyama, Ayano Yashiro, Kento Yoshioka, Yoshio Tanaka

We pharmacologically analyzed clonidine-induced tension changes in endothelium-denuded guinea pig thoracic aorta (GP-TA). Clonidine alone produced little change in basal tension; however, in the presence of tetraethylammonium (TEA) or Ba²⁺, it elicited a pronounced contraction that was almost completely abolished by verapamil. In contrast, phenylephrine alone evoked a robust contraction, which was also further enhanced in the presence of Ba²⁺; this Ba²⁺-potentiated component was nearly abolished by verapamil. The Ba²⁺-enhanced clonidine-evoked contraction was insensitive to the α₂-adrenoceptor (AR) antagonist idazoxan but was competitively inhibited by the α₁-AR antagonists prazosin and tamsulosin, yielding pA₂ values of 8.26 and 9.92, respectively. Clonidine competitively inhibited phenylephrine-induced contraction, with a pA₂ value of 5.67 in the presence of verapamil. Moreover, clonidine suppressed the sustained component of the phenylephrine response; this inhibition was attenuated by Ba²⁺ but remained unchanged in the presence of verapamil. These findings indicate that, in GP-TA, clonidine acts as a biased and partial agonist primarily at α_1L-ARs, promoting Ca²⁺ influx through L-type voltage-dependent Ca²⁺ channels (VDCCs). These L-type VDCC-mediated responses are negatively regulated by Ba²⁺-sensitive K⁺ channels. In addition, clonidine itself appears to directly or indirectly activate Ba²⁺-sensitive K⁺ channels, thereby suppressing the α_1L-AR–L-type VDCC functional coupling.

我们从药理学上分析了可乐定诱导的内皮剥落豚鼠胸主动脉（GP-TA）的张力变化。可乐定对基底张力变化不大；然而，在四乙基铵（TEA）或Ba2+存在时，它引起明显的收缩，而维拉帕米几乎完全消除了这种收缩。相比之下，单用苯肾上腺素引起了强烈的收缩，在Ba2+的存在下收缩也进一步增强；这种Ba2+增强成分几乎被维拉帕米消除。Ba2+增强的clonidine诱发的收缩对α2-肾上腺素受体（AR）拮抗剂idazoxan不敏感，但被α1-AR拮抗剂prazosin和tamsulosin竞争性抑制，pA2值分别为8.26和9.92。可乐定竞争性地抑制苯肾上腺素诱导的收缩，维拉帕米存在时pA2值为5.67。此外，可乐定抑制了苯肾上腺素反应的持续成分；这种抑制作用被Ba2+减弱，但在维拉帕米存在时保持不变。这些发现表明，在GP-TA中，可乐定主要在α1L-ARs中作为一种偏倚和部分激动剂，通过l型电压依赖性Ca2+通道（VDCCs）促进Ca2+内流。这些l型vdcc介导的反应受到Ba2+敏感的K+通道的负调控。此外，可乐定本身似乎直接或间接激活Ba2+敏感的K+通道，从而抑制α 1l - ar - l型VDCC功能偶联。

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引用次数: 0

Bidirectional effects of orexin receptor antagonists on long-term potentiation in the hippocampus of wild type and Alzheimer's disease model mice 食欲素受体拮抗剂对野生型和阿尔茨海默病模型小鼠海马长期增强的双向作用

IF 2.9 3区医学 Q2 PHARMACOLOGY & PHARMACY

Journal of pharmacological sciences

Pub Date : 2025-11-10 DOI: 10.1016/j.jphs.2025.11.003

Yoshiaki Ohi , Kazuhiro Hada , Yuki Murata , Daisuke Kodama , Yoshifumi Wakiya

The orexinergic system is dysregulated in patients with Alzheimer's disease (AD). In the present study, we evaluated the effects of chronic administration of dual orexin receptor antagonists, suvorexant (Suv) and lemborexant (Lem), on long-term potentiation (LTP) in the hippocampal CA1 region of wild-type (WT) and APP^NL−G-F knock-in (APP-KI) mice. LTP was enhanced in APP-KI mice compared with WT mice. Chronic administration of Suv and Lem further potentiated LTP in WT mice. In contrast, in APP-KI mice, Suv moderately and Lem markedly reduced LTP. These findings suggest that orexin receptor antagonists bidirectionally modulate LTP in WT and AD model mice.

阿尔茨海默病（AD）患者的食欲能系统失调。在本研究中，我们评估了长期给药双重食欲素受体拮抗剂suvorexant （Suv）和lemborexant （Lem）对野生型（WT）和APPNL−G-F敲入（APP-KI）小鼠海马CA1区长期增强（LTP）的影响。与WT小鼠相比，APP-KI小鼠的LTP增强。长期给药Suv和Lem进一步增强了WT小鼠的LTP。而在APP-KI小鼠中，中度Suv和Lem均能显著降低LTP。这些发现提示食欲素受体拮抗剂可双向调节WT和AD模型小鼠的LTP。

引用次数: 0

Male mice recognize male-emitted ultrasonic vocalizations in a two-choice test via oxytocin signaling 在一项双选项测试中，雄性小鼠通过催产素信号识别雄性发出的超声波

IF 2.9 3区医学 Q2 PHARMACOLOGY & PHARMACY

Journal of pharmacological sciences

Pub Date : 2025-11-08 DOI: 10.1016/j.jphs.2025.11.001

Tomoya Takemoto , Shotaro Kawano , Rei Endo , Kohei Kitagawa , Yukio Ago , Takefumi Kikusui , Hitoshi Hashimoto , Takanobu Nakazawa

Social behaviors rely on the integration of multiple sensory cues. Among these, ultrasonic vocalizations (USVs) serve as primary auditory cues in rodents. Although the function of USVs has been extensively studied in pup–female and male–female interactions, their role in male–male interactions remain to be elucidated. We tested whether adult male mice recognize male-emitted USVs as social cues using a two-choice playback paradigm. We demonstrated that male mice preferred male-emitted USVs and that oxytocin signaling is essential for perceiving male-emitted USVs. This study provides new insights into the neural mechanisms of male–male social behavior.

社会行为依赖于多种感官线索的整合。其中，超声发声（usv）是啮齿动物的主要听觉线索。虽然usv在幼崽-雌性和雄性-雌性相互作用中的功能已经被广泛研究，但它们在雄性-雄性相互作用中的作用仍有待阐明。我们测试了成年雄性小鼠是否识别雄性发出的usv作为社会线索使用双选择回放范式。我们证明了雄性小鼠更喜欢雄性发出的usv，并且催产素信号对于感知雄性发出的usv是必不可少的。这项研究为研究男性社会行为的神经机制提供了新的见解。

引用次数: 0

Spinal dopamine D1/D2 receptor complex stimulates NGF release to activate astrocytes and promote neuropathic pain 脊髓多巴胺D1/D2受体复合物刺激NGF释放，激活星形胶质细胞，促进神经性疼痛

IF 2.9 3区医学 Q2 PHARMACOLOGY & PHARMACY

Journal of pharmacological sciences

Pub Date : 2025-11-01 DOI: 10.1016/j.jphs.2025.10.005

Yi-Ni Bao , Zi-Meng Zhang , Han Jiang , Rui Wang , Shen Zhang , Dan-Li Zhou , Wen-Ling Dai , Ji-Hua Liu

Aims

Blocking peripheral nerve growth factor (NGF) obviously alleviated neuropathic pain, however, the effect and mechanism of spinal NGF in neuropathic pain are remain controversial. This study further investigated the mechanism by which peripheral NGF is involved in neuropathic pain and found safe, natural compounds that target NGF to attenuate neuropathic pain.

Methods

Chronic constriction injury (CCI) of the sciatic nerve was used to instill neuropathic pain. Pain behaviors were assessed using Von Frey filaments and Hargreaves test. For in vitro studies, primary neurons and astrocytes were cultured. RT-PCR, immunofluorescence and Western blot were used to assess the cell signaling pathway.

Results

Blocking spinal NGF effectively reduced CCI-induced neuropathic pain and suppressed astrocyte activation both in vivo and in vitro. The trends of changes in spinal NGF and the astrocyte marker matched the trends of changes in pain thresholds in CCI. Moreover, NGF-induced hypersensitivity could be abolished by astrocyte inhibitor. NGF was found mainly expressed in spinal neurons, and that the NGF receptor tropomyosin receptor kinase A (TrkA) but not p75, was widely expressed in spinal astrocytes. Dopamine D1/D2 receptor complex could promote NGF expression in spinal neurons, which bind to TrkA to promote astrocytes activation via ASK1-JNK/NF-κB signaling.

Conclusions

These findings imply that D1/D2 receptor complex promotes NGF secretion in spinal neurons, which bind to TrkA to promote astrocyte activation and neuropathic pain via ASK1/JNK/NF-κB pathway.

目的阻断周围神经生长因子（NGF）可明显减轻神经性疼痛，但脊髓NGF在神经性疼痛中的作用和机制仍存在争议。本研究进一步研究了外周NGF参与神经性疼痛的机制，并发现了安全、天然的靶向NGF减轻神经性疼痛的化合物。方法采用坐骨神经慢性收缩损伤法（CCI）灌注神经性疼痛。采用Von Frey细丝法和Hargreaves法评估疼痛行为。体外培养原代神经元和星形胶质细胞。采用RT-PCR、免疫荧光和Western blot检测细胞信号通路。结果阻断脊髓NGF可有效减轻cci诱导的神经性疼痛，抑制星形胶质细胞的激活。脊髓NGF和星形胶质细胞标志物的变化趋势与CCI疼痛阈值的变化趋势一致。星形胶质细胞抑制剂可消除ngf诱导的超敏反应。NGF主要在脊髓神经元中表达，NGF受体原肌球蛋白受体激酶A （TrkA）在脊髓星形胶质细胞中广泛表达，而p75不表达。多巴胺D1/D2受体复合物可促进脊髓神经元中NGF的表达，NGF与TrkA结合，通过ASK1-JNK/NF-κB信号通路促进星形胶质细胞活化。结论D1/D2受体复合物促进脊髓神经元分泌NGF， NGF通过ASK1/JNK/NF-κB通路与TrkA结合，促进星形胶质细胞活化和神经性疼痛。

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引用次数: 0

Feasibility of recent peptide therapy for ischemic stroke: a comprehensive exploration 新近多肽治疗缺血性脑卒中的可行性：综合探讨

IF 2.9 3区医学 Q2 PHARMACOLOGY & PHARMACY

Journal of pharmacological sciences

Pub Date : 2025-10-31 DOI: 10.1016/j.jphs.2025.10.007

Kuo-Feng Tseng , Kuo-Wei Tseng , Hsien-Yin Liao , Pei-Hsien Chen

Ischemic stroke is a prominent cause of disability and mortality worldwide, currently no drug therapy is helpful for post-stroke symptoms; thus, there is a need to develop effective treatment strategies. Peptide medication development has advanced significantly in the recent years and due to its potential to modulate key molecular pathways involved in stroke pathophysiology. This review provides an overview of recent advances in peptide therapy for stroke. These peptides can exert neuroprotective effects by inhibiting excitotoxicity, oxidative stress, and apoptosis, while also promoting neuronal survival and synaptic plasticity. Furthermore, artificial intelligence (AI) with deep learning holds a promising technique in peptide generation by enabling the design of novel peptides with specific binding site of a protein, this may accelerate drug discovery processes through predictive modeling and high-throughput analysis. Overall, peptide therapy holds great potential for improving stroke outcomes and represents a promising avenue for the development of novel stroke treatments.

缺血性卒中是世界范围内致残和死亡的主要原因，目前没有药物治疗对卒中后症状有帮助；因此，有必要制定有效的治疗策略。肽药物的发展近年来取得了显著进展，因为它有可能调节中风病理生理的关键分子途径。本文综述了肽治疗脑卒中的最新进展。这些肽可以通过抑制兴奋毒性、氧化应激和细胞凋亡发挥神经保护作用，同时还可以促进神经元存活和突触可塑性。此外，具有深度学习的人工智能（AI）通过设计具有蛋白质特定结合位点的新肽，在肽生成中具有很好的前景，这可能通过预测建模和高通量分析加速药物发现过程。总的来说，肽治疗在改善中风预后方面具有很大的潜力，并代表了一种有希望的新型中风治疗方法的发展。

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引用次数: 0

Extracellular zinc suppresses microglial inflammatory shift via Zrt- and Irt-related protein 12-dependent uptake 细胞外锌通过Zrt-和irt相关蛋白12依赖性摄取抑制小胶质细胞炎症转移

IF 2.9 3区医学 Q2 PHARMACOLOGY & PHARMACY

Journal of pharmacological sciences

Pub Date : 2025-10-30 DOI: 10.1016/j.jphs.2025.10.006

Takaaki Aratake , Youichirou Higashi , Takahiro Shimizu , Satoshi Fukata , Motoaki Saito

Microglia exhibit phenotypic plasticity between anti-inflammatory M2 and pro-inflammatory M1 states, and the transition from M2 to M1 is implicated in the progression of acute brain injuries. However, the molecular mechanisms that regulate this phenotypic shift remain poorly understood. Zn²⁺, stored in presynaptic vesicles, is extracellularly released during pathological events, such as cerebral ischemia, and modulates microglial function. In this study, we aimed to investigate the role of extracellular Zn²⁺ in the M2-to-M1 transition using BV2 microglial cells. Pretreatment with ZnCl₂ during M2 polarization significantly suppressed lipopolysaccharide-induced production of interleukin (IL)-6 and tumor necrosis factor-α following the phenotypic shift. Among the zinc transporters, Zrt- and Irt-related protein 12 (ZIP12) expression was markedly upregulated by IL-4 stimulation, and siRNA-mediated knockdown of ZIP12 abolished the Zn²⁺-mediated suppression of pro-inflammatory cytokine production. Furthermore, ZIP12 knockdown reduced intracellular Zn²⁺ accumulation in IL-4-treated microglia, as revealed by FluoZin-3 fluorescence. These findings indicate that extracellular Zn²⁺ is taken up via ZIP12 during M2 polarization and subsequently acts to suppress pro-inflammatory cytokine production, thereby restraining the shift toward an M1 phenotype.

小胶质细胞在抗炎M2和促炎M1状态之间表现出表型可塑性，从M2到M1的转变与急性脑损伤的进展有关。然而，调控这种表型转变的分子机制仍然知之甚少。Zn2+储存在突触前囊泡中，在脑缺血等病理事件中被细胞外释放，并调节小胶质细胞功能。在这项研究中，我们旨在通过BV2小胶质细胞研究细胞外Zn2+在m2到m1转化中的作用。在M2极化过程中，ZnCl2预处理显著抑制脂多糖诱导的白细胞介素(IL)-6和肿瘤坏死因子-α在表型转移后的产生。在锌转运体中，IL-4刺激可显著上调Zrt-和irt相关蛋白12 （ZIP12）的表达，sirna介导的ZIP12敲低可消除Zn2+介导的促炎细胞因子产生的抑制。此外，氟ozin -3荧光显示，ZIP12敲除减少了il -4处理的小胶质细胞内Zn2+的积累。这些发现表明，细胞外Zn2+在M2极化过程中通过ZIP12被吸收，随后抑制促炎细胞因子的产生，从而抑制向M1表型的转变。

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引用次数: 0

TEMPORARY REMOVAL: Development and application of a method for quantitative monitoring of Isepamicin plasma concentration in human plasma based on liquid chromatography-mass spectrometry. 临时去除：基于液相色谱-质谱法定量监测人血浆中异帕霉素浓度的方法的开发与应用。

IF 2.9 3区医学 Q2 PHARMACOLOGY & PHARMACY

Journal of pharmacological sciences

Pub Date : 2025-10-28 DOI: 10.1016/j.jphs.2025.10.003

Lili Cui, Yanru Liu, Zhipeng Wang, Jingxue Liu, Shouhong Gao, Yi Shan, Xia Tao, Deduo Xu

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引用次数: 0

Effects of nicotine- and tar-free smoke extracts from combustible cigarettes and heated tobacco products on the function of neutrophil-like HL-60 cells 可燃香烟和加热烟草制品中不含尼古丁和焦油的烟雾提取物对嗜中性粒细胞样HL-60细胞功能的影响

IF 2.9 3区医学 Q2 PHARMACOLOGY & PHARMACY

Journal of pharmacological sciences

Pub Date : 2025-10-27 DOI: 10.1016/j.jphs.2025.10.004

Yuichi Mazaki , Soichi Miwa , Ryosuke Shinkai , Takahiro Horinouchi

Impaired neutrophil function is thought to increase infection risk associated with smoking. We examined the effects of nicotine- and tar-free cigarette smoke extracts (CSEs) from combustible cigarettes (CCs) and heated tobacco products (HTPs) on neutrophil-like HL-60 cells. HTP-derived CSEs exhibited lower cytotoxicity and milder impairment of neutrophil functions, including chemotaxis, reactive oxygen species production, phagocytosis, and neutrophil extracellular trap formation, than those of CC-derived CSEs. However, at higher concentrations, HTP-derived CSEs markedly impaired the cell viability and function. These results indicate that HTP emissions impair neutrophil functions at high concentrations, highlighting the need for cautious health risk evaluation.

中性粒细胞功能受损被认为会增加与吸烟有关的感染风险。我们研究了从可燃香烟（CCs）和加热烟草制品（HTPs）中提取的不含尼古丁和不含焦油的香烟烟雾提取物（ses）对中性粒细胞样HL-60细胞的影响。与cc衍生的CSEs相比，htp衍生的CSEs表现出较低的细胞毒性和较轻的中性粒细胞功能损害，包括趋化性、活性氧产生、吞噬作用和中性粒细胞胞外陷阱形成。然而，在较高浓度下，htp衍生的CSEs明显损害细胞活力和功能。这些结果表明，HTP排放在高浓度下损害中性粒细胞功能，强调需要谨慎的健康风险评估。

引用次数: 0

Astaxanthin suppress ferroptosis through the Akt1-FoxO3a signaling pathway to alleviates brain injury after intracerebral hemorrhage 虾青素通过Akt1-FoxO3a信号通路抑制铁下垂，减轻脑出血后脑损伤

IF 2.9 3区医学 Q2 PHARMACOLOGY & PHARMACY

Journal of pharmacological sciences

Pub Date : 2025-10-17 DOI: 10.1016/j.jphs.2025.10.002

Jianwen Zhang , Qiuwei Hua , Lun Gao , Shangwen Yang , Minghui Lu , Qiang Cai

Intracerebral hemorrhage is the second most common subtype of stroke, characterized by high mortality and disability rates. To date, the mechanism of brain injury caused by intracerebral hemorrhage remains unclear, and there are no effective treatments to delay the progression of brain injury after intracerebral hemorrhage. Increasing evidence suggests that oxidative stress plays a crucial role in secondary injury induced by intracerebral hemorrhage, and ferroptosis plays a dominant role in the pathogenesis of brain injury after intracerebral hemorrhage.

In this study, we demonstrated in an in vitro hemin-induced PC12 cell model that astaxanthin improved cell viability, inhibited oxidative stress after intracerebral hemorrhage, and suppressed ferroptosis by upregulating the expression of glutathione peroxidase 4 and solute carrier family 7a member 11. In an in vivo autologous blood injection intracerebral hemorrhage rat model, we confirmed that astaxanthin could resist oxidative stress, ferroptosis, and further inflammatory responses by upregulating the expression of glutathione peroxidase 4 and solute carrier family 7a member 11 through the Akt1-FoxO3a pathway to protect against brain injury after intracerebral hemorrhage.

脑出血是中风的第二大常见亚型，其特点是高死亡率和致残率。迄今为止，脑出血引起脑损伤的机制尚不清楚，也没有有效的治疗方法来延缓脑出血后脑损伤的进展。越来越多的证据表明，氧化应激在脑出血继发性损伤中起着至关重要的作用，而铁下垂在脑出血后脑损伤的发病机制中起主导作用。在本研究中，我们在体外血红素诱导的PC12细胞模型中证明虾青素通过上调谷胱甘肽过氧化物酶4和溶质载体家族7a成员11的表达，提高细胞活力，抑制脑出血后氧化应激，抑制铁凋亡。在体内自体血液注射脑出血大鼠模型中，我们证实虾青素通过Akt1-FoxO3a通路上调谷胱甘肽过氧化物酶4和溶质载体家族7a成员11的表达，从而抵抗氧化应激、铁凋亡和进一步的炎症反应，保护脑出血后的脑损伤。

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引用次数: 0

Effects of imeglimin on mitochondrial functions and ischemic brain damage in young and aging rats 依米霉素对幼龄和衰老大鼠线粒体功能及缺血性脑损伤的影响

IF 2.9 3区医学 Q2 PHARMACOLOGY & PHARMACY

Journal of pharmacological sciences

Pub Date : 2025-10-10 DOI: 10.1016/j.jphs.2025.10.001

Evelina Paskeviciene, Kristina Skemiene, Katryna Pampuscenko, Silvija Jankeviciute, Vilmante Borutaite

Imeglimin, a novel oral antidiabetic drug, has been suggested to affect mitochondrial functions in some types of cells and tissues, however, it has never been investigated whether aging has an impact on its pharmacological effects in the brain. In this study, we investigated whether imeglimin directly affects functions of brain mitochondria and whether its intraperitoneal injection protects against ischemic brain injury in young, middle-aged and aged Wistar rats. We found that direct addition of imeglimin to mitochondria isolated from young and middle-aged rat brains suppressed oxidative phosphorylation and activities of mitochondrial Complexes I and IV. The opposite, stimulating effect on Complex II activity was observed within the same groups. Injection of imeglimin 24 h before simulated brain ischemia in vitro reduced infarct size only in young and middle-aged rat groups. In the aged rat group, imeglimin did not reduce cerebral infarct size nor directly modulate mitochondrial respiration and activities of the complexes. In conclusion, we provided novel evidence on potential effects of imeglimin in the brain by demonstrating a direct stimulating effect on mitochondrial Complex II activity and age-dependent protective effects against brain injury under in vitro simulated ischemia.

一种新型口服降糖药伊米明被认为可以影响某些类型细胞和组织的线粒体功能，然而，从未研究过衰老是否会影响其在大脑中的药理作用。在本研究中，我们研究了伊米明是否直接影响脑线粒体功能，以及其腹腔注射是否对中青年Wistar大鼠缺血性脑损伤有保护作用。我们发现，在从中青年大鼠脑中分离的线粒体中直接添加imimimin，可以抑制线粒体复合物I和IV的氧化磷酸化和活性。在同一组中，对复合物II的活性有相反的刺激作用。体外模拟脑缺血前24小时注射依米明，仅在中青年大鼠组中减少梗死面积。在老龄大鼠组中，依米霉素没有减少脑梗死面积，也没有直接调节线粒体呼吸和复合物的活性。总之，我们通过在体外模拟缺血下直接刺激线粒体复合体II活性和年龄依赖性脑损伤保护作用，为伊米霉素在脑中的潜在作用提供了新的证据。

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引用次数: 0

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