Neuropharmacology最新文献_第2页

Fentanyl reinforcement history has sex-specific effects on multi-step decision-making 芬太尼强化史对多步骤决策具有性别特异性影响

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2026-05-01 Epub Date: 2026-01-29 DOI: 10.1016/j.neuropharm.2026.110860

Eric Garr , Yifeng Cheng , Andy Dong , Patricia H. Janak

It is commonly thought that drug addiction involves a transition to habitual control of action, where the choice to consume drugs becomes automatized and reflects a failure to deliberate over possible negative outcomes. Determining whether the pursuit of addictive drugs is habitual is hampered by a lack of behavior assessments suitable for use during a bout of actual drug seeking. Therefore, to understand how variable histories of drug reinforcement might affect goal-directed and habitual pursuit of drug, we trained rats to perform a multi-step decision-making task to earn oral fentanyl and sucrose rewards following extensive pretraining with either fentanyl or sucrose. Importantly, this task allowed for independent measurements of goal-directed and habitual choice characteristics during online pursuit of rewards, and habitual choice could be further categorized into perseverative and reward-guided components. Chronic fentanyl led to a bias for reward-guided habitual choice specifically in females, and a high degree of perseveration in both sexes. These behavioral changes after chronic fentanyl pretraining generalized across fentanyl and sucrose seeking. In contrast, acute fentanyl selectively increased perseveration in females, and blunted the gradual within-session improvement in goal-directed choice in both sexes. These results show that chronic fentanyl reinforcement promotes habits that generalize across drug and non-drug reward seeking, and that female rats are especially susceptible to habitual control induced by both chronic and acute fentanyl reinforcement.

人们普遍认为，吸毒成瘾涉及到习惯性控制行为的过渡，在这种情况下，选择吸毒变得自动化，反映了对可能的负面结果进行深思熟虑的失败。由于缺乏适合在实际吸毒期间使用的行为评估，判断追求成瘾性药物是否是习惯性的受到阻碍。因此，为了了解药物强化的可变历史如何影响目标导向和习惯性药物追求，我们训练大鼠在广泛的芬太尼或蔗糖预训练后，执行多步骤决策任务，以获得口服芬太尼和蔗糖奖励。重要的是，这项任务允许在在线追求奖励过程中独立测量目标导向和习惯选择特征，并且习惯选择可以进一步分为持久性和奖励导向成分。慢性芬太尼导致了对奖励引导的习惯性选择的偏见，特别是在女性中，并且在两性中都有高度的持久性。慢性芬太尼预训练后的这些行为改变在芬太尼和蔗糖寻找中普遍存在。相比之下，急性芬太尼选择性地增加了女性的毅力，并削弱了两性在目标导向选择方面的逐渐改善。这些结果表明，慢性芬太尼强化促进了在药物和非药物奖励寻求中普遍存在的习惯，雌性大鼠特别容易受到慢性和急性芬太尼强化诱导的习惯控制。

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引用次数: 0

The novel PSD-95 inhibitor BXOS110 provides neuroprotection in acute ischemic stroke 新型PSD-95抑制剂BXOS110在急性缺血性卒中中提供神经保护

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2026-05-01 Epub Date: 2026-01-20 DOI: 10.1016/j.neuropharm.2026.110845

Huan-Yu Zheng , Ya-Rong Ding , Fei-Yang Guo , Tian-Jie Lyu , Bao-Yu Feng , He Li , Shu-Ya Li , Ge-Hong Dong , Yong-Jun Wang , Zi-Xiao Li , Hua-Min Han

Acute ischemic stroke remains a major public health challenge due to its high incidence and limited effective treatment options. Reperfusion therapies, including thrombolysis and endovascular intervention, help restore blood flow in some patients but often fall short due to ineffective recanalization or reperfusion injury, emphasizing the urgent need for adjunctive neuroprotective strategies. BXOS110, a novel neuroprotective agent, targets PSD-95, a postsynaptic density protein that mediates excitotoxic damage by interacting with N-methyl-D-aspartate (NMDA) receptors and neuronal nitric oxide synthase. In this study, BXOS110 demonstrated a higher binding affinity for PSD-95 than its predecessor, nerinetide (NA-1). Our data further confirmed that BXOS110 directly binds to PSD-95 and mitigates NMDA-induced neurotoxicity in vitro. In vivo, BXOS110 exhibited robust brain penetration and sustained localization in ischemic brain regions of rats, as well as significant neuroprotective effects in both rat and primate models of ischemic stroke when administered within 1 h of ischemia onset. Additionally, we determined that BXOS110 administration must be carefully timed with thrombolytic agents to prevent its degradation, identifying optimal dosing intervals to maximize therapeutic efficacy. These findings highlight the potential of BXOS110 as an integrated stroke therapeutic agent, which combines vascular recanalization with targeted neuroprotection to enhance patient outcomes.

急性缺血性中风由于其高发病率和有限的有效治疗选择，仍然是一个重大的公共卫生挑战。再灌注治疗，包括溶栓和血管内干预，有助于恢复一些患者的血流，但往往因再通无效或再灌注损伤而达不到目的，因此迫切需要辅助的神经保护策略。BXOS110是一种新型神经保护剂，靶向PSD-95， PSD-95是一种突触后密度蛋白，通过与n -甲基- d -天冬氨酸（NMDA）受体和神经元一氧化氮合酶相互作用介导兴奋性损伤。在本研究中，BXOS110比其前身nerinetide （NA-1）对PSD-95表现出更高的结合亲和力。我们的数据进一步证实了BXOS110直接结合PSD-95并减轻nmda诱导的体外神经毒性。在体内实验中，BXOS110在大鼠缺血脑区表现出强大的脑渗透和持续定位，在缺血发作1小时内给药，对大鼠和灵长类动物缺血性脑卒中模型均有显著的神经保护作用。此外，我们确定BXOS110必须谨慎地与溶栓药物一起给药，以防止其降解，确定最佳给药间隔以最大化治疗效果。这些发现强调了BXOS110作为卒中综合治疗剂的潜力，它将血管再通与靶向神经保护相结合，以提高患者的预后。

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引用次数: 0

Psilocin mediates long-term synaptic depression in the prelimbic cortex through 5-HT2A receptor-independent mechanisms Psilocin通过不依赖于5-HT2A受体的机制介导前边缘皮层的长期突触抑制

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2026-05-01 Epub Date: 2026-01-21 DOI: 10.1016/j.neuropharm.2026.110854

Ana Domi , Erika Lucente , Davide Cadeddu , Niklas Bengtsson , Erik Smedler , Louise Adermark

Psilocybin is a naturally occurring psychedelic compound with potential antidepressant effects. Although it has long been used by humans, primarily for recreational purposes, the molecular mechanisms underlying its actions remain incompletely understood. Here, we examined the acute effects of psilocin, the active metabolite of psilocybin, on excitatory neurotransmission in the prefrontal cortex (PFC). Slice electrophysiological whole-cell and field potential recordings were conducted in the rat prelimbic cortex during bath application of psilocin. We observed a sex-independent long-term synaptic depression (LTD) of presynaptic origin. This effect was independent of 5-HT_2A and metabotropic glutamatergic receptor group 2 and mediated through enhanced GABAergic tone. The effect was partially inhibited by 5-HT_1A receptor antagonist and completely blocked in slices pre-treated with the neuronal receptor tyrosine kinase 2 (TrkB) receptor antagonist ANA-12. These findings suggest that psilocin exerts a complex modulatory influence on excitatory neurotransmission in the prelimbic PFC, involving GABAergic and serotonergic interactions, and producing sustained alterations in synaptic activity that persist beyond drug exposure. Psilocin-induced LTD, independent of 5-HT_2A receptor activation, may be associated with the reduced prefrontal connectivity reported in humans after psilocin administration and could have implications for cognitive function.

裸盖菇素是一种天然产生的迷幻化合物，具有潜在的抗抑郁作用。尽管人类长期以来主要是出于娱乐目的而使用它，但其作用背后的分子机制仍然不完全清楚。在这里，我们研究了裸盖菇素（裸盖菇素的活性代谢物）对前额皮质（PFC）兴奋性神经传递的急性影响。对大鼠脑前边缘皮质进行全细胞电生理切片和场电位记录。我们观察到一个性别无关的长期突触抑制（LTD）的突触前起源。这种作用不依赖于5-HT2A和代谢性谷氨酸能受体2组，并通过增强的gaba能张力介导。5-HT1A受体拮抗剂可部分抑制这种作用，而神经元受体酪氨酸激酶2 （TrkB）受体拮抗剂ANA-12预处理后的切片则完全阻断这种作用。这些发现表明，裸盖草素对边缘前部PFC的兴奋性神经传递具有复杂的调节作用，涉及gaba能和5 -羟色胺能的相互作用，并产生持续的突触活性改变，这种改变持续存在于药物暴露之后。psilocin诱导的LTD，独立于5-HT2A受体激活，可能与服用psilocin后人类前额叶连接减少有关，并可能对认知功能有影响。

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引用次数: 0

Adolescent cannabinoid vapour exposure sex-dependently alters the relationship between vulnerability traits and ethanol self-administration and modifies naltrexone actions on ethanol intake in rats 青少年大麻素蒸汽暴露的性别依赖性改变了脆弱性特征和乙醇自我管理之间的关系，并改变了纳曲酮对乙醇摄入的作用。

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2026-05-01 Epub Date: 2026-01-22 DOI: 10.1016/j.neuropharm.2026.110843

Jairo S. Acosta-Vargas , Natalia de las Heras-Martínez , Alberto Marcos , Leonor Nozal , Antonio L. Crego , Marcos Ucha , Alejandro Higuera-Matas

Cannabis use during adolescence is common and may predispose individuals to substance use disorders. Animal studies have explored the gateway hypothesis, but data on ethanol consumption are limited. This study aimed to investigate the potential link between adolescent cannabis exposure and ethanol self-administration, as well as the relationship between predisposing behavioural traits and ethanol consumption. Adolescent rats were exposed to vaporized Δ⁹-tetrahydrocannabinol (THC) alone or with cannabidiol (CBD) at different ratios, or to a vehicle, from postnatal day (PND) 28–44, every other day. Behavioural assessments, including novelty and saccharin preference, goal-tracking, elevated plus maze, and ethanol self-administration (fixed and progressive ratio, punished seeking), were conducted from PND 70. Naltrexone was administered to assess its effects on ethanol intake. Cannabinoid exposure did not significantly affect behavioural traits or ethanol self-administration. However, sex differences emerged, with females showing a more vulnerable pattern of ethanol consumption and seeking. In THC-exposed males, a negative correlation was observed between sucrose preference and compulsive ethanol seeking. In females, THC exposure disrupted the correlation between novelty preference and ethanol intake and was associated with a negative correlation between goal-tracking and compulsive seeking. Naltrexone was most effective in reducing ethanol intake in THC-exposed rats as compared to rats exposed to a high CBD/low THC cannabinoid mixture. Adolescent cannabinoid exposure has limited effects on overall alcohol risk but may alter the psychological framework of alcohol-related behaviours and increase naltrexone potency. The observed sex differences highlight the need for personalized interventions.

在青春期使用大麻是很常见的，可能使个人易患物质使用障碍。动物研究已经探索了通道假说，但关于乙醇消费的数据有限。本研究旨在调查青少年大麻暴露与乙醇自我管理之间的潜在联系，以及易感行为特征与乙醇消费之间的关系。从出生后第28天（PND）到第44天，每隔一天，将青春期大鼠单独暴露于蒸发的Δ9-tetrahydrocannabinol （THC）或以不同比例暴露于大麻二酚（CBD），或暴露于一种载体。行为评估，包括新颖性和糖精偏好，目标跟踪，升高和迷宫，以及乙醇自我给药（固定和渐进比例，惩罚寻求），从PND 70进行。服用纳曲酮以评估其对乙醇摄入的影响。大麻素暴露没有显著影响行为特征或乙醇自我管理。然而，性别差异出现了，女性在酒精消费和寻找方面表现出更脆弱的模式。在四氢大麻酚暴露的男性中，观察到蔗糖偏好与强迫性乙醇寻求之间呈负相关。在女性中，四氢大麻酚暴露破坏了新奇偏好和乙醇摄入之间的相关性，并与目标跟踪和强迫性寻求之间的负相关相关。与暴露于高CBD/低THC大麻素混合物的大鼠相比，纳曲酮在减少四氢大麻酚暴露大鼠的乙醇摄入量方面最有效。青少年大麻素暴露对总体酒精风险的影响有限，但可能改变酒精相关行为的心理框架，并增加纳曲酮的效力。观察到的性别差异突出了个性化干预的必要性。

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引用次数: 0

The interaction between FLOT1 and FOSL2 promotes EphA2 transcription, regulating microglial polarization and affecting neuroinflammation in Alzheimer's disease FLOT1和FOSL2相互作用促进EphA2转录，调节小胶质细胞极化，影响阿尔茨海默病的神经炎症。

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2026-05-01 Epub Date: 2026-01-16 DOI: 10.1016/j.neuropharm.2026.110844

Biyan Li, Jiangxi Xu, Hong Zhu, Dan Ren, Lan Xiao, Ting Zhang, Ruomeng Li

Background

Microglial activation plays a crucial role in Alzheimer's disease (AD), responding to amyloid-beta (Aβ) plaques and tau tangles. Initially protective, microglia clear Aβ deposits and support neuronal health, but later adopt a pro-inflammatory, neurotoxic state, releasing cytokines that exacerbate neuroinflammation and neuronal damage. Understanding the mechanisms driving this shift is essential for developing therapies to modulate microglial activation and slow AD progression.

Methods

Quantitative PCR (qPCR), Western blotting, immunohistochemistry (IHC), and immunofluorescence (IF) assays were performed to confirm gene and protein expression levels. Chromatin immunoprecipitation (ChIP), co-immunoprecipitation (CoIP), and dual-luciferase assays were conducted to assess the interactions among FLOT1, FOSL2, and EphA2. The Morris water maze test was used to evaluate spatial learning and memory, with experiments conducted using the APP/PS1 mouse model.

Results

In this study, we found that silencing of FLOT1 in APP/PS1 mice significantly reduced neuroinflammatory markers, prevented pro-inflammatory polarization, and improved spatial memory. Mechanistically, we observed that FLOT1 interacted with the transcription factor FOSL2, which upregulated EphA2 expression, leading to activation of the p38/MAPK signaling pathway. Disrupting EphA2 expression deactivated this pathway, reducing pro-inflammatory polarization in microglia. Our findings further confirmed that the FLOT1-FOSL2 axis regulated microglial polarization in vivo and that targeting this pathway improved cognitive outcomes in AD models.

Conclusion

Overall, these results highlight the FLOT1-FOSL2-EphA2 pathway as a potential therapeutic target for AD, as modulating this axis may reduce neurotoxic inflammation and help preserve cognitive function.

背景：小胶质细胞激活在阿尔茨海默病（AD）中起着至关重要的作用，对β淀粉样蛋白（a β）斑块和tau缠结做出反应。小胶质细胞最初具有保护作用，清除a β沉积并支持神经元健康，但随后进入促炎、神经毒性状态，释放细胞因子，加剧神经炎症和神经元损伤。了解驱动这种转变的机制对于开发调节小胶质细胞激活和减缓阿尔茨海默病进展的疗法至关重要。方法：采用定量PCR （qPCR）、Western blotting、免疫组化（IHC）和免疫荧光（IF）检测方法，确定基因和蛋白的表达水平。采用染色质免疫沉淀（ChIP）、共免疫沉淀（CoIP）和双荧光素酶测定来评估FLOT1、FOSL2和EphA2之间的相互作用。采用Morris水迷宫实验评估空间学习记忆能力，实验采用APP/PS1小鼠模型。结果：在本研究中，我们发现APP/PS1小鼠的FLOT1沉默显著降低了神经炎症标志物，阻止了促炎极化，改善了空间记忆。在机制上，我们观察到FLOT1与转录因子FOSL2相互作用，上调EphA2的表达，导致p38/MAPK信号通路的激活。破坏EphA2表达使这一途径失活，减少小胶质细胞的促炎极化。我们的研究结果进一步证实了FLOT1-FOSL2轴在体内调节小胶质细胞极化，并且靶向这一途径改善了AD模型的认知结果。结论：总的来说，这些结果突出了FLOT1-FOSL2-EphA2通路作为AD的潜在治疗靶点，因为调节该轴可以减少神经毒性炎症并有助于保持认知功能。

{"title":"The interaction between FLOT1 and FOSL2 promotes EphA2 transcription, regulating microglial polarization and affecting neuroinflammation in Alzheimer's disease","authors":"Biyan Li, Jiangxi Xu, Hong Zhu, Dan Ren, Lan Xiao, Ting Zhang, Ruomeng Li","doi":"10.1016/j.neuropharm.2026.110844","DOIUrl":"10.1016/j.neuropharm.2026.110844","url":null,"abstract":"<div><h3>Background</h3><div>Microglial activation plays a crucial role in Alzheimer's disease (AD), responding to amyloid-beta (Aβ) plaques and tau tangles. Initially protective, microglia clear Aβ deposits and support neuronal health, but later adopt a pro-inflammatory, neurotoxic state, releasing cytokines that exacerbate neuroinflammation and neuronal damage. Understanding the mechanisms driving this shift is essential for developing therapies to modulate microglial activation and slow AD progression.</div></div><div><h3>Methods</h3><div>Quantitative PCR (qPCR), Western blotting, immunohistochemistry (IHC), and immunofluorescence (IF) assays were performed to confirm gene and protein expression levels. Chromatin immunoprecipitation (ChIP), co-immunoprecipitation (CoIP), and dual-luciferase assays were conducted to assess the interactions among FLOT1, FOSL2, and EphA2. The Morris water maze test was used to evaluate spatial learning and memory, with experiments conducted using the APP/PS1 mouse model.</div></div><div><h3>Results</h3><div>In this study, we found that silencing of FLOT1 in APP/PS1 mice significantly reduced neuroinflammatory markers, prevented pro-inflammatory polarization, and improved spatial memory. Mechanistically, we observed that FLOT1 interacted with the transcription factor FOSL2, which upregulated EphA2 expression, leading to activation of the p38/MAPK signaling pathway. Disrupting EphA2 expression deactivated this pathway, reducing pro-inflammatory polarization in microglia. Our findings further confirmed that the FLOT1-FOSL2 axis regulated microglial polarization <em>in vivo</em> and that targeting this pathway improved cognitive outcomes in AD models.</div></div><div><h3>Conclusion</h3><div>Overall, these results highlight the FLOT1-FOSL2-EphA2 pathway as a potential therapeutic target for AD, as modulating this axis may reduce neurotoxic inflammation and help preserve cognitive function.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"288 ","pages":"Article 110844"},"PeriodicalIF":4.6,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145998629","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Ivabradine reduces seizure susceptibility in a genetic model of mixed epilepsies 伊伐布雷定降低混合性癫痫遗传模型的癫痫易感性。

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2026-05-01 Epub Date: 2026-01-21 DOI: 10.1016/j.neuropharm.2026.110853

Gleice Kelli Silva-Cardoso, Prosper N'Gouemo

Ivabradine is an approved medication that lowers heart rate by inhibiting hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, which are critical regulators of neuronal excitability. This study investigated the effects of ivabradine on seizure susceptibility in genetically epilepsy-prone rats (GEPR-3s), known for their seizure phenotypes driven by the brainstem and limbic system. In the initial experiments, male and female GEPR-3s were administered ivabradine at acute doses (0, 5, 10, or 20 mg/kg, p. o.) or at repeated doses (5 mg/kg, p. o.). Following treatment, GEPR-3s were evaluated for acoustically evoked generalized tonic-clonic seizures (GTCS). Seizure severity, latency, and duration were recorded at various time intervals (0.5, 1, 2, 4, and 24 h). In subsequent experiments, GEPR-3s underwent repeated episodes of acoustically evoked seizure or audiogenic kindling, leading to generalized clonic seizures (GCSs) seen in fully kindled GEPR-3s. The results revealed that acute administration of ivabradine significantly decreased the incidence and severity of GTCSs, while increasing seizure latencies and reducing seizure durations in both male and female GEPR-3s. Furthermore, repeated administration of ivabradine over five days resulted in notable suppression of GTCSs in both sexes. Additionally, acute ivabradine treatment effectively decreased the severity of GCSs in kindled GEPR-3s. In conclusion, Ivabradine exhibits notable anticonvulsant effects by modulating seizure activity within both the brainstem and limbic networks of the GEPR-3, an inherited model of epilepsy characterized by mixed seizure phenotypes.

伊伐布雷定是一种被批准的药物，通过抑制超极化激活的环核苷酸门控（HCN）通道来降低心率，HCN通道是神经元兴奋性的关键调节因子。本研究调查了伊伐布雷定对遗传性癫痫易感大鼠（GEPR-3s）癫痫易感性的影响，GEPR-3s以脑干和边缘系统驱动的癫痫发作表型而闻名。在最初的实验中，雄性和雌性GEPR-3s分别以急性剂量（0、5、10或20 mg/kg， p.o）或重复剂量（5 mg/kg, p.o）给予伊伐布雷定。治疗后，对gepr -3进行声诱发全身性强直-阵挛性发作（GTCS）评估。在不同的时间间隔（0.5、1、2、4和24小时）记录癫痫发作的严重程度、潜伏期和持续时间。在随后的实验中，GEPR-3s经历了反复的声诱发癫痫发作或听源性点燃，导致完全点燃的GEPR-3s出现全身性阵挛发作（GCSs）。结果显示，急性给药伊伐布雷定显著降低了gtcs的发生率和严重程度，同时增加了男性和女性GEPR-3s的癫痫发作潜伏期，缩短了癫痫发作持续时间。此外，反复服用伊伐布雷定超过5天导致两性gtcs的显著抑制。此外，急性伊伐布雷定治疗有效地降低了点燃的GEPR-3s的gcs的严重程度。综上所述，伊伐布雷定通过调节GEPR-3脑干和边缘网络的癫痫活动表现出显著的抗惊厥作用，GEPR-3是一种以混合癫痫发作表型为特征的遗传性癫痫模型。

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引用次数: 0

Assessing the utility of the neurosteroid zuranolone to modify alcohol-related behaviours 评估神经类固醇祖拉诺酮对改变酒精相关行为的效用。

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2026-05-01 Epub Date: 2026-01-10 DOI: 10.1016/j.neuropharm.2026.110833

Lauren T. Ursich , Amy J. Pearl , Xavier J. Maddern , Andrew J. Lawrence , Leigh C. Walker

Alcohol use is a leading risk factor for premature mortality, yet effective pharmacotherapies remain limited. Neurosteroids, such as allopregnanolone, modulate γ-aminobutyric acid type A (GABA_A) receptors and influence alcohol-related behaviours. Zuranolone, an orally bioavailable synthetic analogue of allopregnanolone recently approved for postpartum depression, represents a potential candidate for therapeutic repurposing in alcohol use disorder (AUD). Here, we assessed the effects of acute and daily zuranolone on alcohol-related behaviours in a preclinical binge drinking model, comparing outcomes across sexes and contrasted to the effects of allopregnanolone. Allopregnanolone produced dose-related locomotor responses, characterised by mid dose transient hyperlocomotion and high dose sedation; the mid dose also reduced alcohol intake in both sexes. In contrast, zuranolone produced sex- and dosing schedule-related effects on alcohol consumption: acute high dose administration transiently reduced intake in males in the Latin square design, whereas mid dose administration increased intake under dose escalation in both sexes, particularly in males; however, total intake was unchanged across dosing schedules. Daily zuranolone transiently reduced alcohol intake in males during the first week only. In locomotor assays, acute high dose zuranolone induced sustained hyperactivity in males that was attenuated in females, supporting sex-related differences in sensitivity. Despite its structural similarity to allopregnanolone, zuranolone produced unique behavioural responses, suggesting their pharmacological profiles may differ. Overall, our data do not show robust reductions in alcohol intake following zuranolone administration across dosing schedules in either sex in preclinical models of binge drinking. Future studies are required to explore its potential relevance in comorbid AUD and affective disorders.

饮酒是过早死亡的主要危险因素，但有效的药物治疗仍然有限。神经类固醇，如异孕酮，调节γ-氨基丁酸A型（GABAA）受体并影响酒精相关行为。祖拉诺酮是一种口服合成异孕酮类似物，最近被批准用于产后抑郁症，它代表了酒精使用障碍（AUD）治疗再利用的潜在候选物。在本研究中，我们在临床前狂饮模型中评估了急性和每日使用祖拉诺酮对酒精相关行为的影响，比较了不同性别的结果，并与异孕酮的效果进行了对比。异孕酮产生剂量相关的运动反应，表现为中剂量瞬时运动过度和高剂量镇静；中等剂量也减少了两性的酒精摄入量。相反，祖拉诺酮对饮酒量产生与性别和给药计划相关的影响：拉丁方设计中，急性高剂量给药会短暂减少男性的摄入量，而中剂量给药会在剂量递增的情况下增加两性的摄入量，尤其是男性；然而，总摄入量在给药方案中没有变化。仅在第一周内，每日服用祖拉诺酮可短暂减少男性的酒精摄入量。在运动试验中，急性高剂量祖拉诺酮诱导雄性持续多动，雌性减弱，支持敏感性的性别相关差异。尽管其结构与异孕酮相似，但祖拉诺酮产生了独特的行为反应，表明它们的药理学特征可能不同。总的来说，我们的数据并没有显示在狂饮的临床前模型中，无论男女，在不同的给药方案中服用祖拉诺酮后，酒精摄入量都有明显的减少。未来的研究需要探索其在共病性AUD和情感性障碍中的潜在相关性。

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引用次数: 0

The potent and selective adenosine A2AR antagonists P400 and P625 protect against symptoms in autoimmune experimental encephalomyelitis by attenuating neuroinflammation and demyelination 强效和选择性腺苷A2AR拮抗剂P400和P625通过减轻神经炎症和脱髓鞘来保护自身免疫性实验性脑脊髓炎的症状

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2026-05-01 Epub Date: 2026-01-27 DOI: 10.1016/j.neuropharm.2026.110857

M. Morozzi , V. Borgonetti , C. Sasia , G. Videtta , S. Calenda , D. Catarzi , F. Varano , V. Colotta , N. Galeotti

Multiple sclerosis (MS) is an autoimmune chronic inflammatory disease of the central nervous system characterized by oxidative stress, demyelination, and neuronal damage. Current MS therapies are unsatisfactory and new therapies are encouraged. Adenosine is highly implicated in MS as it regulates, via activation of its A_2A receptor (A_2AR), the inflammatory and immune response. The aim of this study is to investigate the therapeutic potential of new selective A_2AR antagonists, P400 and P625, in the experimental autoimmune encephalomyelitis (EAE), the principal animal model of MS. P400 and P625 administration (10 μg/mouse intranasal) for 14 days reduced motor disability (clinical score, rotarod) and thermal (hot plate) and mechanical (von Frey) hypernociceptive symptoms associated with a chronic MS model. Quantitative analysis of lymphocytes infiltration in the spinal cord sections stained with hematoxylin and eosin (H&E) showed a larger number of inflammatory cells in EAE sections that were markedly reduced by P400 and P625. P400 also reduced the immunostaining of Iba1, marker of microglia. Luxol Fast Blue (LFB) staining and myelin basic protein (MBP) immunostaining of spinal cord sections showed a robust loss of myelin that was partially restored by P400 and P625. Both treatments increased spinal neurofilament H (NfH) and GAP43 protein expression compared to untreated immunize mice. These data illustrate the efficacy of the new selective A_2AR antagonists in ameliorating EAE symptoms by attenuating neuroinflammation and demyelination. These findings further highlight A_2AR blocking as a promising perspective to control neurological disturbances in MS patients.

多发性硬化症（MS）是一种以氧化应激、脱髓鞘和神经元损伤为特征的中枢神经系统自身免疫性慢性炎症性疾病。目前的多发性硬化症治疗并不令人满意，鼓励新的治疗方法。腺苷通过激活其A2A受体（A2AR）调节炎症和免疫反应，与MS密切相关。本研究的目的是探讨新的选择性A2AR拮抗剂P400和P625在实验性自身免疫性脑脊髓炎（EAE）中的治疗潜力，P400和P625 （10 μg/小鼠鼻内）给药14天可减轻慢性MS模型相关的运动障碍（临床评分，rotarod）和热（热板）和机械（von Frey）高痛感症状。苏木精和伊红（H&；E）染色脊髓切片淋巴细胞浸润定量分析显示，EAE切片炎症细胞数量较多，P400和P625明显减少。P400还降低了小胶质细胞标志物Iba1的免疫染色。脊髓切片的Luxol Fast Blue （LFB）染色和髓磷脂碱性蛋白（MBP）免疫染色显示髓磷脂的大量丢失，P400和P625部分恢复髓磷脂。与未治疗的免疫小鼠相比，两种治疗均增加了脊髓神经丝H （NfH）和GAP43蛋白的表达。这些数据说明了新的选择性A2AR拮抗剂通过减轻神经炎症和脱髓鞘来改善EAE症状的有效性。这些发现进一步强调了A2AR阻断在控制多发性硬化症患者神经障碍方面的前景。

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引用次数: 0

Short RFamide, CFamide and FCamide peptides as novel positive modulators of ASIC3 with similar potentiating effects but different reversibility 短RFamide， CFamide和FCamide肽作为ASIC 3的新阳性调节剂，具有相似的增强作用，但可逆性不同。

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2026-04-01 Epub Date: 2025-12-23 DOI: 10.1016/j.neuropharm.2025.110813

Maurizio Toft , Maëva Meynier , Hélène Lubrano Di Scampamorte , Cédric Vallée , Miguel Salinas , Peijun Zhang , Jessica Tacco , Anne-Sophie Gay , Emmanuel Bourinet , Eric Lingueglia , Emmanuel Deval

Acid-sensing ion channels (ASICs) are members of the DEG/ENaC family that includes the only known peptide-gated ion channels. While ASICs are gated by protons, they are also sensitive to peptides and are modulated by the molluscan FMRFamide and other mammalian neuropeptides ending by the RFamide motif. We identified a set of synthetic short amidated hexapeptides, which not only end by the RFamide motif but also by CFamide and FCamide, as potent positive modulators of ASIC3 acid-induced activity. We focused on two of them, a RFamide peptide (FR

\overline{CC}

RFamide) and a CFamide peptide (FR

\overline{CRC}

Famide), demonstrating that they have similar specificity for and effects on ASIC3. The potentiating effects of the two peptides are due to a strong slow-down of desensitization, leading to an increase in the amount of current induced by acid pH (≤pH6.6), with apparent affinities ranging from 1 to 5 μM. Surprisingly, the washout kinetic of FR

\overline{CC}

RFamide peptide was much slower than those of FR

\overline{CRC}

Famide and other known RFamide peptides, suggesting potential differences in their mechanisms of action. Computational modeling and structure-function analysis reveal interactions of both peptides with the non-proton binding site of ASIC3 as already reported before for other RFamide peptides, but our data also suggest possible additional effects of FR

\overline{CC}

RFamide involving directly or indirectly the proton binding domain. These findings expand our understanding of ASICs’ modulation by peptides, identifying novel short modulators of ASIC3, including peptides with new CFamide and FCamide ending motifs, and showing differences between these peptides using their washout kinetic as a new parameter.

酸敏感离子通道（asic）是DEG/ENaC家族的成员，包括唯一已知的肽门控离子通道。虽然asic是由质子门控的，但它们也对肽敏感，并由软体动物FMRFamide和其他以RFamide基序结尾的哺乳动物神经肽调节。我们发现了一组合成的短修饰六肽，它们不仅以RFamide基序结尾，而且以CFamide和FCamide结尾，它们是ASIC3酸诱导活性的有效正向调节剂。我们重点研究了其中的两个，RFamide肽（FR RFamide）和CFamide肽（FR Famide），证明它们对ASIC3具有相似的特异性和作用。这两种多肽的增强作用是由于对脱敏作用的强烈减缓，导致酸性pH（≤pH6.6）诱导的电流量增加，表观亲和范围为1 ~ 5 μM。令人惊讶的是，FR RFamide肽的洗脱动力学比FR Famide和其他已知的RFamide肽慢得多，这表明它们的作用机制可能存在差异。计算模型和结构-功能分析揭示了这两种肽与ASIC3的非质子结合位点的相互作用，正如之前报道的其他RFamide肽一样，但我们的数据还表明FR RFamide可能直接或间接涉及质子结合域的其他作用。这些发现扩大了我们对肽对asic的调节的理解，鉴定了新的ASIC3短调节因子，包括具有新的CFamide和FCamide结尾基序的肽，并使用它们的冲刷动力学作为新参数显示了这些肽之间的差异。

{"title":"Short RFamide, CFamide and FCamide peptides as novel positive modulators of ASIC3 with similar potentiating effects but different reversibility","authors":"Maurizio Toft , Maëva Meynier , Hélène Lubrano Di Scampamorte , Cédric Vallée , Miguel Salinas , Peijun Zhang , Jessica Tacco , Anne-Sophie Gay , Emmanuel Bourinet , Eric Lingueglia , Emmanuel Deval","doi":"10.1016/j.neuropharm.2025.110813","DOIUrl":"10.1016/j.neuropharm.2025.110813","url":null,"abstract":"<div><div>Acid-sensing ion channels (ASICs) are members of the DEG/ENaC family that includes the only known peptide-gated ion channels. While ASICs are gated by protons, they are also sensitive to peptides and are modulated by the molluscan FMRFamide and other mammalian neuropeptides ending by the RFamide motif. We identified a set of synthetic short amidated hexapeptides, which not only end by the RFamide motif but also by CFamide and FCamide, as potent positive modulators of ASIC3 acid-induced activity. We focused on two of them, a RFamide peptide (FR<span><math><mrow><mover><mtext>CC</mtext><mo>‾</mo></mover></mrow></math></span>RFamide) and a CFamide peptide (FR<span><math><mrow><mover><mtext>CRC</mtext><mo>‾</mo></mover></mrow></math></span>Famide), demonstrating that they have similar specificity for and effects on ASIC3. The potentiating effects of the two peptides are due to a strong slow-down of desensitization, leading to an increase in the amount of current induced by acid pH (≤pH6.6), with apparent affinities ranging from 1 to 5 μM. Surprisingly, the washout kinetic of FR<span><math><mrow><mover><mtext>CC</mtext><mo>‾</mo></mover></mrow></math></span>RFamide peptide was much slower than those of FR<span><math><mrow><mover><mtext>CRC</mtext><mo>‾</mo></mover></mrow></math></span>Famide and other known RFamide peptides, suggesting potential differences in their mechanisms of action. Computational modeling and structure-function analysis reveal interactions of both peptides with the non-proton binding site of ASIC3 as already reported before for other RFamide peptides, but our data also suggest possible additional effects of FR<span><math><mrow><mover><mtext>CC</mtext><mo>‾</mo></mover></mrow></math></span>RFamide involving directly or indirectly the proton binding domain. These findings expand our understanding of ASICs’ modulation by peptides, identifying novel short modulators of ASIC3, including peptides with new CFamide and FCamide ending motifs, and showing differences between these peptides using their washout kinetic as a new parameter.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"287 ","pages":"Article 110813"},"PeriodicalIF":4.6,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145834400","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

NLRP10 ablation alleviates neuropathic pain by inhibiting excessive NIX/LC3-dependent mitophagy in the spinal cord NLRP10消融通过抑制脊髓过度的NIX/ lc3依赖性有丝分裂来减轻神经性疼痛。

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2026-04-01 Epub Date: 2026-01-06 DOI: 10.1016/j.neuropharm.2026.110831

Xiaoyu Zhang, Jiale Sun, Fengtian Zhao, Ting Liu, Shangchen Yu, Wen Zhang, Xuebi Tian

Objective

Neuropathic pain (NP) presents a significant clinical challenge due to its physical and psychological impact and the lack of effective treatments. While the pathogenesis of NP remains incompletely understood, emerging evidence suggests that Nod-like receptor pyrin domain-containing protein 10 (NLRP10) participates in neurological disorders via neuroinflammation and mitochondrial autophagy. This study investigates roles of NLRP10 in NP pathogenesis and elucidates its mechanism in triggering neuroinflammation-mediated NIX/LC3-dependent mitochondrial dysfunction.

Methods

A spared nerve injury (SNI) mouse model was established to investigate neuropathic pain (NP) mechanisms. Pain behaviors were assessed using the mechanical pain withdrawal threshold (MPWT). Adeno-associated virus (AAV) was administered to the spinal dorsal horn (SDH) to downregulate NLRP10 or overexpress NIX. Neuroinflammatory responses and alterations in mitophagy were subsequently evaluated using Western blotting, ELISA, immunofluorescence, and transmission electron microscopy.

Results

SNI mice exhibited upregulated NLRP10 inflammasome expression and enhanced activation of the downstream NLRP12/ASC/Caspase1 pathway in the SDH. This was accompanied by significant increases in NIX/LC3 protein concentrations and decreased mitochondrial-related protein levels after surgery. NLRP10 predominantly colocalized with neuronal marker NeuN in SDH. Transmission electron microscopy revealed characteristic mitochondrial damage. Knockdown of NLRP10 with mNLRP10 effectively suppressed inflammatory activation, attenuated excessive mitochondrial autophagy, and alleviated NP manifestations. Notably, NIX overexpression abolished the protective effects of NLRP10 reduction in SNI mice.

Conclusion

In summary, our findings demonstrate that NLRP10 downregulation inhibit NLRP12/ASC/Caspase1 pathway activation and prevents pathological mitochondrial autophagy, ultimately alleviating NP. These results identify NLRP10 as a promising therapeutic target for NP management.

目的：神经性疼痛（NP）由于其对身体和心理的影响以及缺乏有效的治疗方法，给临床带来了重大挑战。虽然NP的发病机制尚不完全清楚，但新出现的证据表明，nod样受体pyrin结构域蛋白10 （NLRP10）通过神经炎症和线粒体自噬参与神经系统疾病。本研究探讨了NLRP10在NP发病机制中的作用，并阐明了其引发神经炎症介导的NIX/ lc3依赖性线粒体功能障碍的机制。方法：建立神经损伤（SNI）小鼠模型，探讨神经性疼痛（NP）的机制。采用机械疼痛戒断阈值（MPWT）评估疼痛行为。将腺相关病毒（AAV）注入脊髓背角（SDH），下调NLRP10或过表达NIX。随后使用Western blotting、ELISA、免疫荧光和透射电镜评估神经炎症反应和线粒体自噬的改变。结果：SNI小鼠在SDH中NLRP10炎性小体表达上调，下游NLRP12/ASC/Caspase1通路激活增强。这伴随着手术后NIX/LC3蛋白浓度的显著增加和线粒体相关蛋白水平的降低。NLRP10在SDH中主要与神经元标记物NeuN共定位。透射电镜显示特征性线粒体损伤。用mNLRP10敲低NLRP10可有效抑制炎症激活，减轻线粒体过度自噬，减轻NP表现。值得注意的是，NIX过表达消除了SNI小鼠NLRP10减少的保护作用。结论：综上所述，我们的研究结果表明，NLRP10下调可抑制NLRP12/ASC/Caspase1通路的激活，阻止病理性线粒体自噬，最终缓解NP。这些结果确定NLRP10是NP治疗的有希望的治疗靶点。

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引用次数: 0