Neuropharmacology最新文献_第3页

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 : 2026-01-21 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

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 : 2026-01-21 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

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 : 2026-01-20 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

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 : 2026-01-16 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。

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引用次数: 0

The frequency of binge-like ethanol exposure bidirectionally regulates hippocampal mGlu-LTD via synaptic mechanisms and this effect is reversed by minocycline 酗酒样乙醇暴露的频率通过突触机制双向调节海马mGlu-LTD，这种作用被米诺环素逆转

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2026-01-14 DOI: 10.1016/j.neuropharm.2026.110836

M. Debris , C. Deschamps , M. Martin , L. Zabijak , M. Ouriemi , M. Ropiquet , C. Vilpoux , M. Naassila , O. Pierrefiche

Alcohol addiction may begin in young adults through binge drinking (BD) with its frequency as key criterion. In rodents, BD impairs memory and hippocampal synaptic plasticity on the short term and induced neuroinflammation. Memory impairments may persist into adulthood, whereas long-lasting disturbances in hippocampus synaptic plasticity have not been documented. Moreover, the impact of BD frequency on such disturbances and the potential of anti-inflammatory agents to reverse BD-induced alterations remain unclear. Using hippocampal slices from male rats subjected to eight binge-like episodes delivered at high (HF) or low (LF) frequency during adolescence, we found that alterations in group I metabotropic long-term depression (mGlu_1/5-LTD) were related to binge-like exposure frequency, with HF reducing mGlu_1/5-LTD and intriguingly, LF increasing it. Inhibiting mTORC1 with rapamycin partially corrected LF and HF effects, without alteration of ribosomal protein S6 phosphorylation, a protein downstream of mTORC1, after LF and, a decrease of rp-S6^235/236 after HF. Moreover, LF decreased presynaptic GABA vesicular transporter and bicuculline replicated the increased mGlu_1/5-LTD after LF. Additionally, N-methyl-D-aspartate receptor-dependent LTD was transiently reduced after HF or LF and rescued with a GluN2B antagonist. Finally, the anti-inflammatory agent, minocycline, administered after the ethanol exposure, reversed all synaptic plasticity alterations. We concluded that bidirectional alteration in mGlu_1/5-LTD is a hallmark of ethanol binge exposure frequency, involving pre- and postsynaptic mechanisms. Targeting GluN2B and using anti-inflammatory agents offers promising therapeutic strategies to mitigate the synaptic effects of BD. Our findings highlight the frequency of ethanol exposure as a key determinant of neuronal impact.

酒精成瘾可能始于年轻人的酗酒（BD），其频率是关键标准。在啮齿类动物中，双相障碍在短期内损害记忆和海马突触可塑性并诱发神经炎症。记忆障碍可能会持续到成年，而海马体突触可塑性的长期紊乱尚未被证实。此外，BD频率对这种紊乱的影响以及抗炎药逆转BD诱导的改变的潜力仍不清楚。通过对青春期经历8次高（HF）或低（LF）频率暴饮暴食样发作的雄性大鼠的海马切片，我们发现I组代谢性长期抑郁（mGlu1/5-LTD）的变化与暴饮暴食样暴露频率有关，HF降低了mGlu1/5-LTD，有趣的是，LF增加了mGlu1/5-LTD。用雷帕霉素抑制mTORC1部分纠正了LF和HF的作用，而不改变LF后mTORC1下游蛋白S6的核糖体磷酸化，HF后rp-S6235/236的降低。此外，LF降低了突触前GABA囊泡转运蛋白，双球茎碱复制了LF后增加的mGlu1/5-LTD。此外，n -甲基-d -天冬氨酸受体依赖性LTD在HF或LF后短暂降低，并使用GluN2B拮抗剂进行挽救。最后，在乙醇暴露后给予抗炎剂二甲胺四环素，逆转了所有突触可塑性的改变。我们得出结论，mGlu1/5-LTD的双向改变是乙醇暴暴露频率的标志，涉及突触前和突触后机制。靶向GluN2B并使用抗炎药物为减轻双相障碍的突触效应提供了有希望的治疗策略。我们的研究结果强调了乙醇暴露频率是神经元影响的关键决定因素。

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引用次数: 0

Electrocorticographic, Astrocytic and Transcriptomic Signatures in the Triple Transgenic Mouse Model of Alzheimer's Disease submitted to Stearoyl-CoA Desaturase Inhibition. 硬脂酰辅酶a去饱和酶抑制下阿尔茨海默病三重转基因小鼠模型的皮质电图、星形细胞和转录组特征

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2026-01-13 DOI: 10.1016/j.neuropharm.2026.110835

Audrey Hector, Tanya Leduc, Maria João da Costa Caiado, Benoît Delignat-Lavaud, Julien Dufort-Gervais, Caroline Daneault, Christine Des Rosiers, Clément Bourguignon, Jean-Marc Lina, Karl Fernandes, Jonathan Brouillette, Valérie Mongrain

Alzheimer's disease (AD) is associated with cognitive deficits and sleep disturbances. Research suggests the involvement of dysfunctions in lipid metabolism in the brain of AD patients and animal models. The inhibition of stearoyl-CoA desaturase (SCD), a lipid-converting enzyme, was shown to restore memory in triple transgenic (3xTg)-AD mice. In the brain, astrocytes regulate the synthesis of specific lipids. This project tested whether the inhibition of SCD restores sleep in 3xTg-AD mice, and whether this associates with modifications in lipids, astrocytic function and the transcriptome. Wild-type (WT) and 3xTg-AD female mice received a SCD inhibitor (SCDi) or vehicle, which was followed by an electrocorticographic (ECoG) recording. Brain slices were stained for lipid droplets, astrocytic markers or processed for spatial transcriptomics. The reduced time spent awake (increased time spent in slow wave sleep) in 3xTg-AD mice was not restored by SCDi treatment. Rhythmic and scale-free ECoG activities were markedly altered in 3xTg-AD mice for all wake/sleep states, and SCDi changed these ECoG signatures differently in mutant in comparison to WT mice. GFAP-positive cell density and lipid droplet count were elevated in hippocampal CA1, and rescued by SCDi. The treatment also rescued the expression of several genes in a manner mainly overlapping between brain regions. The findings suggest that the multiple wake/sleep alterations in 3xTg-AD mice are not mitigated by SCD inhibition, but that this treatment can revert changes in hippocampal astrocytes, lipids and in the brain transcriptome. This work will benefit the understanding of the AD pathophysiology and associated sleep disturbances.

阿尔茨海默病（AD）与认知缺陷和睡眠障碍有关。研究表明，AD患者和动物模型的脑脂质代谢功能障碍参与其中。脂质转化酶硬脂酰辅酶a去饱和酶（SCD）的抑制被证明可以恢复三重转基因(3xTg)-AD小鼠的记忆。在大脑中，星形胶质细胞调节特定脂质的合成。该项目测试了SCD的抑制是否能恢复3xTg-AD小鼠的睡眠，以及这是否与脂质、星形细胞功能和转录组的改变有关。野生型（WT）和3xTg-AD雌性小鼠接受SCD抑制剂（SCDi）或载药，随后进行皮质电图（ECoG）记录。对脑切片进行脂滴、星形细胞标记物染色或空间转录组学处理。3xTg-AD小鼠清醒时间的减少（慢波睡眠时间的增加）未被SCDi治疗恢复。在3xTg-AD小鼠的所有清醒/睡眠状态下，节律性和无标度ECoG活动都显著改变，与WT小鼠相比，SCDi在突变体中改变了这些ECoG特征。海马CA1中gfap阳性细胞密度和脂滴计数升高，并被SCDi挽救。这种治疗还以一种主要在大脑区域之间重叠的方式挽救了几个基因的表达。研究结果表明，3xTg-AD小鼠的多重觉醒/睡眠改变不会因SCD抑制而减轻，但这种治疗可以恢复海马星形胶质细胞、脂质和脑转录组的变化。这项工作将有助于了解阿尔茨海默病的病理生理和相关的睡眠障碍。

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引用次数: 0

Lactate-driven H3K27 lactylation promotes Olig2-dependent remyelination and motor recovery after spinal cord injury 乳酸驱动的H3K27乳酸化促进脊髓损伤后寡糖依赖的髓鞘再生和运动恢复。

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2026-01-10 DOI: 10.1016/j.neuropharm.2026.110832

Zongxin Zhu , Ximiao Chen , Hanwen Zhang , Ronghui Miao , Huiling Yu , Shiying Zhao , Youli Zhang , Tanxin Yu , Di Zhang , Yifei Zhou , Xiaolei Zhang , Wei Zhang

Demyelination caused by oligodendrocyte death is a key contributor to neurological deficits after spinal cord injury (SCI), highlighting the critical need to promote oligodendrocyte precursor cell (OPC) differentiation and remyelination. The transcription factor Olig2 is a master regulator of this process; however, its activation mechanism remains unclear. Given the marked lactate accumulation in post-SCI ischemic microenvironments, we investigated the role of lactate in SCI as well as its regulation on OPC differentiation. In a rat SCI model, it is found that exogenous lactate administration significantly improves motor recovery, preserves neurons and axons, modulates the glial response. Mechanistically, lactate induces histone H3K27 lactylation (H3K27la), which specifically upregulates Olig2 expression, thereby activating OPC differentiation and remyelination. This study uncovers the lactate-H3K27la-Olig2 metabolic-epigenetic axis as a novel endogenous repair mechanism for SCI, providing a foundation for metabolism-targeted therapeutic strategies.

少突胶质细胞死亡导致的脱髓鞘是脊髓损伤（SCI）后神经功能缺损的一个关键因素，因此迫切需要促进少突胶质前体细胞（OPC）分化和髓鞘再生。转录因子Olig2是这一过程的主要调控因子；然而，其激活机制尚不清楚。鉴于脊髓损伤后缺血微环境中乳酸的显著积累，我们研究了乳酸在脊髓损伤中的作用及其对OPC分化的调控。在大鼠脊髓损伤模型中，外源性乳酸可显著改善运动恢复，保护神经元和轴突，调节神经胶质反应。在机制上，乳酸诱导组蛋白H3K27乳酸化（H3K27la），特异性上调Olig2表达，从而激活OPC分化和髓鞘再生。本研究揭示了乳酸- h3k27la - olig2代谢-表观遗传轴作为一种新的内源性损伤修复机制，为制定代谢靶向治疗策略提供了基础。

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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 : 2026-01-10 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

Brain-penetrant microtubule-stabilizer epothilone B delays isoflurane-induced unconsciousness in mice 脑渗透微管稳定剂艾替隆B延缓异氟醚诱导的小鼠意识缺失。

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2026-01-08 DOI: 10.1016/j.neuropharm.2026.110834

Yixiang Huang , Zitong Qiu , Xinyue Yu, Sophia Lee, Xiran Zeng, Abbie Chang, Michael C. Wiest

Inhalational anesthetics are currently believed to cause unconsciousness by acting on multiple molecular targets including neural ion channels, receptors, mitochondria, synaptic proteins, and cytoskeletal proteins. Inhalational anesthetics including isoflurane bind to cytoskeletal microtubules (MTs), potentially contributing to causing unconsciousness. This possibility is supported by our demonstration of isoflurane resistance in rats treated once with the brain-penetrant MT-stabilizing drug epothilone B (epoB), and by a recent study in mice using a similar drug given daily over two weeks, which found increased sensitivity to isoflurane. To further characterize the contribution of MTs as functionally relevant targets of volatile anesthetics in mice, we measured latencies to loss of righting reflex (LORR) under isoflurane in mice injected once subcutaneously with vehicle or epoB.

We found significantly increased LORR latencies (i.e., anesthetic resistance) in 8 mg/kg epoB-treated mice on the day following injection, with reduced effects on subsequent days. The 29-s within-subject increase in LORR latencies is not large compared to the variability among different animals, but it represents a statistically large within-subject effect as represented by a Cohen's d of 0.8. The effect could not be accounted for by tolerance from repeated exposure to isoflurane. Our results support that binding of the inhalational anesthetic isoflurane to MTs contributes to LORR in mice, as it does in rats. Our findings support the Orchestrated Objective Reduction (Orch OR) model that posits consciousness as a property of a quantum physical state of neural MTs. We also discuss possible sex differences in anesthetic mechanisms suggested by our data.

目前认为，吸入麻醉剂通过作用于多种分子靶点，包括神经离子通道、受体、线粒体、突触蛋白和细胞骨架蛋白，导致无意识。包括异氟醚在内的吸入麻醉剂与细胞骨架微管（MTs）结合，可能导致无意识。这种可能性得到了我们的证明，即大鼠对异氟烷产生了耐药性，这些大鼠曾接受过一次脑渗透性mt稳定药物epothilone B （epoB）的治疗，而最近的一项研究发现，每天服用类似药物的小鼠在两周内对异氟烷的敏感性增加。为了进一步表征MTs作为挥发性麻醉药在小鼠中的功能相关靶点的作用，我们测量了异氟醚对小鼠的转直反射（LORR）丧失的潜伏期，这些小鼠皮下注射一次载药或epoB。我们发现8 mg/kg epob处理的小鼠在注射后一天的LORR潜伏期（即麻醉抗性）显著增加，随后几天的影响减弱。与不同动物之间的可变性相比，29秒内LORR潜伏期的增加并不大，但它代表了统计学上较大的被试内效应，用Cohen's d = 0.8表示。这种影响不能用反复接触异氟醚的耐受性来解释。我们的研究结果支持吸入麻醉剂异氟醚与MTs的结合有助于小鼠的LORR，正如它在大鼠中的作用一样。我们的研究结果支持了“协调客观还原”（Orch OR）模型，该模型认为意识是神经mt量子物理状态的一种属性。我们还讨论了数据所提示的麻醉机制中可能存在的性别差异。

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引用次数: 0

Acetazolamide alleviates motion sickness by inhibiting inner ear carbonic anhydrase 2 and reducing endolymph volume 乙酰唑胺通过抑制内耳碳酸酐酶2和减少内淋巴体积减轻晕动病

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2026-01-07 DOI: 10.1016/j.neuropharm.2026.110829

Miao-Miao Chen , Chao-Yue Tian , Jian-Gang Ge , Xia Li , Bin Peng , Wei Ji , Lei Cui , Li-Hua Xu , Zheng-Lin Jiang

Motion sickness is common in aerospace, aviation and maritime operations, and travel by vehicles or ships. Existing preventive and therapeutic drugs for motion sickness induce central nervous system (CNS)-related side effects; therefore, there is an urgent need to find new anti-motion sickness targets and to develop novel drugs with reduced adverse effects. In this study, we found that rotational stimulation significantly upregulated carbonic anhydrase 2 (CA2) expression in the inner ears of guinea pigs and mice. Pretreatment with acetazolamide (AZ), an inhibitor of carbonic anhydrase, effectively mitigated motion sickness-related behavioral symptoms in both species and inhibited increase in the inner ear endolymph volume induced by rotational stimulation. Further investigations revealed that AZ mediated its anti-motion sickness effects primarily through mechanisms involving the reduction of intracellular H⁺ concentrations in vestibular epithelial cells, inhibition of Na⁺-K⁺-ATPase activity, and modulation of intracellular Na⁺ and K⁺ homeostasis, thereby attenuating endolymph accumulation in the inner ear. This study demonstrated for the first time an involvement of the inner ear CA2 in the induction of motion sickness and an anti-motion sickness effect of its inhibitor AZ, providing a new strategy for developing anti-motion sickness drugs acting on the inner ear.

晕动病在航天、航空和海上作业以及乘坐车辆或船只旅行中很常见。现有的预防和治疗晕车的药物会引起中枢神经系统（CNS）相关副作用；因此，迫切需要寻找新的抗晕动病靶点，开发副作用较小的新药。在这项研究中，我们发现旋转刺激显著上调豚鼠和小鼠内耳中的碳酸酐酶2 （CA2）表达。乙酰唑胺（acetazolamide， AZ）是一种碳酸酐酶抑制剂，可以有效缓解两种动物的晕动病相关行为症状，并抑制旋转刺激引起的内耳内淋巴体积增加。进一步的研究表明，阿兹兰抗晕动病的作用机制主要包括降低前庭上皮细胞内H+浓度，抑制Na+-K+- atp酶活性，调节细胞内Na+和K+稳态，从而减轻内耳淋巴积聚。本研究首次证实了内耳CA2参与晕动病的诱导及其抑制剂AZ的抗晕动病作用，为开发内耳抗晕动病药物提供了新的策略。

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引用次数: 0