Neuropharmacology最新文献_第4页

Intranasal AdipoRon mitigates motor and cognitive deficits in hemiparkinsonian rats through neuroprotective mechanisms against oxidative stress and synaptic dysfunction 通过针对氧化应激和突触功能障碍的神经保护机制，鼻内注射 AdipoRon 可减轻半帕金森大鼠的运动和认知障碍。

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2024-10-10 DOI: 10.1016/j.neuropharm.2024.110180

Soraya Alimohammadi , Gisou Mohaddes , Rana Keyhanmanesh , Seyed Zanyar Athari , Negin Azizifar , Fereshteh Farajdokht

While motor symptoms are the most well-known manifestation of Parkinson's disease (PD), patients may also suffer from non-motor signs like cognitive impairments. The adiponectin receptor agonist AdipoRon (Adipo) has shown neuroprotective effects in preclinical studies. The objective of this study was to determine the potential benefits of chronic intranasal treatment of Adipo on motor function and cognitive performance in a hemiparkinsonian rat model caused by injecting 6-hydroxydopamine (6-OHDA) into the left forebrain bundle. After one week, PD rats were given either a vehicle or one of three dosages of Adipo (0.1, 1, and 10 μg) or levodopa (10 mg/kg orally) daily for 21 days. Recognition and spatial memory were determined using the novel object recognition test (NORT) and the Barnes maze test, respectively. The hippocampal tissues of the animals were harvested to examine oxidative stress status as well as the protein expressions of brain-derived neurotrophic factor (BDNF) and postsynaptic density protein 95 (PSD-95). In hemiparkinsonian rats, motor impairments, recognition memory, and spatial memory were all improved by chronic intranasal Adipo at 1 and 10 μg. Furthermore, we found that unilateral 6-OHDA injection elevated hippocampal oxidative stress (ROS) while concurrently reducing total antioxidant capacity (TAC), BDNF, PSD-95, and antioxidant enzymes (SOD, GPx). However, Adipo 10 μg significantly reduced these biochemical alterations in the hippocampus of 6-OHDA-lesioned rats. Chronic intranasal Adipo ameliorated spatial and recognition memory deterioration in hemiparkinsonian rats, presumably by increasing hippocampal synaptic protein levels, reducing oxidative stress, and increasing BDNF.

运动症状是帕金森病（PD）最广为人知的表现，但患者也可能出现认知障碍等非运动症状。在临床前研究中，脂肪素受体激动剂 AdipoRon（Adipo）已显示出神经保护作用。本研究的目的是通过向左前脑束注射 6-羟基多巴胺（6-OHDA），确定长期鼻内注射 Adipo 对偏帕金森病大鼠模型的运动功能和认知能力的潜在益处。一周后，给帕金森病大鼠服用药物或阿迪波（0.1、1 和 10 μg）或左旋多巴（10 mg/kg 口服）三种剂量中的一种，每天服用 21 天。分别使用新物体识别测试（NORT）和巴恩斯迷宫测试测定识别记忆和空间记忆。采集动物的海马组织以检测氧化应激状态以及脑源性神经营养因子（BDNF）和突触后密度蛋白95（PSD-95）的蛋白表达。在半帕金森病大鼠中，长期鼻内注射 1 和 10 μg 的阿迪波可改善运动障碍、识别记忆和空间记忆。此外，我们还发现单侧注射 6-OHDA 会升高海马氧化应激（ROS），同时降低总抗氧化能力（TAC）、BDNF、PSD-95 和抗氧化酶（SOD、GPx）。然而，阿迪肽 10 μg 能显著减少 6-OHDA 失神经大鼠海马中的这些生化改变。长期鼻内注射阿迪波可改善半帕金森病大鼠的空间记忆和识别记忆衰退，这可能是通过提高海马突触蛋白水平、减少氧化应激和增加 BDNF 实现的。

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引用次数: 0

Activation of ventral pallidum-projecting neurons in the nucleus accumbens via 5-HT2C receptor stimulation regulates motivation for wheel running in male mice 通过5-HT2C受体刺激激活脊髓灰质核中的腹侧苍白球投射神经元可调节雄性小鼠车轮跑步的动机。

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2024-10-10 DOI: 10.1016/j.neuropharm.2024.110181

Kazuhei Niitani, Ryoma Nishida, Yusaku Futami, Naoya Nishitani, Satoshi Deyama, Katsuyuki Kaneda

Rodents have a strong motivation for wheel running; however, the neural mechanisms that regulate their motivation remain unknown. We investigated the possible involvement of serotonin (5-HT) systems in regulating motivation for wheel running in male mice. Systemic administration of a 5-HT_1A receptor antagonist (WAY100635) increased the number of wheel rotations, whereas administration of a 5-HT_2A or 5-HT_2C receptor antagonist (volinanserin or SB242084, respectively) decreased it. In the open field test, neither WAY100635 nor volinanserin affected locomotor activity, whereas SB242084 increased locomotor activity. To identify the brain regions on which these antagonists act, we locally injected these into the motivational circuitry, including the nucleus accumbens (NAc), dorsomedial striatum (DM-Str), and medial prefrontal cortex (mPFC). Injection of SB242084 into the NAc, but not the DM-Str or mPFC, reduced the number of wheel rotations without altering locomotor activity. The local administration of WAY100635 or volinanserin to these brain regions did not affect the number of wheel rotations. Immunohistochemical analyses revealed that wheel running increased the number of c-Fos-positive cells in the NAc medial shell (NAc-MS), which was reduced by systemic SB242084 administration. In vitro slice whole-cell recordings showed that bath application of the 5-HT_2C receptor agonist lorcaserin increased the frequency of spontaneous excitatory and inhibitory postsynaptic currents in the ventral tegmental area (VTA)-projecting neurons, whereas it only increased the frequency of spontaneous excitatory postsynaptic currents in ventral pallidum (VP)-projecting neurons in the NAc-MS. These findings suggest that the activation of VP-projecting NAc-MS neurons via 5-HT_2C receptor stimulation regulates motivation for wheel running.

啮齿类动物有强烈的轮跑动机，但调节其动机的神经机制仍然未知。我们研究了5-羟色胺（5-HT）系统可能参与调节雄性小鼠车轮跑步动机的机制。全身给药 5-HT1A 受体拮抗剂（WAY100635）会增加小鼠车轮转动的次数，而给药 5-HT2A 或 5-HT2C 受体拮抗剂（分别为 volinanserin 或 SB242084）则会减少小鼠车轮转动的次数。在开阔地试验中，WAY100635和伏立南色林都不会影响运动活动，而SB242084则会增加运动活动。为了确定这些拮抗剂作用的脑区，我们将这些拮抗剂局部注射到动机回路中，包括伏隔核（NAc）、背内侧纹状体（DM-Str）和内侧前额叶皮层（mPFC）。向NAc注射SB242084，而不向DM-Str或mPFC注射SB242084，可减少车轮转动的次数，而不改变运动活动。在这些脑区局部注射 WAY100635 或 volinanserin 不会影响车轮转动的次数。免疫组化分析表明，车轮运转增加了NAc内侧壳（NAc-MS）中c-Fos阳性细胞的数量，而全身注射SB242084后，这种现象有所减少。体外切片全细胞记录显示，水浴应用5-HT2C受体激动剂洛卡色林可增加腹侧被盖区（VTA）投射神经元的自发兴奋性和抑制性突触后电流的频率，而只增加NAc-MS中腹侧苍白球（VP）投射神经元的自发兴奋性突触后电流的频率。这些发现表明，通过5-HT2C受体刺激激活VP投射的NAc-MS神经元可调节车轮跑步的动机。

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引用次数: 0

Binge ethanol consumption can be attenuated by systemic administration of minocycline and is associated with enhanced neuroinflammation in the central amygdala 全身服用米诺环素可减轻狂饮乙醇的情况，而狂饮乙醇与杏仁核中枢神经炎症的增强有关。

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2024-10-05 DOI: 10.1016/j.neuropharm.2024.110174

Sean Schrank , Joshua P. Sevigny , N. Ika Yunus , Katherine R. Vetter , Oscar D. Aguilar , Vivek Ily , Mikaela Valchinova , Alexandra T. Keinath , Dennis R. Sparta

Alcohol use disorder (AUD) has a complicated pathophysiology. Binge ethanol intoxication may produce long-lasting changes throughout extended amygdala neurocircuitry including neuroinflammation, often leading to relapse. Therefore, understanding the role of binge drinking induced neuroinflammation on extended amygdala neurocircuitry is critically important for treatment. We sought to understand the role of neuroinflammation in a naturalized form of rodent binge ethanol drinking (Drinking in the Dark (DID)). In a 5-week DID paradigm, we demonstrate that acute intraperitoneal (IP) injection of the anti-inflammatory drug minocycline significantly reduced binge drinking repeatedly in male and female Cx3CR1-GFP and C57BL/6J mice. Importantly, IP administration transiently decreased intermittent access sucrose consumption, was not observed on the second IP injection, but did not significantly alter food or water consumption, suggesting that minocycline may produce initial acute aversive effects and may not alter long-term consumption of natural rewards. Examination of rodent behaviors post ethanol binge drinking reveals no lasting effects of minocycline treatment on locomotion or anxiety-like behavior. To assess neuroinflammation, we developed a novel analysis method using a Matlab image analysis script, which allows for non-biased skeletonization and evaluation of microglia morphology to determine a possible activation state in Cx3CR1-GFP knock-in mice after repeated DID. We observed significant morphological changes of microglia within the CeA, but no differences in the BLA. Taken together, this study demonstrates repeated binge ethanol consumption can produce significant levels of microglia morphology changes within the CeA, and that immunomodulatory therapies may be an intriguing pharmacological candidate for the treatment of AUD.

酒精使用障碍（AUD）的病理生理学十分复杂。狂饮乙醇中毒可能会使整个杏仁核神经环路发生长期变化，包括神经炎症，这往往会导致复发。因此，了解暴饮引起的神经炎症对扩展杏仁核神经环路的作用对治疗至关重要。我们试图了解神经炎症在啮齿类狂饮乙醇（黑暗中饮酒，DID）中的作用。在一个为期 5 周的 DID 范例中，我们证明了急性腹腔注射（IP）抗炎药物米诺环素能显著减少雌雄 Cx3CR1-GFP 和 C57BL/6J 小鼠反复暴饮的情况。重要的是，IP给药会短暂降低间歇性蔗糖摄入量，第二次IP注射时则不会出现这种情况，但不会明显改变食物或水的摄入量，这表明米诺环素可能会产生最初的急性厌恶效应，但不会改变自然奖赏的长期摄入量。对啮齿动物狂饮乙醇后行为的研究表明，米诺环素治疗对运动或焦虑样行为没有持久影响。为了评估神经炎症，我们使用 Matlab 图像分析脚本开发了一种新的分析方法，该方法可对小胶质细胞形态进行无偏见的骨骼化和评估，以确定 Cx3CR1-GFP 基因敲入小鼠在重复 DID 后可能出现的激活状态。我们观察到小胶质细胞在 CeA 中发生了明显的形态变化，但在 BLA 中没有差异。综上所述，本研究表明，反复摄入大量乙醇会导致 CeA 内的小胶质细胞形态发生显著变化，而免疫调节疗法可能是治疗 AUD 的一种有趣的药理学候选疗法。

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引用次数: 0

Abnormal increased mTOR signaling regulates seizure threshold in Dravet syndrome 异常增加的 mTOR 信号调节着德雷韦综合征的癫痫阈值。

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2024-10-05 DOI: 10.1016/j.neuropharm.2024.110166

Che-Wen Tsai , Shih-Yin Ho , I Chun Chen , Kai-Chieh Chang , Hou-Jen Chen , Feng-Chiao Tsai , Horng-Huei Liou

Excessive activation of mTOR has been observed in the brains of mouse models for Dravet syndrome. We aim to confirm whether that the overactivation of mTOR contributes to the neuropathological changes leading to epileptogenesis and neurobehavior deficits to support a novel pharmacological therapeutic approach for Dravet syndrome. The mTOR inhibitor everolimus, as a clinical antiseizure medication, was utilized to investigate whether mTOR is involved in hyperthermia-induced seizures, anxiety-like, and autism-like behaviors, as well as to explore potential pathogenic mechanisms in Scn1a^E1099X/+ mice, a model of Dravet syndrome. First, we found that mTOR signaling was upregulated in hippocampus tissues and neural cultures derived from Scn1a^E1099X/+ mice prior to seizure onset. Behaviorally, everolimus increased the seizure threshold and improved anxiety-like and autism-like behaviors in Scn1a^E1099X/+ mice. Electrophysiologically, everolimus reduced the frequency of spontaneous excitatory postsynaptic currents in dentate granule neurons from Scn1a^E1099X/+ mice. Biochemically, everolimus prevented hyperthermia-induced phosphorylation of hippocampal S6 ribosome in hippocampus, and it delayed hyperthermia-induced increase of cytosolic Ca²⁺ level in primary neuronal cultures derived from Scn1a^E1099X/+ mice. Our results provide the evidence that overactivated mTOR as an important neuropathological change which regulates seizure threshold, impairments of neurobehavior, neuronal glutamatergic transmission and intracellular Ca²⁺ levels in Scn1a^E1099X/+ mice. Inhibition of mTOR is a potential pharmacological therapeutic approach.

研究人员已观察到，mTOR过度活化现象存在于小鼠模型的大脑中。我们的目的是确认 mTOR 的过度激活是否导致了神经病理学的变化，从而导致癫痫的发生和神经行为障碍，以支持一种新的药物治疗方法来治疗德雷维综合征。作为一种临床抗癫痫药物，mTOR抑制剂依维莫司被用来研究mTOR是否参与了高热诱导的癫痫发作、焦虑样行为和自闭症样行为，并探索了Scn1aE1099X/+小鼠--一种德雷维综合征模型--的潜在致病机制。首先，我们发现在癫痫发作前，来自 Scn1aE1099X/+ 小鼠的海马组织和神经培养物中的 mTOR 信号上调。在行为学上，依维莫司提高了Scn1aE1099X/+小鼠的癫痫发作阈值，并改善了焦虑样和自闭症样行为。电生理学上，依维莫司降低了Scn1aE1099X/+小鼠齿状颗粒神经元自发兴奋突触后电流的频率。从生物化学角度看，依维莫司能阻止高热诱导的海马 S6 核糖体磷酸化，并能延缓高热诱导的 Scn1aE1099X/+ 小鼠原代神经元培养物中细胞膜 Ca2+ 水平的升高。我们的研究结果证明，过度激活的 mTOR 是一种重要的神经病理学变化，它调节 Scn1aE1099X/+ 小鼠的癫痫阈值、神经行为障碍、神经元谷氨酸能传导和细胞内 Ca2+ 水平。抑制 mTOR 是一种潜在的药物治疗方法。

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引用次数: 0

PET imaging identifies anti-inflammatory effects of fluoxetine and a correlation of glucose metabolism during epileptogenesis with chronic seizure frequency PET 成像确定了氟西汀的抗炎作用以及癫痫发生过程中葡萄糖代谢与慢性癫痫发作频率的相关性。

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2024-10-05 DOI: 10.1016/j.neuropharm.2024.110178

Marion Bankstahl , Ina Jahreis , Bettina J. Wolf , Tobias L. Ross , Jens P. Bankstahl , Pablo Bascuñana

The serotonergic system has shown to be altered during epileptogenesis and in chronic epilepsy, making selective serotonin reuptake inhibitors interesting candidates for antiepileptogenic therapy. In this study, we aimed to evaluate disease-modifying effects of fluoxetine during experimental epileptogenesis.

Status epilepticus (SE) was induced by lithium-pilocarpine, and female rats were treated either with vehicle or fluoxetine over 15 days. Animals were subjected to ¹⁸F-FDG (7 days post-SE), ¹⁸F-GE180 (15 days post-SE) and ¹⁸F-flumazenil positron emission tomography (PET, 21 days post-SE). Uptake (¹⁸F-FDG), volume of distribution (¹⁸F-GE180) and binding potential (¹⁸F-flumazenil) were calculated. In addition, hyperexcitability testing and video-EEG monitoring were performed.

Fluoxetine treatment did not alter brain glucose metabolism. ¹⁸F-GE180 PET indicated lower neuroinflammation in the hippocampus of treated animals (−22.6%, p = 0.042), but no differences were found in GABA_A receptor density. Video-EEG monitoring did not reveal a treatment effect on seizure frequency. However, independently of the treatment, hippocampal FDG uptake 7 days after SE correlated with seizure frequency during the chronic phase (r = −0.58; p = 0.015).

Fluoxetine treatment exerted anti-inflammatory effects in rats during epileptogenesis. However, this effect did not alter disease outcome. Importantly, FDG-PET in early epileptogenesis showed biomarker potential as higher glucose metabolism correlated to lower seizure frequency in the chronic phase.

血清素能系统在癫痫发生过程中和慢性癫痫中发生改变，因此选择性血清素再摄取抑制剂成为抗癫痫治疗的有趣候选药物。在这项研究中，我们旨在评估氟西汀在实验性癫痫发生过程中的疾病调节作用。锂-匹罗卡品诱发癫痫状态（SE），雌性大鼠接受药物或氟西汀治疗，为期15天。动物分别接受了18F-FDG（SE后7天）、18F-GE180（SE后15天）和18F-氟马西尼正电子发射断层扫描（PET，SE后21天）。计算了摄取量（18F-FDG）、分布容积（18F-GE180）和结合电位（18F-氟马西尼）。此外，还进行了过度兴奋测试和视频脑电图监测。氟西汀治疗没有改变大脑葡萄糖代谢。18F-GE180 PET显示治疗动物海马区的神经炎症程度较低（-22.6%，P=0.042），但在GABAA受体密度方面未发现差异。视频脑电图监测并未显示治疗对癫痫发作频率的影响。然而，与治疗无关的是，SE 7 天后海马 FDG 摄取与慢性期癫痫发作频率相关（r=-0.58；p=0.015）。氟西汀治疗可在大鼠癫痫发生过程中发挥抗炎作用。然而，这种作用并没有改变疾病的结局。重要的是，癫痫发生早期的 FDG-PET 显示出生物标志物的潜力，因为葡萄糖代谢较高与慢性期癫痫发作频率较低相关。

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引用次数: 0

The role of gene-environment interactions in social dysfunction: Focus on preclinical evidence from mouse studies 基因与环境的相互作用在社会功能障碍中的作用：关注小鼠研究的临床前证据。

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2024-10-05 DOI: 10.1016/j.neuropharm.2024.110179

Giulia Castellano, Johana Bonnet Da Silva, Susanna Pietropaolo

Human and animal research has demonstrated that genetic and environmental factors can strongly modulate behavioral function, including the expression of social behaviors and their dysfunctionalities. Several genes have been linked to pathologies characterized by alterations in social behaviors, e.g., aggressive/antisocial personality disorder (ASPD), or autism spectrum disorder (ASD). Environmental stimulation (e.g., physical exercise, environmental enrichment) or adversity (e.g., chronic stress, social isolation) may respectively improve or impair social interactions. While the independent contribution of genetic and environmental factors to social behaviors has been assessed in a variety of human and animal studies, the impact of their interactive effects on social functions has been less extensively investigated. Genetic mutations and environmental changes can indeed influence each other through complex mutual effects, e.g., inducing synergistic, antagonistic or interactive behavioral outcomes. This complexity is difficult to be disentangled in human populations, thus encouraging studies in animal models, especially in the mouse species which is the most suitable for genetic manipulations. Here we review the available preclinical evidence on the impact of gene-environment interactions on social behaviors and their dysfunction, focusing on studies in laboratory mice. We included findings combining naturally occurring mutations, selectively bred or transgenic mice with multiple environmental manipulations, including positive (environmental enrichment, physical exercise) and aversive (social isolation, maternal separation, and stress) experiences. The impact of these results is critically discussed in terms of their generalizability across mouse models and social tests, as well as their implications for human studies on social dysfunction.

人类和动物研究表明，遗传和环境因素可对行为功能产生强烈的调节作用，包括社会行为的表达及其功能障碍。一些基因与以社会行为改变为特征的病症有关，如攻击性/反社会人格障碍（ASPD）或自闭症谱系障碍（ASD）。环境刺激（如体育锻炼、丰富环境）或逆境（如慢性压力、社会隔离）可能会分别改善或损害社会交往。虽然遗传和环境因素对社会行为的独立影响已在各种人类和动物研究中进行了评估，但它们对社会功能的交互影响却鲜有广泛研究。基因突变和环境变化确实可以通过复杂的相互影响而相互影响，例如诱发协同、拮抗或互动的行为结果。这种复杂性在人类群体中很难分解，因此鼓励在动物模型中进行研究，尤其是最适合进行遗传操作的小鼠物种。在此，我们回顾了基因与环境相互作用对社会行为及其功能障碍影响的临床前证据，重点是对实验室小鼠的研究。我们将自然发生的突变、选择性繁殖或转基因小鼠与多种环境操作相结合，包括积极（丰富环境、体育锻炼）和厌恶（社会隔离、母体分离和压力）经历的研究结果纳入其中。我们从这些结果在不同小鼠模型和社会测试中的通用性，以及它们对人类社会功能障碍研究的影响方面，对这些结果的影响进行了批判性的讨论。

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引用次数: 0

P2X7 receptors modulate acquisition of cue fear extinction and contextual background memory generalization in male mice P2X7受体调节雄性小鼠对线索恐惧消退和背景记忆泛化的获得。

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2024-10-02 DOI: 10.1016/j.neuropharm.2024.110177

Luana Barreto Domingos , Antonio Furtado da Silva Júnior , Cassiano Ricardo Alves Faria Diniz , Jessica Rosa , Ana Luisa B. Terzian , Leonardo Barbosa Moraes Resstel

The purinergic P2X7 receptors (P2X7R) are activated by adenosine triphosphate (ATP) in several brain regions, particularly those involved with emotional control and the regulation of fear-related memories. Here, we investigate the role of P2X7R in fear learning memory, specifically in the acquisition and consolidation phases of the cued fear conditioning paradigm. C57Bl/6 wildtype (WT) male mice that received a single i.p. injection of the selective P2X7R antagonist A438079 prior the conditioning session showed generalization of cued fear memory and impaired fear extinction recall in the test session, while those treated prior the extinction session exhibited a similar behavior profile accompanied by resistance in the extinction learning. However, no effects were observed when this drug was administered immediately after the conditioning, extinction, or before the test session. Our results with P2X7R knockout (P2X7 KO) mice showed a behavioral profile that mirrored the collective effects observed across all pharmacological treatment conditions. This suggests that the P2X7R KO model effectively replicates the behavioral changes induced by the pharmacological interventions, demonstrating that we have successfully isolated the role of P2X7R in the fear and extinction phases of memory. These findings highlight the role of P2X7R in the acquisition and recall of extinction memory and supports P2X7R as a promising candidate for controlling abnormal fear processing, with potential applications for stress exposure-related disorders such as post-traumatic stress disorder (PTSD).

嘌呤能 P2X7 受体（P2X7R）在多个脑区被三磷酸腺苷（ATP）激活，尤其是那些参与情绪控制和恐惧相关记忆调节的脑区。在这里，我们研究了 P2X7R 在恐惧学习记忆中的作用，特别是在诱导恐惧条件反射范式的获得和巩固阶段。C57Bl/6野生型（WT）雄性小鼠在条件反射前接受一次选择性P2X7R拮抗剂A438079的静脉注射后，在测试环节中表现出诱导恐惧记忆的泛化和恐惧消退回忆的受损，而在消退环节前接受治疗的小鼠则表现出类似的行为特征，并在消退学习中表现出抵抗。然而，如果在条件反射、消退后或测试前立即给药，则没有观察到任何影响。我们对 P2X7R 基因敲除（P2X7 KO）小鼠的研究结果显示，其行为特征与在所有药物治疗条件下观察到的集体效应一致。这表明 P2X7R KO 模型有效地复制了药理学干预所诱导的行为变化，证明我们已经成功地分离出 P2X7R 在记忆的恐惧和消退阶段的作用。这些发现强调了 P2X7R 在消减记忆的获得和回忆中的作用，并支持 P2X7R 成为控制异常恐惧处理的候选药物，有望应用于创伤后应激障碍（PTSD）等应激暴露相关疾病。

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引用次数: 0

Midazolam - A diazepam replacement for the management of nerve agent-induced seizures 咪达唑仑--地西泮的替代品，用于治疗神经毒剂引起的癫痫发作。

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2024-10-02 DOI: 10.1016/j.neuropharm.2024.110171

Lukas Gorecki , Jaroslav Pejchal , Carilyn Torruellas , Jan Korabecny , Ondrej Soukup

A benzodiazepine, diazepam, has been the leading antidote for seizures caused by nerve agents, the most toxic chemical weapons of mass destruction, since the 1960s. However, its limitations have often brought questions about its usefulness. Extensive effort has been devoted into exploring alternatives, such as other benzodiazepines, anticholinergics, or glutamate antagonists. However, only few showed clear clinical benefit. The only two options to ultimately reach clinical milestones are Avizafone, a water-soluble prodrug of diazepam adopted by the French and UK armed forces, and intramuscular midazolam, adopted by the US Army. The recently FDA-approved new intramuscular application of midazolam brought several advantages, such as rapid onset of action, short duration with predictable pharmacokinetics, increased water solubility for aqueous injectable solutions, and prolonged storage stability. Herein, we discuss the pitfalls and prospects of using midazolam as a substitute in anticonvulsant therapy with a particular focus on military purposes in combat casualty care. We have also considered and discussed several other alternatives that are currently at the experimental level. Recent studies have shown the superiority of midazolam over other benzodiazepines in the medical management of poisoned casualties. While its use in emergency care is straightforward, the proper dose for soldiers under battlefield conditions is questionable due to its sedative effects.

自 20 世纪 60 年代以来，苯二氮卓类药物地西泮一直是治疗神经毒剂（毒性最强的大规模杀伤性化学武器）引起的癫痫发作的主要解毒剂。然而，它的局限性常常让人质疑其效用。人们投入了大量精力探索替代品，如其他苯二氮卓类药物、抗胆碱能药物或谷氨酸拮抗剂。然而，只有少数药物显示出明显的临床疗效。最终达到临床里程碑的只有两种选择，一种是法国和英国军队采用的地西泮水溶性原药 Avizafone，另一种是美国军队采用的肌肉注射咪达唑仑。最近获得 FDA 批准的咪达唑仑肌肉注射新药具有多种优势，如起效迅速、持续时间短且药代动力学可预测、水溶性注射液的水溶性增加以及储存稳定性延长。在此，我们讨论了在抗惊厥治疗中使用咪达唑仑作为替代品的隐患和前景，尤其侧重于作战伤员护理中的军事用途。我们还考虑并讨论了目前处于实验阶段的其他几种替代品。最近的研究表明，在对中毒伤员进行医疗处理时，咪达唑仑比其他苯二氮卓类药物更有优势。虽然咪达唑仑在急救中的使用简单明了，但由于其镇静作用，在战场条件下对士兵使用的适当剂量却值得商榷。

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引用次数: 0

Nitrous oxide induces hypothermia and TrkB activation: Maintenance of body temperature abolishes antidepressant-like effects in mice 一氧化二氮诱导低体温和 TrkB 激活：维持体温可消除小鼠的抗抑郁样效应

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2024-10-02 DOI: 10.1016/j.neuropharm.2024.110172

Okko Alitalo , Samuel Kohtala , Marko Rosenholm , Roosa Saarreharju , Gemma González-Hernández , Mirkka Sarparanta , Stanislav Rozov , Tomi Rantamäki

Recent studies indicate that nitrous oxide (N₂O), a gaseous anesthetic and an NMDA (N-methyl-D-aspartate) receptor antagonist, produces rapid antidepressant effect in patients suffering from treatment-resistant depression. Our recent work implies that hypothermia and reduced energy expenditure are connected with antidepressant-induced activation of TrkB neurotrophin receptors — a key regulator of synaptic plasticity. In this study, we demonstrate that a brief exposure to N₂O leads to a drop in body temperature following the treatment, which is linked to decreased locomotor activity; enhanced slow-wave electroencephalographic activity; reduced brain glucose utilization; and increased phosphorylation of TrkB, GSK3β (glycogen synthase kinase 3β), and p70S6K (a kinase downstream of mTor (mammalian target of rapamycin)) in the medial prefrontal cortex of adult male mice. Moreover, preventing the hypothermic response in a chronic corticosterone stress model of depression attenuated the antidepressant-like behavioral effects of N₂O in the saccharin preference test. These findings indicate that N₂O treatment modulates TrkB signaling and related neurotrophic signaling pathways in a temperature-dependent manner, suggesting that the phenomenon driving TrkB activation — altered thermoregulation and energy expenditure — is linked to antidepressant-like behavioral responses.

最近的研究表明，一氧化二氮（N2O）是一种气态麻醉剂，也是一种 NMDA（N-甲基-D-天冬氨酸）受体拮抗剂，它能对耐药性抑郁症患者产生快速抗抑郁效果。我们最近的研究表明，低体温和能量消耗减少与抗抑郁药诱导的 TrkB 神经营养素受体激活有关，而 TrkB 神经营养素受体是突触可塑性的关键调节因子。在这项研究中，我们证明了短暂暴露于一氧化二氮会导致治疗后体温下降，而体温下降与运动活动减少、慢波脑电图活动增强、脑葡萄糖利用率降低以及成年雄性小鼠内侧前额叶皮层中TrkB、GSK3β（糖原合酶激酶3β）和p70S6K（mTor（哺乳动物雷帕霉素靶标）下游激酶）的磷酸化增加有关。此外，在慢性皮质酮应激抑郁模型中，防止低体温反应可减轻 N2O 在糖精偏好试验中的抗抑郁样行为效应。这些研究结果表明，氧化亚氮处理以温度依赖的方式调节TrkB信号和相关神经营养信号通路，表明驱动TrkB激活的现象--体温调节和能量消耗的改变--与抗抑郁样行为反应有关。

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引用次数: 0

The crucial role of NR2A mediating the activation of satellite glial cells in the trigeminal ganglion contributes to orofacial inflammatory pain during TMJ inflammation NR2A 在三叉神经节卫星神经胶质细胞的激活过程中起着至关重要的作用，它是颞下颌关节炎期间口面部炎性疼痛的原因之一。

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2024-09-30 DOI: 10.1016/j.neuropharm.2024.110173

Qin-Xuan Song , Yan-Yan Zhang , Yue-Ling Li , Fei Liu , Ya-Jing Liu , Yi-Ke Li , Chun-jie Li , Cheng Zhou , Jie-Fei Shen

Temporomandibular joint inflammatory diseases are a significant subtype of temporomandibular disorders (TMD) characterized by inflammatory pain in the orofacial area. The N-methyl-D-aspartate receptor (NMDAR), specifically the NR2A subtype, was crucial in neuropathic pain. However, the exact role of NR2A in inflammatory pain in the TMJ and the molecular and cellular mechanisms mediating peripheral sensitization in the trigeminal ganglion (TG) remain unclear. This study utilized male and female mice to induce the TMJOA model by injecting Complete Freund's adjuvant (CFA) into the TMJ and achieve conditional knockout (CKO) of NR2A in the TG using Cre/Loxp technology. The Von-Frey filament test results showed that CFA-induced orofacial pain with reduced mechanical withdrawal threshold (MWT), which was not developed in NR2A CKO mice. Additionally, the up-regulation of interleukin (IL)-1β, IL-6, and nerve growth factor (NGF) in the TG induced by CFA did not occur by NR2A deficiency. In vitro, NMDA activated satellite glial cells (SGCs) with high expression of glial fibrillary acidic protein (GFAP), and both NMDA and LPS led to increased IL-1β, IL-6, and NGF in SGCs. NR2A deficiency reduced these stimulating effects of NMDA and LPS. The regulation of IL-1β involved the p38, Protein Kinase A (PKA), and Protein Kinase C (PKC) pathways, while IL-6 signaling relied on PKA and PKC pathways. NGF regulation was primarily through the p38 pathway. This study highlighted NR2A's crucial role in the TG peripheral sensitization during TMJ inflammation by mediating ILs and NGF, suggesting potential targets for orofacial inflammatory pain management.

颞下颌关节炎性疾病是颞下颌关节紊乱症（TMD）的一个重要亚型，其特征是口面部区域的炎性疼痛。N-甲基-D-天冬氨酸受体（NMDAR），特别是 NR2A 亚型，在神经病理性疼痛中至关重要。然而，NR2A 在颞下颌关节炎性疼痛中的确切作用以及介导三叉神经节（TG）外周敏化的分子和细胞机制仍不清楚。本研究利用雌雄小鼠，通过向颞下颌关节注射完全弗氏佐剂（CFA）诱导颞下颌关节疼痛模型，并利用 Cre/Loxp 技术在三叉神经节中实现 NR2A 的条件性基因敲除（CKO）。Von-Frey丝试验结果表明，CFA诱发的口面部疼痛会降低机械退缩阈值（MWT），而NR2A CKO小鼠不会出现这种情况。此外，白细胞介素（IL）-1β、IL-6和神经生长因子（NGF）在CFA诱导的TG中的上调不会因NR2A缺乏而发生。在体外，NMDA 激活了神经胶质纤维酸性蛋白（GFAP）高表达的卫星神经胶质细胞（SGCs），NMDA 和 LPS 均导致卫星神经胶质细胞中的 IL-1β、IL-6 和 NGF 增加。NR2A 缺乏会降低 NMDA 和 LPS 的刺激作用。IL-1β的调节涉及p38、蛋白激酶A（PKA）和蛋白激酶C（PKC）途径，而IL-6的信号传导则依赖于PKA和PKC途径。NGF 主要通过 p38 通路进行调节。这项研究强调了 NR2A 通过介导 ILs 和 NGF 在颞下颌关节炎症期间对 TG 外周敏感性的关键作用，为口腔炎症性疼痛的治疗提供了潜在靶点。

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引用次数: 0