Journal of pharmacological sciences最新文献_第3页

Resveratrol promotes autophagosome elimination via SIRT1 in cardiomyocytes 白藜芦醇通过心肌细胞中的SIRT1促进自噬体的消除。

IF 3 3区医学 Q2 PHARMACOLOGY & PHARMACY

Journal of pharmacological sciences

Pub Date : 2025-01-01 DOI: 10.1016/j.jphs.2024.11.006

Atsushi Kuno , Ryusuke Hosoda , Yukika Saga , Naotoshi Iwahara , Yuki Tatekoshi , Ryo Numazawa , Yoshiyuki Horio

The processes of autophagy, including autophagosome formation, fusion of autophagosomes with lysosomes, and degradation of autophagosomes by lysosomes, are regulated by various mechanisms. We recently found that treatment with resveratrol, an activator of the NAD⁺-dependent protein deacetylase Sirtuin-1 (SIRT1), in a mouse model prevented autophagosome accumulation in the heart with high mTORC1 activity. In this study, we investigated whether SIRT1 mediates the effects of resveratrol on autophagosome elimination using a cardiomyocyte model. In H9c2 cardiomyocytes, treatment with the mTORC1 activator MHY1485 induced autophagosome accumulation accompanied by increases in fragmented mitochondria within the autophagosomes and levels of intracellular reactive oxygen species (ROS), indicative of impaired autophagy-mediated elimination of mitochondria and resultant oxidative stress. MHY1485 suppressed the fusion of autophagosomes with lysosomes. Co-treatment with resveratrol attenuated the MHY1485-induced increases in autophagosomes, mitochondria within autophagosomes, and levels of ROS. Knockdown of Sirt1 reversed the reductions in autophagosomes and ROS levels induced by resveratrol under the condition of MHY1485 treatment. Neither resveratrol treatment nor Sirt1 knockdown modulated the phosphorylation levels of UVRAG, a target of mTORC1 for suppression of autophagosome-lysosome fusion. Our findings suggest that SIRT1 mediates the resveratrol-induced promotion of autophagosome elimination in cells with high mTORC1 activity.

自噬的过程包括自噬体的形成、自噬体与溶酶体的融合以及溶酶体对自噬体的降解，这些过程受到多种机制的调控。我们最近发现，在小鼠模型中，白藜芦醇（一种NAD+依赖性蛋白去乙酰化酶Sirtuin-1 （SIRT1）的激活剂）可以阻止具有高mTORC1活性的心脏中的自噬体积累。在这项研究中，我们通过心肌细胞模型研究了SIRT1是否介导白藜芦醇对自噬体消除的影响。在H9c2心肌细胞中，mTORC1激活剂MHY1485诱导自噬体积累，并伴随自噬体内线粒体碎片和细胞内活性氧（ROS）水平的增加，表明自噬介导的线粒体消除受损和由此产生的氧化应激。MHY1485抑制自噬体与溶酶体的融合。与白藜芦醇共处理可减弱mhy1485诱导的自噬体、自噬体内线粒体和ROS水平的增加。在MHY1485处理条件下，Sirt1的下调逆转了白藜芦醇诱导的自噬体和ROS水平的降低。白藜芦醇处理和Sirt1敲低都不能调节UVRAG的磷酸化水平，UVRAG是mTORC1抑制自噬体-溶酶体融合的靶标。我们的研究结果表明，SIRT1介导白藜芦醇诱导的高mTORC1活性细胞的自噬体消除。

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引用次数: 0

Involvement of N-methyl-D-aspartate receptor GluN2C/GluN2D subunits in social behavior impairments in mice exposed to social defeat stress as juveniles

IF 3 3区医学 Q2 PHARMACOLOGY & PHARMACY

Journal of pharmacological sciences

Pub Date : 2024-12-28 DOI: 10.1016/j.jphs.2024.12.007

Mikio Yoshida , Hikari Katada , Yuya Isozumi , Chiharu Suzuki , Akira Yoshimi , Norio Ozaki , Yukihiro Noda

Glutamatergic system dysfunction is associated with the pathophysiology of stress-related psychiatric disorders. However, the role of N-methyl-D-aspartate (NMDA) receptor GluN2C and GluN2D subunits in the pathophysiology of adverse juvenile experiences remain unclear. This study aimed to investigate the involvement of GluN2C and GluN2D subunits in social behavior impairments in mice exposed to social defeat stress as juveniles. Acute administration of PPDA, a GluN2C/GluN2D antagonist, and ketamine, a non-competitive NMDA receptor antagonist, attenuated social behavior impairments in stressed mice. This attenuating effect of ketamine was partially inhibited by the administration of CIQ, a GluN2C/GluN2D-containing NMDA potentiator. The prefrontal cortex of stressed mice exhibited significantly elevated levels of GluN2C and GluN2D proteins compared to control mice. These findings suggest that activation of GluN2C- and/or GluN2D-containing NMDA receptors contributes to the development of social behavioral impairments induced by juvenile social defeat stress. Moreover, these subunits may play a role in the therapeutic effects of ketamine. Targeting GluN2C/GluN2D subunits of NMDA receptors may be novel therapeutic strategies for stress-related psychiatric disorders in adolescents with adverse juvenile experiences.

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引用次数: 0

Okanin alleviates symptoms of nociceptive-like responses in diabetic peripheral neuropathy in type 1 diabetic Wistar rats by regulating the AGEs/NF-κB/Nrf-2 pathway Okanin通过调节AGEs/NF-κB/Nrf-2通路，减轻1型糖尿病Wistar大鼠糖尿病周围神经病变损伤样反应症状

IF 3 3区医学 Q2 PHARMACOLOGY & PHARMACY

Journal of pharmacological sciences

Pub Date : 2024-11-22 DOI: 10.1016/j.jphs.2024.11.003

Mohammad Rafiq Ganie , Nadeem Khan , Manish Shukla , Shreya Sood , Sushma Devi , Poonam Arora , Manish Kumar , Imtiyaz Ahmed Najar , Jianlei Tang

Elevated reactive species and AGEs contribute to deregulation of transcription factors e.g., NF-κB and Nrf2 in diabetic peripheral neuropathy (DPN). Okanin, a bioactive chalcone, is active against redox imbalance, immune response, and pro-inflammatory events. The current investigation assessed effects of okanin in streptozotocin-induced DPN in rats. Wistar rats were divided into 6 groups (n = 6): Control, DPN, Okanin 2.5, Okanin 5, Okanin 10, and Gpn (Gabapentin). After 6 weeks of streptozotocin (55 mg/kg) injection, okanin (2.5, 5, 10 mg/kg), and gabapentin (50 mg/kg), were administered for 4 weeks. The streptozotocin-induced reduction in body weight, and increased feed/water intake, insulin, glucose, and HbA1c levels were mitigated by okanin or gabapentin. In DPN rats, Okanin or gabapentin ameliorated insulin resistance and β-cell function, inflammatory indices, and oxidative stress in the sciatic nerve of rodents thereby culminating in a decrease in hyperalgesia and allodynia. Okanin and streptozotocin-treated rats had significantly declined levels of AGEs, the receptor for AGEs, and NF-κB, and an upsurge in Nrf2 expression. In streptozotocin-induced DPN model, okanin ameliorates nociceptive-like responses by regulating the AGEs/NF-κB/Nrf2 pathway, suggesting that okanin has therapeutic value against DPN which needs further studies involving human subjects.

在糖尿病周围神经病变（DPN）中，反应性物质和AGEs的升高会导致转录因子如NF-κB和Nrf2的失调。Okanin是一种生物活性查尔酮，对氧化还原失衡、免疫反应和促炎事件有活性。目前的研究评估了山核桃素在链脲佐菌素诱导的大鼠DPN中的作用。Wistar大鼠分为6组（n = 6）：对照、DPN、Okanin 2.5、Okanin 5、Okanin 10、Gpn（加巴喷丁）。注射链脲佐菌素（55 mg/kg） 6周后，再注射山核桃素（2.5、5、10 mg/kg）和加巴喷丁（50 mg/kg） 4周。链脲佐菌素引起的体重下降、饲料/水摄取量增加、胰岛素、葡萄糖和HbA1c水平的增加可以通过狗蛋白或加巴喷丁缓解。在DPN大鼠中，山核桃素或加巴喷丁改善了啮齿动物坐骨神经的胰岛素抵抗和β细胞功能、炎症指数和氧化应激，从而最终减少了痛觉过敏和异位性疼痛。Okanin和streptozotocin处理大鼠的AGEs、AGEs受体和NF-κB水平显著下降，Nrf2表达升高。在链脲佐菌素诱导的DPN模型中，okanin通过调节AGEs/NF-κB/Nrf2通路改善伤害样反应，提示okanin对DPN具有治疗价值，需要进一步的人体实验研究。

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引用次数: 0

Paclitaxel-induced peripheral neuropathy in male rats attenuated by calmangafodipir, a superoxide dismutase mimetic 紫杉醇诱导的雄性大鼠外周神经病变可通过超氧化物歧化酶模拟物卡马福地平（Calangafodipir）得到缓解

IF 3 3区医学 Q2 PHARMACOLOGY & PHARMACY

Journal of pharmacological sciences

Pub Date : 2024-11-20 DOI: 10.1016/j.jphs.2024.11.004

Takehiro Kawashiri , Kohei Mori , Haruna Ishida , Mami Ueda , Kozo Yao , Fumiko Nagahama , Keisuke Mine , Yusuke Mori , Yusuke Koura , Shunsuke Fujita , Takao Shimazoe , Daisuke Kobayashi

Paclitaxel induces peripheral neuropathy, which is considered a dose-limiting factor. However, appropriate prophylactic agents are currently unavailable. We investigated the prophylactic effects of calmangafodipir, a superoxide dismutase mimetic, on paclitaxel-induced peripheral neuropathy using a male rat model. Repeated administration of paclitaxel (6 mg/kg, intraperitoneal, once weekly for 4 weeks) resulted in mechanical allodynia in the von Frey test and axonal degeneration in the sciatic nerve. Conversely, calmangafodipir (1–10 mg/kg, intravenous, thrice weekly for 4 weeks) prevented mechanical allodynia and axonal degeneration induced by paclitaxel. These results suggest that calmangafodipir may inhibit paclitaxel-induced peripheral neuropathy.

紫杉醇会诱发周围神经病变，这被认为是一个剂量限制因素。然而，目前还没有合适的预防药物。我们以雄性大鼠为模型，研究了超氧化物歧化酶模拟物钙拮抗剂对紫杉醇诱导的周围神经病变的预防作用。重复给予紫杉醇（6 毫克/千克，腹腔注射，每周一次，连续 4 周）会导致 von Frey 试验中的机械异感和坐骨神经轴突变性。相反，卡马福迪皮（1-10 毫克/千克，静脉注射，每周三次，连续 4 周）可防止紫杉醇引起的机械异感和轴突变性。这些结果表明，钙泊三醇可抑制紫杉醇诱导的周围神经病变。

引用次数: 0

Different sensitivities of porcine coronary arteries and veins to BAY 60–2770, a soluble guanylate cyclase activator 猪冠状动脉和静脉对可溶性鸟苷酸环化酶激活剂 BAY 60-2770 的不同敏感性

IF 3 3区医学 Q2 PHARMACOLOGY & PHARMACY

Journal of pharmacological sciences

Pub Date : 2024-11-14 DOI: 10.1016/j.jphs.2024.11.002

Masashi Tawa, Keisuke Nakagawa, Mamoru Ohkita

Nitric oxide (NO)-donor drugs, which stimulate reduced form of soluble guanylate cyclase (sGC), have different efficacy to the arteries and veins. This study examined whether sGC activators, which activate oxidized/apo sGC, also have arteriovenous selectivity similar to that of NO-donor drugs. The mechanical responses of the isolated blood vessels were assessed using the organ chamber technique and protein expression was verified using western blotting. BAY 60–2770 (sGC activator) caused concentration-dependent relaxation in both porcine coronary arteries and veins, with the response being slightly more pronounced in the arteries. In contrast, sodium nitroprusside (NO-donor drug)-induced relaxation of the arteries was slightly weaker than that of the veins. Vasorelaxant responses to 8-Br-cGMP (cGMP analog) did not differ between the arteries and veins. In the presence of ODQ (heme oxidant), the heterogeneities in the responses to BAY 60–2770 and sodium nitroprusside between the arteries and veins disappeared. The sGC expression in the arteries did not differ from that in the veins. These findings suggest that sGC activators, in contrast to NO-donor drugs, have greater effects on the arteries than on the veins. This may be due to differences in the balance of sGC forms expressed in the arteries and veins.

一氧化氮（NO）供体药物可刺激还原型可溶性鸟苷酸环化酶（sGC），但对动脉和静脉的疗效不同。本研究探讨了激活氧化型/apo型sGC的sGC激活剂是否也具有类似于一氧化氮供体药物的动静脉选择性。使用器官室技术评估了离体血管的机械反应，并使用 Western 印迹技术验证了蛋白质的表达。BAY 60-2770（sGC 激活剂）在猪冠状动脉和静脉中都能引起浓度依赖性松弛，在动脉中反应略微明显。相比之下，硝普钠（NO 供体药物）诱导的动脉松弛作用略弱于静脉松弛作用。动脉和静脉对 8-Br-cGMP（cGMP 类似物）的血管舒张反应没有差异。在 ODQ（血红素氧化剂）存在的情况下，动脉和静脉对 BAY 60-2770 和硝普钠反应的异质性消失了。动脉中的 sGC 表达与静脉中的没有差异。这些研究结果表明，与 NO 供体药物不同，sGC 激活剂对动脉的影响大于对静脉的影响。这可能是由于动脉和静脉中表达的 sGC 形式的平衡存在差异。

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引用次数: 0

Rehmannioside A promotes the osteoblastic differentiation of MC3T3-E1 cells via the PI3K/AKT signaling pathway and inhibits glucocorticoid-induced bone loss in vivo 地黄甙 A 通过 PI3K/AKT 信号通路促进 MC3T3-E1 细胞的成骨细胞分化并抑制糖皮质激素诱导的体内骨质流失

IF 3 3区医学 Q2 PHARMACOLOGY & PHARMACY

Journal of pharmacological sciences

Pub Date : 2024-11-06 DOI: 10.1016/j.jphs.2024.11.001

Haisheng Huang , Fang Ji , Guobin Qi , Yuting Cao , Xuecheng He , Hao Wang , Zengxin Jiang

Glucocorticoid-induced osteoporosis (GIOP) is a widespread disease characterized by low bone density. There remains a lack of effective means for osteoporosis. Rehmannioside A (ReA), an iridoid glycoside, exhibits various pharmacological activities. This study aimed to explore the role and mechanism of ReA in osteogenic differentiation of osteoblasts. Cell viability, reactive oxygen species (ROS) generation, and cell apoptosis were assessed using corresponding assay kits. Real-time quantitative polymerase chain reaction, Western blotting, and alkaline phosphatase (ALP) staining were performed to evaluate the osteogenic differentiation of MC3T3-E1 cells. Alizarin red S staining was used to assess the mineralization of MC3T3-E1 cells. Protein expression associated with the phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) signaling pathway was analyzed using Western blotting. Micro-computed tomography, histopathological, and immunohistochemical analyses were performed to determine the therapeutic effect of ReA on GIOP in vivo.The results showed that ReA promoted the osteogenic differentiation of MC3T3-E1 cells by regulating the PI3K/AKT signaling pathway and protected mice against glucocorticoid-induced bone loss by promoting osteoblast-mediated bone formation in vivo. The findings of the current study revealed that ReA is a potential therapeutic agent for osteoporosis.

糖皮质激素诱导的骨质疏松症（GIOP）是一种以骨密度低为特征的广泛疾病。目前仍缺乏治疗骨质疏松症的有效方法。Rehmannioside A（ReA）是一种鸢尾甙，具有多种药理活性。本研究旨在探索 ReA 在成骨细胞成骨分化中的作用和机制。使用相应的检测试剂盒对细胞活力、活性氧（ROS）生成和细胞凋亡进行了评估。对 MC3T3-E1 细胞的成骨分化进行了实时定量聚合酶链反应、Western 印迹和碱性磷酸酶（ALP）染色。茜素红 S 染色用于评估 MC3T3-E1 细胞的矿化情况。用Western印迹法分析了与磷脂酰肌醇3-激酶/蛋白激酶B（PI3K/AKT）信号通路相关的蛋白质表达。结果显示，ReA 通过调节 PI3K/AKT 信号通路促进 MC3T3-E1 细胞的成骨分化，并通过促进成骨细胞介导的体内骨形成保护小鼠免受糖皮质激素诱导的骨质流失。目前的研究结果表明，ReA 是一种潜在的骨质疏松症治疗药物。

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引用次数: 0

Targeting TMEM16A ion channels suppresses airway hyperreactivity, inflammation, and remodeling in an experimental Guinea pig asthma model 在实验性几内亚猪哮喘模型中，靶向 TMEM16A 离子通道可抑制气道过度反应、炎症和重塑

IF 3 3区医学 Q2 PHARMACOLOGY & PHARMACY

Journal of pharmacological sciences

Pub Date : 2024-10-28 DOI: 10.1016/j.jphs.2024.10.004

Jozef Mažerik , Eduard Gondáš , Matúš Dohál , Lukáš Smieško , Marta Jošková , Soňa Fraňová , Martina Šutovská

Asthma is a chronic inflammatory disease characterized by airway hyperresponsiveness, inflammation, and remodeling. Calcium (Ca²⁺)-activated chloride (Cl⁻) channels, such as TMEM16A, are inferred to be involved in asthma. Therefore, the present study investigated the therapeutic potential of TMEM16A inhibition in a guinea pig model of ovalbumin (OVA)-induced allergic asthma. Guinea pigs were treated with a specific blocker, CaCCinh-A01 (10 μM), administered via inhalation. A significant reduction in cough reflex sensitivity and specific airway resistance was observed in animals treated with CaCCinh-A01, highlighting its potential to improve airway function. Despite a reduction in ciliary beating frequency (CBF), CaCCinh-A01 reduced airway mucus viscosity by decreasing the production of mucin-5AC (MUC5AC). The nonspecific reduction in the Th1/Th2 cytokine spectrum following CaCCinh-A01 treatment indicated the suppression of airway inflammation. Additionally, markers associated with airway remodeling were diminished, suggesting that CaCCinh-A01 may counteract structural changes in airway tissues. Therefore, inhibition appears to mitigate the pathological aspects of asthma, including airway hyperresponsiveness, inflammation, and remodeling. However, further studies are required to comprehensively evaluate the potential of TMEM16A as a therapeutic target for asthma.

哮喘是一种以气道高反应性、炎症和重塑为特征的慢性炎症性疾病。据推断，钙（Ca2+）激活的氯离子（Cl-）通道（如 TMEM16A）与哮喘有关。因此，本研究在卵清蛋白（OVA）诱发过敏性哮喘的豚鼠模型中研究了抑制 TMEM16A 的治疗潜力。豚鼠通过吸入特异性阻断剂 CaCCinh-A01 （10 μM）进行治疗。在接受 CaCCinh-A01 治疗的动物身上观察到咳嗽反射敏感性和特定气道阻力明显降低，凸显了其改善气道功能的潜力。尽管纤毛跳动频率（CBF）降低了，但 CaCCinh-A01 通过减少粘蛋白-5AC（MUC5AC）的产生降低了气道粘液粘度。CaCCinh-A01 治疗后 Th1/Th2 细胞因子谱的非特异性减少表明气道炎症受到了抑制。此外，与气道重塑相关的标记物也有所减少，这表明 CaCCinh-A01 可能会抵消气道组织的结构变化。因此，抑制剂似乎能减轻哮喘的病理方面，包括气道高反应性、炎症和重塑。然而，要全面评估 TMEM16A 作为哮喘治疗靶点的潜力，还需要进一步的研究。

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引用次数: 0

Glucosylceramide synthase inhibitor ameliorates chronic inflammatory pain 葡萄糖酰胺合成酶抑制剂可改善慢性炎症性疼痛

IF 3 3区医学 Q2 PHARMACOLOGY & PHARMACY

Journal of pharmacological sciences

Pub Date : 2024-10-15 DOI: 10.1016/j.jphs.2024.10.003

Shun Watanabe , Misa Oyama , Takashi Iwai , Mitsuo Tanabe

Gangliosides play pivotal roles in neuronal tissue processes, such as axonal elongation, synaptic transmission, and neuronal degeneration. Several studies have shown that mice injected with gangliosides synthesized from glucosylceramide exhibit mechanical allodynia. Thus, we hypothesized that glucosylceramide synthase inhibitors affect nociceptive behavior. We investigated the analgesic effect of intrathecal glucosylceramide inhibition on bilateral allodynia caused by prolonged unilateral hind paw inflammation in mice. Repeated administration of a glucosylceramide inhibitor reduced mechanical allodynia in both inflamed and non-inflamed hind paws. These results suggested that ganglioside reduction is critical for analgesia during inflammatory pain.

神经节苷脂在轴突伸长、突触传递和神经元变性等神经元组织过程中发挥着关键作用。多项研究表明，注射了由葡萄糖基甘油酰胺合成的神经节苷脂的小鼠会出现机械异感。因此，我们假设葡萄糖苷甘油酰胺合成酶抑制剂会影响痛觉行为。我们研究了鞘内葡萄糖酰甘油酰胺抑制剂对小鼠单侧后爪长时间发炎引起的双侧异动症的镇痛效果。重复给药葡萄糖苷酸甘油三酯抑制剂可减少发炎和未发炎后爪的机械异感。这些结果表明，神经节苷脂的减少对炎症性疼痛的镇痛至关重要。

引用次数: 0

Analgesic effect of Keishinieppiittokajutsubu on low barometric pressure-induced pain response in arthritic model rats Keishinieppiittokajutsubu 对低气压引起的关节炎模型大鼠疼痛反应的镇痛效果

IF 3 3区医学 Q2 PHARMACOLOGY & PHARMACY

Journal of pharmacological sciences

Pub Date : 2024-10-09 DOI: 10.1016/j.jphs.2024.10.002

Yuki Kurauchi , Kana Inoue , Tomoka Kawakami , Manami Ueda , Tomoko Yamaguchi , Junji Akaki , Masahiko Komorisono , Hiroshi Katsuki

Rheumatoid arthritis (RA) is a disease that causes inflammation of joints, resulting in pain and swelling. Reduced barometric pressure induces painful symptom of RA, but there is no appropriate animal model and pharmacological evaluation. Keishinieppiittokajutsubu (KNEIJB), a Kampo medicine used to treat RA; however, its mechanism of action is not clear. Here, we found that KNEIJB suppressed the low barometric pressure (LP)-induced pain response in CFA-induced arthritic model rats. Furthermore, we found that KNEIJB reduced plasma IL-6 levels. These results suggest that KNEIJB might be beneficial in the treatment of RA or some other arthralgia induced by LP.

类风湿性关节炎（RA）是一种引起关节炎症的疾病，会导致疼痛和肿胀。气压降低会诱发类风湿关节炎的疼痛症状，但目前还没有合适的动物模型和药理评估。Keishinieppiittokajutsubu（KNEIJB）是一种用于治疗 RA 的康波药物，但其作用机制尚不清楚。在这里，我们发现 KNEIJB 可抑制低气压（LP）诱导的 CFA 关节炎模型大鼠的疼痛反应。此外，我们还发现 KNEIJB 降低了血浆 IL-6 的水平。这些结果表明，KNEIJB可能有益于治疗由低气压诱发的RA或其他关节痛。

引用次数: 0

TND1128, a 5-deazaflavin derivative with auto-redox ability, facilitates polarization of mitochondrial membrane potential (ΔΨm) and on-demand ATP synthesis in mice brain slices TND1128是一种具有自动氧化还原能力的5-去氮黄素衍生物，可促进小鼠脑切片线粒体膜电位（ΔΨm）的极化和按需合成 ATP

IF 3 3区医学 Q2 PHARMACOLOGY & PHARMACY

Journal of pharmacological sciences

Pub Date : 2024-10-09 DOI: 10.1016/j.jphs.2024.10.001

Nanae Takahashi , Tomohisa Nagamatsu , Norio Akaike , Yoshihisa Kudo

TND1128, a 5-deazaflavin derivative, is a drug with self-redox ability. We examined the effect of TND1128 on the level of mitochondrial membrane potential (ΔΨ_m), which is the most critical motive power for the biosynthesis of ATP. We prepared brain slices from mice pretreated with TND1128 (0.1–10 mg/kg, intraperitoneally) and detected ΔΨ_m level with JC-1, a fluorescence ΔΨ_m indicator. We further examined the depolarization of ΔΨ_m under 5-min exposure to 25 mM KCl-ACSF (25K-ACSF), which activated neuronal voltage-dependent Ca²⁺ channels. We evaluated the effect of TND1128 by using the inverse number of the ΔΨ_m value as the ATP synthesis index (ASI). The level of ΔΨ_m increased significantly by 24-h pretreatment with TND1128 (10 mg/kg), and significantly higher depolarization of the ΔΨ_m was observed with 25K-ACSF exposure than in non-treated control. We found a significant decrease in 25K-ACSF induced [Ca²⁺]_c and [Ca²⁺]_m levels in the TND1128-pretreated preparations. We confirmed the dose and time-dependent facilitatory effects of TND1128 on the ASI. This study suggested that TND1128 could be incorporated into the TCA cycle and electron transfer chains to facilitate the polarization of ΔΨ_m and activate on-demand ATP synthesis. TND1128 might rescue neurons in various brain diseases caused by energy defects. (198)

TND1128是一种5-去氮黄素衍生物，是一种具有自我氧化还原能力的药物。我们研究了 TND1128 对线粒体膜电位（ΔΨm）水平的影响，线粒体膜电位是生物合成 ATP 的最关键动力。我们制备了用 TND1128（0.1-10 mg/kg，腹腔注射）预处理的小鼠脑片，并用荧光ΔΨm 指示剂 JC-1 检测ΔΨm 水平。我们进一步检测了ΔΨm在暴露于25 mM KCl-ACSF（25K-ACSF）5分钟后的去极化情况，KCl-ACSF可激活神经元电压依赖性Ca2+通道。我们用ΔΨm值的倒数作为ATP合成指数（ASI）来评估TND1128的效果。用TND1128（10 mg/kg）预处理24小时后，ΔΨm的水平明显升高，并且观察到暴露于25K-ACSF的ΔΨm的去极化程度明显高于未处理的对照组。我们发现，在 TND1128 预处理的制备物中，25K-ACSF 诱导的[Ca2+]c 和[Ca2+]m 水平明显下降。我们证实了 TND1128 对 ASI 的促进作用具有剂量和时间依赖性。这项研究表明，TND1128可被纳入TCA循环和电子传递链，以促进ΔΨm的极化并激活按需ATP合成。TND1128 可能会挽救因能量缺陷导致的各种脑部疾病中的神经元。(198)

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引用次数: 0