Neuroscience Letters最新文献_第2页

L17E cell-penetrating peptide enhances intranasal delivery of IgG to the cerebrospinal fluid in mice L17E细胞穿透肽增强小鼠脑脊液中IgG的鼻内递送。

IF 2 4区医学 Q3 NEUROSCIENCES

Neuroscience Letters

Pub Date : 2026-01-17 DOI: 10.1016/j.neulet.2026.138521

Naoya Hashikawa, Taiki Terado, Takuya Noda, Riyo Kashimoto, Takumi Iima, Masamune Oro, Sora Tambara, Narumi Hashikawa-Hobara

Antibody-based therapeutics are promising for treating central nervous system (CNS) diseases; however, brain delivery is severely restricted by the blood–brain barrier (BBB). Intranasal administration has gained attention as a noninvasive route proposed to reduce the impact of the BBB; however, the efficiency of delivering large biomolecules, such as antibodies, remains insufficiently characterized. This study aimed to investigate whether cell-penetrating peptides (CPPs) could increase detectable IgG levels in the cerebrospinal fluid (CSF) following intranasal administration in mice. Rabbit IgG was intranasally administered to ICR mice, either alone or in combination with CPPs (R9, Penetratin, or L17E). IgG levels in the CSF and serum were quantified by ELISA, and both time-course and dose-dependent effects were analyzed. IgG alone was not detected in the CSF, whereas serum IgG levels increased dose-dependently. Co-administration of Penetratin or L17E resulted in detectable CSF IgG levels, with L17E exceeding Penetratin. By contrast, no delivery was observed in the R9 group. Serum IgG levels also increased in the Penetratin and L17E groups. Time-course analysis with L17E showed that CSF IgG reached its highest measured level at 24 h and declined thereafter, whereas serum IgG reached higher levels at earlier time points and remained relatively stable. Dose–response analysis revealed linear increases in serum IgG, while CSF IgG levels depended on the concentration of L17E. These findings indicate that co-administration with amphipathic CPPs, particularly L17E, enables detectable IgG delivery to the CSF following intranasal administration in mice, although the underlying mechanisms and therapeutic relevance remain to be clarified.

基于抗体的治疗方法有望治疗中枢神经系统疾病；然而，脑输送受到血脑屏障（BBB）的严重限制。鼻内给药作为一种减少血脑屏障影响的无创途径而受到关注；然而，递送大型生物分子（如抗体）的效率仍然没有得到充分的表征。本研究旨在探讨细胞穿透肽（CPPs）在小鼠鼻内给药后是否能增加脑脊液（CSF）中可检测到的IgG水平。兔IgG单独或与CPPs （R9、Penetratin或L17E）联合经鼻给药给ICR小鼠。ELISA法测定血清和脑脊液中IgG水平，并分析时间和剂量依赖性效应。CSF中未检测到IgG单独，而血清IgG水平呈剂量依赖性增加。同时使用Penetratin或L17E可检测到CSF IgG水平，L17E高于Penetratin。相比之下，R9组未观察到分娩。穿透素组和L17E组血清IgG水平升高。L17E的时间过程分析显示，CSF IgG在24 h时达到最高水平，此后下降，而血清IgG在较早的时间点达到较高水平，并保持相对稳定。剂量-反应分析显示血清IgG呈线性升高，而脑脊液IgG水平与L17E浓度有关。这些发现表明，与两亲性CPPs（尤其是L17E）共同给药，可以在小鼠鼻内给药后将IgG递送到CSF，尽管其潜在机制和治疗相关性仍有待阐明。

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引用次数: 0

Repeated exposure to motor imagery enhances focal brain activation during motor imagery practice after stroke 反复暴露于运动意象增强脑卒中后运动意象练习局灶性激活。

IF 2 4区医学 Q3 NEUROSCIENCES

Neuroscience Letters

Pub Date : 2026-01-16 DOI: 10.1016/j.neulet.2026.138510

Sara M. Klick , Cristina Rubino , Justine R. Magnuson , Lauren Penko , Anjana Rajendran , Ronan Denyer , Christina B. Jones , Jordan Brocato , Chris Lamb , Cristina Schaurich , Lara A. Boyd , Sarah N. Kraeutner

Stroke results in motor impairments of the upper limbs, linked to altered activation in sensorimotor regions. Motor imagery (MI; the mental rehearsal of movement) activates sensorimotor regions, providing the basis for its effectiveness as an intervention for motor recovery after stroke. Yet, the effect of repeated MI on brain activation after stroke is unexplored. In this study, thirty-three individuals with stroke (>3 months) performed MI of an upper-limb movement using their paretic arm and hand across two sessions on two different days. Brain activation was obtained via functional magnetic resonance imaging (fMRI). Group-level contrasts revealed: 1) focal brain activation in Session 2 relative to Session 1, and 2) functional localization to sensorimotor regions. Together, these findings demonstrate that MI induces changes in brain activation after only two sessions in individuals with stroke, specifically encompassing activation in sensorimotor areas. Familiarizing individuals to MI prior to its use may improve applications of MI for learning and recovery.

中风导致上肢运动障碍，与感觉运动区域的激活改变有关。运动意象（MI；运动的心理预演）激活感觉运动区域，为其作为中风后运动恢复干预的有效性提供了基础。然而，反复心肌梗死对脑卒中后脑活动的影响尚不清楚。在这项研究中，33名中风患者（50 - 3个月）在两个不同的日子里用他们的双亲手臂和手进行了上肢运动的心肌梗死。脑活动通过功能性磁共振成像（fMRI）获得。组水平对比显示：1)第二阶段相对于第一阶段的局灶性脑激活；2)感觉运动区域的功能定位。综上所述，这些发现表明，心肌梗死仅在中风患者的两个疗程后就会引起大脑激活的变化，特别是在感觉运动区域的激活。在使用心肌梗死之前使个体熟悉它可以改善心肌梗死在学习和康复中的应用。

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引用次数: 0

Dose-dependent impact of extremely low-frequency electromagnetic field (ELF-EMF) on the neuroplasticity in the hippocampus of adult rats 极低频电磁场（ELF-EMF）对成年大鼠海马神经可塑性的剂量依赖性影响

IF 2 4区医学 Q3 NEUROSCIENCES

Neuroscience Letters

Pub Date : 2026-01-14 DOI: 10.1016/j.neulet.2026.138520

Maciej Klimiuk , Hanna Kletkiewicz , Joanna Wyszkowska , Karol Dokladny , Justyna Rogalska

Extremely low-frequency electromagnetic field (ELF-EMF) therapy is gaining attention for its potential benefits in treating neurodegenerative conditions. However, the underlying molecular mechanisms responsible for the possible protective effects of ELF-EMF remain unclear. Our previous research revealed that ELF-EMF exposure can establish a new “set-point” for stress responses, with outcomes dependent on field intensity. Stress hormones have been shown to modulate hippocampal function and plasticity. Therefore, our study aimed to assess how ELF-EMF exposure affects the expression of transcripts related to hippocampal plasticity, including genes related to neurogenesis (BDNF, TrkB, GAP43), synaptic activity (PSD95, SYN1), and cell survival (Bcl-2, Bcl-xL, Bak1). Adult rats were exposed to ELF-EMF (50 Hz) at 1 mT and 7 mT intensities for three 7-day periods, 1 h/day, with 3-week break between each cycle. A subset of animals was sacrificed after each exposure to collect hippocampi. The relative expression of neural/synaptic genes and anti-/pro-survival factors was measured by real-time quantitative polymerase chain reaction. Our findings indicate that ELF-EMF exposure modulates mRNA expression of neural/synaptic genes and anti-/pro-survival factors. The direction and dynamics of changes depend on ELF-EMF intensity and the number of exposures. “Low-intensity” ELF-EMF (1 mT) increased pro-neuroplastic factors expression, while “high-intensity” ELF-EMF (7 mT) decreased them. In summary, “low-intensity” ELF-EMF enhances adaptive processes like neuroplasticity by eliciting a mild stress response, while “high-intensity” exposure disrupts homeostasis and brain function by inducing severe stress. Our findings indicate that the overall effects of ELF-EMF depend on the intricate interplay between stress reactions and long-term brain plasticity.

极低频电磁场（ELF-EMF）疗法因其治疗神经退行性疾病的潜在益处而受到关注。然而，造成极低频电磁场可能的保护作用的潜在分子机制仍不清楚。我们之前的研究表明，ELF-EMF暴露可以为应力反应建立一个新的“设定点”，其结果取决于场强。应激激素已被证明可以调节海马的功能和可塑性。因此，我们的研究旨在评估ELF-EMF暴露如何影响海马可塑性相关转录本的表达，包括与神经发生（BDNF、TrkB、GAP43）、突触活性（PSD95、SYN1）和细胞存活（Bcl-2、Bcl-xL、Bak1）相关的基因。成年大鼠在1 mT和7 mT强度下暴露于50 Hz的ELF-EMF (50 Hz)，为期3天，每天1小时，每个周期之间休息3周。每次暴露后，处死一部分动物以收集海马。实时定量聚合酶链反应检测神经/突触基因和抗/促生存因子的相对表达。我们的研究结果表明，ELF-EMF暴露可调节神经/突触基因和抗/促生存因子的mRNA表达。变化的方向和动态取决于极低频电动势强度和暴露次数。“低强度”ELF-EMF （1 mT）增加了前神经可塑性因子的表达，而“高强度”ELF-EMF （7 mT）降低了它们的表达。总之，“低强度”的ELF-EMF通过引起轻微的应激反应来增强神经可塑性等适应性过程，而“高强度”的暴露通过引起严重的应激而破坏体内平衡和大脑功能。我们的研究结果表明，ELF-EMF的整体影响取决于压力反应和长期大脑可塑性之间复杂的相互作用。

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引用次数: 0

Mutant glial fibrillary acidic protein reduces the capacity for glutamate uptake in hippocampal astrocytes 突变的胶质原纤维酸性蛋白降低了海马星形胶质细胞摄取谷氨酸的能力

IF 2 4区医学 Q3 NEUROSCIENCES

Neuroscience Letters

Pub Date : 2026-01-13 DOI: 10.1016/j.neulet.2026.138511

Yoshihiko Yamazaki , Hiroki Fujiwara , Jun-Ichi Goto , Kenji F. Tanaka

Astrocytes preserve synaptic function and maintain excitatory–inhibitory balance by regulating neurotransmitter homeostasis, notably through the clearance of glutamate from the extracellular space. This process is essential for preventing excitotoxicity in the central nervous system. Mutations in glial fibrillary acidic protein (GFAP) are associated with astrocytic dysfunction, leading to neurological symptoms, e.g., seizures. Although such mutations are implicated in neurological disorders including Alexander disease, their direct impact on the astrocytic uptake of synaptically released glutamate has not been demonstrated. Here, we assessed glutamate uptake in hippocampal astrocytes of mice expressing mutant GFAP using whole-cell recordings of transporter-mediated currents in acute hippocampal slices. Glutamate release into the synaptic cleft varied according to the intensity of afferent fiber stimulation, but transporter current amplitudes did not differ significantly between mutant and control mice under baseline conditions. In contrast, when adenosine A₁ receptors were blocked to relieve the tonic inhibition of glutamate release, transporter currents were significantly smaller in mutant mice than in controls at high stimulation intensities. These findings indicate that astrocytes expressing mutant GFAP exhibit impaired glutamate uptake capacity, which may be insufficient to prevent excitotoxicity or seizures under conditions of excessive glutamate release.

星形胶质细胞通过调节神经递质稳态，特别是通过清除细胞外空间的谷氨酸来维持突触功能和兴奋-抑制平衡。这个过程对于防止中枢神经系统的兴奋性毒性是必不可少的。胶质原纤维酸性蛋白（GFAP）突变与星形细胞功能障碍相关，导致神经系统症状，如癫痫发作。虽然这些突变与包括亚历山大病在内的神经系统疾病有关，但它们对星形细胞摄取突触释放的谷氨酸的直接影响尚未得到证实。在这里，我们利用急性海马切片中转运蛋白介导电流的全细胞记录，评估了表达突变GFAP的小鼠海马星形胶质细胞中的谷氨酸摄取。谷氨酸释放到突触间隙的变化取决于传入纤维刺激的强度，但在基线条件下，突变小鼠和对照小鼠之间的转运体电流振幅没有显著差异。相反，当腺苷A1受体被阻断以缓解谷氨酸释放的强紧性抑制时，在高刺激强度下，突变小鼠的转运体电流明显小于对照组。这些发现表明，表达突变GFAP的星形胶质细胞表现出谷氨酸摄取能力受损，这可能不足以防止谷氨酸过度释放时的兴奋性毒性或癫痫发作。

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引用次数: 0

Medial prefrontal Cortex, dopamine and glutamate modulation in regulating Reward-Seeking and frustration responses 内侧前额叶皮质，多巴胺和谷氨酸调节在调节奖励寻求和挫折反应。

IF 2 4区医学 Q3 NEUROSCIENCES

Neuroscience Letters

Pub Date : 2026-01-09 DOI: 10.1016/j.neulet.2026.138506

Crysvane Araújo de Oliveira Lima , Polliany da Silva Mendonça , Joelson Germano Crispim , Roger Luis da Silva , Ryan Cordeiro Silva , Lucas Felipe de Melo Alcantara , Filipe Silveira Duarte , Moacyr Jesus de Melo Rego , Maira Galdino da Rocha Pitta , Michelly Cristiny Pereira , Michelle Melgarejo da Rosa

Background

Behavior is often reinforced by rewarding experiences, which promote actions that yield positive outcomes contributing to adaptive decision-making. However, the absence of an anticipated reward can provoke negative emotional responses, such as frustration and anxiety, potentially leading to maladaptive behaviors. Understanding how the brain responds to reward and its omission is a growing focus in neuroscience, especially regarding how neurotransmitter systems in key circuits manage unmet expectations. The medial prefrontal cortex (mPFC), a central integrative hub, regulates downstream regions to process both rewarding and aversive outcomes. Although dopamine is known to guide reward prediction and adaptive behavior, the specific roles of dopaminergic and glutamatergic pathways in the mPFC remain unclear. Methods: In this study, we investigated the influence of mPFC and the differential roles of dopaminergic D2 and NMDA receptors within the mPFC on reward-seeking behaviors using a cued sucrose-seeking task. Results: Our results show that D2 dopamine receptor and NMDA receptor activity in the mPFC are essential for maintaining reward-seeking behaviors when expected rewards are omitted, highlighting dopamine and glutamate’s role in sustaining reward-persistent behavior. Conversely, only D2 blockade into mPFC affected cue-reward seeking behavior. Solely NMDA blockage in the mPFC and mPFC silencing reduced anxiety, suggesting a nuanced role for mPFC and glutamatergic signaling in managing the emotional response to unmet expectations. Conclusion: These findings provide new insights into how distinct neurotransmitter systems in the mPFC and mPFC itself contribute to the behavioral and emotional adjustments following reward and reward omission.

背景：行为通常通过奖励经验得到强化，这促进了产生积极结果的行为，有助于适应性决策。然而，缺乏预期的奖励会引发消极的情绪反应，如沮丧和焦虑，潜在地导致适应不良行为。了解大脑如何对奖励和它的遗漏作出反应是神经科学日益关注的焦点，特别是关于关键回路中的神经递质系统如何管理未满足的期望。内侧前额叶皮层（mPFC）是一个中央整合中枢，调节下游区域处理奖励和厌恶结果。虽然已知多巴胺指导奖励预测和适应性行为，但多巴胺能和谷氨酸能通路在mPFC中的具体作用尚不清楚。方法：在本研究中，我们研究了mPFC的影响，以及mPFC内多巴胺能D2和NMDA受体在提示蔗糖寻求任务中对奖励寻求行为的不同作用。结果：我们的研究结果表明，当预期奖励被忽略时，mPFC中D2多巴胺受体和NMDA受体的活性对于维持奖励寻求行为至关重要，突出了多巴胺和谷氨酸在维持奖励持久行为中的作用。相反，只有D2阻断进入mPFC才会影响线索奖励寻求行为。仅mPFC中的NMDA阻断和mPFC沉默减少了焦虑，这表明mPFC和谷氨酸信号在管理未满足期望的情绪反应中起着微妙的作用。结论：这些发现提供了关于mPFC和mPFC中不同的神经递质系统如何在奖励和奖励遗漏后促进行为和情绪调整的新见解。

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引用次数: 0

Enhanced antidepressant effects of fluoxetine combined with quercetin: studies in vitro and in vivo 氟西汀联合槲皮素增强抗抑郁作用：体外和体内研究。

IF 2 4区医学 Q3 NEUROSCIENCES

Neuroscience Letters

Pub Date : 2026-01-08 DOI: 10.1016/j.neulet.2026.138507

Ran Yang , Yifan Mao , Jialin Yang , Hai Ma , Jianying Shen

Objectives

This study aims to explore the enhanced antidepressant effects of the commonly used depressant fluoxetine combined with a dietary supplement quercetin, using both in vitro and in vivo models.

Methods

In vitro, we established both hydrogen peroxide (H₂O₂)-damaged and glutamate-damaged SH-SY5Y cells as cellular models. SH-SY5Y cells were exposed to 250 μM H₂O₂ or 16 mM glutamate and co-treated with 1 μM fluoxetine, 10 μM quercetin, or their combination for 24 h. Cell viability was detected. In vivo, we applied a chronic unpredictable mild stress (CUMS) animal model. C57BL/6 mice were treated with fluoxetine (5 or 10 mg/kg), quercetin (40 mg/kg), or their combinations. Depressive-like behaviors including Sucrose preference test (SPT), Tail suspension test (TST), and Forced swimming test (FST) were assessed. Nissl staining was carried out for observing changes in hippocampal neurons.

Results

Fluoxetine combined with quercetin protected SH-SY5Y cells from H₂O₂– or glutamate-induced damage, improved depressive-like behaviors and reduced hippocampal neuronal injury in CUMS mice, demonstrating enhanced antidepressant effects compared to monotherapy.

Conclusion

Combining fluoxetine with quercetin enhances antidepressant effects, suggesting a way to reduce the clinically required dosage of fluoxetine, thereby reducing its side effects.

目的：本研究旨在通过体外和体内模型，探讨常用抑制剂氟西汀与膳食补充剂槲皮素联合使用后的抗抑郁效果。方法：体外建立过氧化氢（H2O2）损伤和谷氨酸损伤的SH-SY5Y细胞模型。SH-SY5Y细胞暴露于250 μM H2O2或16 mM谷氨酸，并与1 μM氟西汀、10 μM槲皮素或其组合共处理24 h。检测细胞活力。在体内，我们采用慢性不可预测轻度应激（CUMS）动物模型。C57BL/6小鼠分别给予氟西汀（5或10 mg/kg）、槲皮素（40 mg/kg）或其联合治疗。抑郁样行为包括蔗糖偏好测试（SPT）、悬尾测试（TST）和强迫游泳测试（FST）。采用尼氏染色观察海马神经元的变化。结果：氟西汀联合槲皮素保护SH-SY5Y细胞免受H2O2或谷氨酸诱导的损伤，改善CUMS小鼠的抑郁样行为，减少海马神经元损伤，与单药治疗相比，显示出更强的抗抑郁作用。结论：氟西汀联合槲皮素可增强抗抑郁作用，提示减少氟西汀临床所需剂量，从而减少其副作用。

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引用次数: 0

G protein-coupled receptor 17 promotes neuropathic pain in male mice by upregulating spinal NMDAR subunit expression G蛋白偶联受体17通过上调脊髓NMDAR亚基表达促进雄性小鼠神经性疼痛。

IF 2 4区医学 Q3 NEUROSCIENCES

Neuroscience Letters

Pub Date : 2026-01-08 DOI: 10.1016/j.neulet.2026.138509

Biyun Li, Xueqin Xu, Qin Xiao, Kunyu Zhang, Xiuqin Yu, Yangqiao Xiao, Shuangshuang Lu, Wenjiao Jin, Panpan Sun, Longhui Li, Chunyu Ma, Zihao Lu, Yanqiong Wu, Changbin Ke

Neuropathic pain is a prevalent and debilitating chronic condition for which current treatments often provide inadequate relief. This constitutes a significant unmet clinical need, highlighting the importance of identifying novel molecular targets for more effective pharmacotherapy. Synaptic remodeling-mediated central sensitization is a key regulatory factor. Glutamate is a major excitatory transmitter in the central nervous system and binds to NMDA receptors in the postsynaptic membrane to promote synaptic remodeling. In C57 mice with spared nerve injury, it was noted that GPR17 and the GluN2A and GluN2B subunits of the NMDA receptor were elevated in the L4-L6 region of the spinal cord. Lentiviral knockdown of spinal GPR17 attenuated mechanical allodynia, suppressed astrocyte activation, and decreased levels of GluN2A and GluN2B subunits. GPR17 controls neuropathic pain, stimulates astrocyte activation, and NMDA receptor overexpression on neurons. Targeting GPR17 may represent a new therapeutic strategy for the management of neuropathic pain.

神经性疼痛是一种普遍的、使人衰弱的慢性疾病，目前的治疗方法往往不能提供足够的缓解。这构成了一个重要的未满足的临床需求，突出了识别新的分子靶点对更有效的药物治疗的重要性。突触重塑介导的中枢致敏是一个关键的调节因子。谷氨酸是中枢神经系统中一种主要的兴奋性递质，与突触后膜的NMDA受体结合，促进突触重构。在C57神经损伤小鼠中，我们发现脊髓L4-L6区GPR17和NMDA受体GluN2A和GluN2B亚基升高。慢病毒敲低脊髓GPR17可减轻机械性异常痛，抑制星形胶质细胞激活，降低GluN2A和GluN2B亚基水平。GPR17控制神经性疼痛，刺激星形胶质细胞激活和神经元上NMDA受体的过表达。靶向GPR17可能是神经性疼痛治疗的一种新的治疗策略。

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引用次数: 0

Differential neuroinflammatory trajectories in the hippocampus and prefrontal cortex after acute LPS administration 急性LPS处理后海马和前额皮质的不同神经炎症轨迹。

IF 2 4区医学 Q3 NEUROSCIENCES

Neuroscience Letters

Pub Date : 2026-01-08 DOI: 10.1016/j.neulet.2026.138504

Zhouli Yue , Mengyuan Li , Jiahui Wang , Siqi Quan , Yiqi Wang , Zhanying Niu , Yucheng Li

Neuroinflammation is a key pathological feature of central nervous system disorders, yet its temporal and regional dynamics remain poorly defined. In this study, we systematically investigated neuroinflammatory responses and neuronal injury in the hippocampus and prefrontal cortex following a single intraperitoneal injection of lipopolysaccharide (LPS, 1 mg/kg) in mice. Fifty-four male C57BL/6N mice were randomly divided into six groups, and serum and brain tissues were collected at 0, 3, 6, 12, 24, and 48 h after LPS administration. Cytokine levels were detected by enzyme-linked immunosorbent assay (ELISA), neuronal injury was assessed by Nissl staining, and proteins expression was examined by Western blot. The results showed that peripheral cytokines, including interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6), exhibited a rapid and transient increase, peaking at 3 h and returning to baseline within 24 h, whereas central inflammatory responses displayed marked region- and time-dependent differences. In the hippocampus, IL-1β showed delayed but sustained elevation, peaking at 12 h and accompanied by progressive neuronal injury. In contrast, the prefrontal cortex exhibited an early cytokines surge at 3 h, with prolonged IL-1β elevation, and a biphasic pattern of neuronal damage characterized by early injury, partial recovery, and delayed exacerbation. These spatiotemporal dynamics were paralleled by differential activation of the TLR4/MyD88/NF-κB pathway. These findings reveal that LPS-induced neuroinflammation is a heterogeneous and dynamic process rather than a uniform response, providing new insight into region-specific vulnerability and the dissociation between peripheral and central inflammatory kinetics.

神经炎症是中枢神经系统疾病的一个关键病理特征，但其时间和区域动态仍不明确。在这项研究中，我们系统地研究了单次腹腔注射脂多糖（LPS, 1 mg/kg）后小鼠海马和前额皮质的神经炎症反应和神经元损伤。将54只雄性C57BL/6N小鼠随机分为6组，分别于LPS给药后0、3、6、12、24、48 h采集血清和脑组织。采用酶联免疫吸附法（ELISA）检测细胞因子水平，尼氏染色检测神经元损伤，Western blot检测蛋白表达。结果显示，包括白细胞介素-1β (IL-1β)、肿瘤坏死因子-α (TNF-α)和白细胞介素-6 （IL-6）在内的外周细胞因子表现出快速和短暂的增加，在3 h达到峰值，并在24 h内恢复到基线，而中枢炎症反应表现出明显的区域和时间依赖性差异。在海马中，IL-1β表现出延迟但持续的升高，在12 h达到峰值，并伴有进行性神经元损伤。相比之下，前额叶皮层在3 h时表现出早期细胞因子激增，IL-1β升高时间延长，神经元损伤呈双相模式，其特征是早期损伤、部分恢复和延迟恶化。这些时空动态与TLR4/MyD88/NF-κB通路的差异激活有关。这些发现表明，lps诱导的神经炎症是一个异质性和动态的过程，而不是一个统一的反应，为区域特异性易感性和外周和中枢炎症动力学之间的分离提供了新的见解。

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引用次数: 0

Comparative effects of antidepressants on cocaine-induced hyperthermia in rats: a preclinical study 抗抑郁药对大鼠可卡因热疗的比较作用：一项临床前研究

IF 2 4区医学 Q3 NEUROSCIENCES

Neuroscience Letters

Pub Date : 2026-01-07 DOI: 10.1016/j.neulet.2026.138508

Tsuyoshi Okada , Seiji Obi , Manabu Takano , Katsutoshi Shioda , Shiro Suda

Purpose

Cocaine abuse is a major public health concern and is often associated with acute hyperthermia, which can be fatal and has limited pharmacological interventions for its management. Although antidepressants are frequently prescribed to cocaine users, particularly to those with comorbid depression, their safety within this context remains unclear, as some can exacerbate the toxicity of cocaine. This study aimed to evaluate the effects of various antidepressants on cocaine-induced hyperthermia in rats to identify safer treatment options.

Subjects and methods

Adult male Wistar rats received intraperitoneal injections of cocaine (30 mg/kg) following pretreatment with one of the following antidepressants: mirtazapine, fluoxetine, venlafaxine, amitriptyline, or moclobemide. To elucidate the mechanism underlying the effects of mirtazapine, the selective 5-HT2A receptor antagonists ketanserin and ritanserin were also tested. Rectal temperature was measured every 30 min for up to 240 min after cocaine administration.

Results

Cocaine administration significantly elevated body temperature in control rats. However, pretreatment with mirtazapine significantly suppressed this hyperthermic response, presumably via central 5-HT2A receptor antagonism. Ketanserin and ritanserin similarly suppressed hyperthermia, supporting this proposed mechanism. In contrast, moclobemide exacerbated the hyperthermia, venlafaxine prolonged the hyperthermic response, and fluoxetine and amitriptyline had no significant effect on the hyperthermic response.

Conclusion

Mirtazapine may be a safer antidepressant option for managing depression in cocaine users because of its capacity to suppress hyperthermia without enhancing monoamine reuptake inhibition. Notably, caution should be exercised when prescribing monoamine oxidase inhibitors and SNRIs to this population. However, further clinical studies are required to validate these findings.

目的：可卡因滥用是一个重大的公共卫生问题，通常与急性高热有关，而急性高热可能是致命的，治疗的药物干预措施有限。虽然抗抑郁药经常被开给可卡因使用者，特别是那些患有共病抑郁症的人，但在这种情况下，它们的安全性尚不清楚，因为有些药物会加剧可卡因的毒性。本研究旨在评估各种抗抑郁药对大鼠可卡因致热的影响，以确定更安全的治疗方案。研究对象和方法：成年雄性Wistar大鼠在使用米氮平、氟西汀、文拉法辛、阿米替林或莫氯贝胺等抗抑郁药物进行预处理后，腹腔注射可卡因（30 mg/kg）。为了阐明米氮平作用的机制，我们还测试了选择性5-HT2A受体拮抗剂酮色林和利坦色林。在可卡因给药后，每30分钟测量一次直肠温度，直至240分钟。结果给药后大鼠体温明显升高。然而，米氮平预处理可能通过中枢5-HT2A受体拮抗作用显著抑制了这种高热反应。克坦色林和利坦色林同样抑制高热，支持这一提出的机制。莫氯贝胺加重了热疗，文拉法辛延长了热疗反应，氟西汀和阿米替林对热疗反应无显著影响。结论米氮平具有抑制高温的作用，且不增强单胺再摄取抑制作用，可能是治疗可卡因使用者抑郁症的更安全的抗抑郁药物。值得注意的是，在给这一人群开单胺氧化酶抑制剂和SNRIs时应谨慎行事。然而，需要进一步的临床研究来验证这些发现。

{"title":"Comparative effects of antidepressants on cocaine-induced hyperthermia in rats: a preclinical study","authors":"Tsuyoshi Okada , Seiji Obi , Manabu Takano , Katsutoshi Shioda , Shiro Suda","doi":"10.1016/j.neulet.2026.138508","DOIUrl":"10.1016/j.neulet.2026.138508","url":null,"abstract":"<div><h3>Purpose</h3><div>Cocaine abuse is a major public health concern and is often associated with acute hyperthermia, which can be fatal and has limited pharmacological interventions for its management. Although antidepressants are frequently prescribed to cocaine users, particularly to those with comorbid depression, their safety within this context remains unclear, as some can exacerbate the toxicity of cocaine. This study aimed to evaluate the effects of various antidepressants on cocaine-induced hyperthermia in rats to identify safer treatment options.</div></div><div><h3>Subjects and methods</h3><div>Adult male Wistar rats received intraperitoneal injections of cocaine (30 mg/kg) following pretreatment with one of the following antidepressants: mirtazapine, fluoxetine, venlafaxine, amitriptyline, or moclobemide. To elucidate the mechanism underlying the effects of mirtazapine, the selective 5-HT2A receptor antagonists ketanserin and ritanserin were also tested. Rectal temperature was measured every 30 min for up to 240 min after cocaine administration.</div></div><div><h3>Results</h3><div>Cocaine administration significantly elevated body temperature in control rats. However, pretreatment with mirtazapine significantly suppressed this hyperthermic response, presumably via central 5-HT2A receptor antagonism. Ketanserin and ritanserin similarly suppressed hyperthermia, supporting this proposed mechanism. In contrast, moclobemide exacerbated the hyperthermia, venlafaxine prolonged the hyperthermic response, and fluoxetine and amitriptyline had no significant effect on the hyperthermic response.</div></div><div><h3>Conclusion</h3><div>Mirtazapine may be a safer antidepressant option for managing depression in cocaine users because of its capacity to suppress hyperthermia without enhancing monoamine reuptake inhibition. Notably, caution should be exercised when prescribing monoamine oxidase inhibitors and SNRIs to this population. However, further clinical studies are required to validate these findings.</div></div>","PeriodicalId":19290,"journal":{"name":"Neuroscience Letters","volume":"873 ","pages":"Article 138508"},"PeriodicalIF":2.0,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145939813","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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

Electroacupuncture at GV20 and GV24 acupoints ameliorates migraine by blocking NLRP3-mediated pyroptosis via inhibiting the Piezo1 channel 电针GV20和GV24穴位通过抑制Piezo1通道阻断nlrp3介导的热凋亡来改善偏头痛。

IF 2 4区医学 Q3 NEUROSCIENCES

Neuroscience Letters

Pub Date : 2026-01-06 DOI: 10.1016/j.neulet.2026.138505

Jianchang Luo , Liyao Feng , Wenbin Xu, Jiawang Lang, Luodan Wang, Zhipeng Zhao, Boxu Lang

Migraine is a complex neuro-glio-vascular disorder, and electroacupuncture (EA) have been recommended as an alternative therapy for migraine. However, the mechanism of action of EA on GV20 (Baihui) and GV24 (Shenting) acupoints in treating migraine remains unclear. Thus, this study was performed to explore the potential mechanisms underlying the therapeutic influence of EA stimulation at GV20 and GV24 acupoints in the migraine treatment. After therapeutic effects of EA stimulation at GV20 and GV24 acupoints on migraine rat model established by dural electrical stimuli (DES) stimulation exploration, numerous approaches, such as qRT-PCR, immunofluorescence, and western blot, were applied to assess the expression of Piezo1 and pyroptosis-related proteins. Finally, Piezo1 activator (Yoda1) was used to confirm the involvement of Piezo1 channel in the treatment actions of EA stimulation at GV20 and GV24 acupoints on migraine. The results showed that EA stimulation at GV20 and GV24 acupoints forcefully alleviated the mechanical allodynia and central sensitization in rat model of migraine, also downregulated the expression of pro-inflammatory cytokines, containing TNF-α, IL-6, and IL-1β. In addition, EA stimulation at GV20 and GV24 acupoints also changed the expression of Piezo1 and pyroptosis-related proteins in rat model of migraine. Interestingly, treatment with the Yoda1 could reverse the therapeutic influences of EA stimulation at GV20 and GV24 acupoints in migraine rat model. Of note, the effect of EA stimulation at GV20 and GV24 acupoints on the expression of pyroptosis-related proteins could also be reverse by Yoda1 administration. This study emphasizes the EA efficacy at GV20 and GV24 acupoints on the migraine rat model established by DES stimulation, and proposes a mechanism involving inhibition of Piezo1 channel to block NLRP3-mediated pyroptosis in migraine.

偏头痛是一种复杂的神经-胶质-血管疾病，电针（EA）已被推荐作为偏头痛的替代疗法。然而，EA对GV20（百会）和GV24（神庭）穴治疗偏头痛的作用机制尚不清楚。因此，本研究旨在探讨EA刺激GV20和GV24穴位治疗偏头痛的潜在机制。通过硬脑膜电刺激（DES）探索建立偏头痛大鼠模型，观察EA刺激GV20和GV24穴位的治疗效果，采用qRT-PCR、免疫荧光、western blot等多种方法评估Piezo1和热休克相关蛋白的表达。最后，利用Piezo1激活剂（Yoda1）证实Piezo1通道参与EA刺激GV20和GV24穴位对偏头痛的治疗作用。结果表明，EA刺激GV20和GV24穴位可有效缓解大鼠偏头痛模型的机械异常性痛和中枢致敏，并下调促炎因子TNF-α、IL-6和IL-1β的表达。此外，EA刺激GV20和GV24穴位也改变了偏头痛大鼠模型中Piezo1和焦热相关蛋白的表达。有趣的是，Yoda1可以逆转EA刺激偏头痛大鼠GV20和GV24穴位的治疗作用。值得注意的是，EA刺激GV20和GV24穴位对焦解热相关蛋白表达的影响也可以被Yoda1逆转。本研究强调了EA作用于GV20和GV24穴位对DES刺激所致偏头痛大鼠模型的影响，并提出了通过抑制Piezo1通道阻断nlrp3介导的偏头痛热凋亡的机制。

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引用次数: 0