Neuropharmacology最新文献_第2页

Discovery of a novel IMS48 as a dual inhibitor of acetylcholinesterase and butyrylcholinesterase: In vitro and in vivo study for Alzheimer therapy 发现一种新的IMS48作为乙酰胆碱酯酶和丁基胆碱酯酶的双重抑制剂：阿尔茨海默病治疗的体外和体内研究。

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2026-01-31 DOI: 10.1016/j.neuropharm.2026.110856

Samman Munir , Zunera Chauhdary , Imran Ahmad Khan , Matloob Ahmad , Mohsin Khurshid , Usman Ali Ashfaq

Current medications for Alzheimer's disease (AD) provide symptomatic relief only and fail to prevent neurodegeneration, necessitating the development of new therapeutic agents. This study aimed to evaluate benzimidazole (BIM) analogs as potential inhibitors for AD. In vitro screening identified 1-benzyl-3-(2-((3-chlorophenyl)amino)-2-oxoethyl)-1H-benzo[d]imidazole-3-ium chloride (IMS48) as a potent inhibitor of both acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), with IC₅₀ values of 0.31 ± 0.04 μM and 1.85 ± 0.05 μM, respectively, outperforming the standard drug donepezil. In the in vivo study, rats were administered D-gal (300 mg/kg) and AlCl₃ (150 mg/kg) orally for three weeks to induce AD-like symptoms. Concurrently, IMS48 was administered at doses of 0.75 mg/kg and 1.5 mg/kg for 21 days. Donepezil (DON) was used as a positive control to evaluate the therapeutic efficacy of the IMS8 compound. IMS48 treatment significantly reversed behavioral alterations and improved learning ability. Histopathological analysis demonstrated that IMS48 effectively inhibited neuronal death and neurofibrillary tangles in the brain tissue. Furthermore, IMS48 restored the altered antioxidant enzyme levels (p < 0.001), reducing malondialdehyde (MDA) concentration and enhancing superoxide dismutase (SOD), glutathione (GSH), and catalase (CAT) concentrations. IMS48 also downregulated the gene expression of AChE (1.56 ± 0.10-fold and 1.71 ± 1.76-fold), APP (1.96 ± 0.17-fold and 3.39 ± 0.139-fold), BACE1 (1.92 ± 0.10-fold and 2.59 ± 0.04-fold), TNFα (2.16 ± 0.21-fold and 3.35 ± 0.17-fold), IL-1α (1.86 ± 0.236-fold and 2.56 ± 0.15-fold), and IL-1β (1.58 ± 1.82-fold and 2.32 ± 0.13-fold), associated with AD pathology and neuroinflammation. Overall, these findings highlight the neuroprotective potential of IMS48 in enhancing cognitive function and mitigating neurodegeneration in AD.

目前治疗阿尔茨海默病（AD）的药物仅提供症状缓解，而不能预防神经退行性变，因此需要开发新的治疗药物。本研究旨在评估苯并咪唑（BIM）类似物作为AD的潜在抑制剂。体外筛选发现，1-苄基-3-（2-（3-氯苯基）氨基）-2-氧乙基)- 1h -苯并[d]咪唑-3-氯化铵（IMS48）是乙酰胆碱酯酶（AChE）和丁基胆碱酯酶（BChE）的有效抑制剂，IC50值分别为0.31±0.04 μM和1.85±0.05 μM，优于标准药物多奈哌齐。在体内研究中，大鼠口服d -半乳糖（300 mg/kg）和AlCl3 (150 mg/kg) 3周，诱导ad样症状。同时，以0.75 mg/kg和1.5 mg/kg剂量给药IMS48 21天。以多奈哌齐（Donepezil， DON）为阳性对照，评价IMS8化合物的治疗效果。IMS48治疗显著逆转了行为改变，提高了学习能力。组织病理学分析表明，IMS48有效抑制脑组织神经元死亡和神经原纤维缠结。此外，IMS48恢复了改变的抗氧化酶水平(p

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引用次数: 0

Pharmacological modulation of wakefulness and extracellular hypothalamic histamine release in adult male mice using TAK-925, modafinil, pitolisant, MK-8133 and Lu AF11167 TAK-925、莫达非尼、匹托力、MK-8133和Lu AF11167对成年雄性小鼠清醒和细胞外下丘脑组胺释放的药理调节

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2026-01-30 DOI: 10.1016/j.neuropharm.2026.110862

Camille G. Hviid , Gunnar Sørensen , Birgitte R. Kornum , Kjartan F. Herrik

Histamine is a key regulator of wake and arousal, however its role in pharmacological modulation of wake is largely unknown. Specifically, whether histamine is always activated during pharmacologically induced wake promotion or even necessary for wake remains unclear. This study therefore measured EEG/EMG and accelerometer activity to determine sleep/wake states and locomotor activity and determined extracellular hypothalamic histamine levels using microdialysis following treatment with five wake- and sleep-modulatory compounds. We investigated the effects of three presumed wake-promoting compounds TAK-925 (danavorexton), modafinil and pitolisant as well as two presumed sleep-inducing compounds MK-8133 and Lu AF11167 in adult male mice. TAK-925 and modafinil dose-dependently prolonged wakefulness, whereas pitolisant had no effect. In contrast, TAK-925 and pitolisant increased extracellular histamine levels in hypothalamus, whereas modafinil had no effect. MK-8133 and Lu AF11167 both reduced wakefulness and decreased extracellular hypothalamic histamine levels. In vehicle-treated male mice, histamine levels were correlated with wakefulness but in pharmacologically treated male mice, this correlation was decoupled. These data demonstrate that wake can be modulated without modulating histamine signaling and vice versa.

组胺是清醒和觉醒的关键调节因子，但其在清醒的药理调节中的作用在很大程度上是未知的。具体来说，在药理学诱导的清醒促进过程中，组胺是否总是被激活，甚至是清醒所必需的，目前尚不清楚。因此，本研究测量了脑电图/肌电图和加速度计的活动，以确定睡眠/清醒状态和运动活动，并在使用五种清醒和睡眠调节化合物治疗后使用微透析测定了细胞外下丘脑组胺水平。我们研究了三种假定的促进觉醒的化合物TAK-925 （danavorexton）、莫达非尼和pitolisant以及两种假定的睡眠诱导化合物MK-8133和Lu AF11167对成年雄性小鼠的影响。TAK-925和莫达非尼的剂量依赖性延长清醒时间，而匹托耐则没有效果。相比之下，TAK-925和pitolisant增加了下丘脑的细胞外组胺水平，而莫达非尼没有影响。MK-8133和Lu AF11167都能减少清醒和降低下丘脑细胞外组胺水平。在给药的雄性小鼠中，组胺水平与清醒程度相关，但在给药的雄性小鼠中，这种相关性不存在。这些数据表明，wake可以在不调节组胺信号的情况下被调节，反之亦然。

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引用次数: 0

Sevoflurane, but not alphaxalone, causes lasting autism spectrum disorder-like pathology in male mice after exposure occurs during synaptogenesis 七氟醚，而不是阿尔法霉素，在雄性小鼠突触发生过程中暴露后，会导致持续的自闭症谱系障碍样病理。

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2026-01-30 DOI: 10.1016/j.neuropharm.2026.110861

Benjamin Volvovitz , Adre Newson , Andjelko Milosevic , Tamara Timic Stamenic , Nemanja Useinovic , Natalija Milosavljevic , Slobodan M. Todorovic , Vesna Jevtovic-Todorovic

Background and purpose

Early-life general anesthesia (GA) may cause changes in socio-emotional behaviors in animals and autism spectrum disorder (ASD) in humans. The mechanisms behind GA-induced ASD symptoms are unknown. We investigate the mTOR activation as a potential cause of ASD. We assess ASD-like pathology after neonatal GA exposure to a volatile agent, sevoflurane, or an injectable GA, alphaxalone.

Experimental approach

We exposed male mouse pups on postnatal day 7 (PND7) to sevoflurane or alphaxalone (and their respective vehicles) for 6 h. We performed histomorphological analysis of caspase-3 activity in subiculum 2 h post-GA exposure and Western blot analysis of mTOR activation in hippocampus 24 h post-GA exposure. Spike firing in thalamic neurons was assessed at 4–6 weeks post-GA exposure. Behavioral tests for ASD-like features, including ultrasonic vocalization (USV) at PND8, nestlet shredding, marble burying, and 3-chamber social tests were conducted in adulthood.

Key results

Sevoflurane, unlike alphaxalone, induced more nestlet shredding/marble burying compared to controls, and caused a shift away from the social preference and towards inanimate object. USV suggested a reduction in ultrasonic calls after sevoflurane, but not alphaxalone. The behavioral changes with sevoflurane were accompanied by an increase in caspase-3 activation, hyperactivation of mTOR, and an increase in neuronal firing compared to controls. The sevoflurane effects were largely reversed with rapamycin (a negative modulator of mTOR).

Conclusion and implications

Unlike sevoflurane, alphaxalone does not cause long-lasting ASD-type behaviors and does not affect the mTOR activation and histomorphology, suggesting that alphaxalone could be a safer alternative to sevoflurane.

背景与目的：早期全身麻醉（GA）可能导致动物社会情绪行为和人类自闭症谱系障碍（ASD）的改变。ga诱发ASD症状的机制尚不清楚。我们研究mTOR激活作为ASD的潜在原因。我们评估新生儿GA暴露于挥发性剂七氟醚或可注射GA α xalone后的asd样病理。实验方法：我们在出生后第7天（PND7）将雄性小鼠幼仔暴露于七氟醚或阿片类药物（及其各自的载体）6小时。我们对ga暴露后2小时的枕骨下caspase-3活性进行了组织形态学分析，并对暴露后24小时的海马mTOR激活进行了Western blot分析。在ga暴露后4-6周评估丘脑神经元的Spike放电。在成年期进行asd样特征的行为测试，包括PND8时的超声发声（USV）、破巢、埋大理石和3室社会测试。关键结果：七氟醚，不像alphaxalone，诱导更多的巢粉碎/大理石埋葬与对照组相比，并导致从社会偏好转向无生命的物体。USV建议在使用七氟醚后减少超声波呼叫，而不是使用alphaxalone。与对照组相比，七氟醚的行为改变伴随着caspase-3激活的增加、mTOR的过度激活和神经元放电的增加。七氟醚的作用在很大程度上被雷帕霉素（mTOR的一种负调节剂）逆转。结论和意义：与七氟醚不同，甲氯哌酮不会引起长期的asd型行为，也不会影响mTOR的激活和组织形态学，提示甲氯哌酮可能是七氟醚更安全的替代品。

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引用次数: 0

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 : 2026-01-29 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 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 : 2026-01-27 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

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 : 2026-01-22 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

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