Neuropharmacology最新文献_第4页

c/EBPβ-driven Uchl3-mediated deubiquitination of TRPV1 promotes neuropathic pain by inducing mitochondrial fission in male rats. c/ ebp β驱动的uchl3介导的TRPV1去泛素化通过诱导雄性大鼠线粒体分裂促进神经性疼痛。

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2026-03-19 DOI: 10.1016/j.neuropharm.2026.110939

Ziyun Qiang, Dongxue Sun, Qian Lei, Ruowei Guan, Jinchi Cai, Dongxu Wang, Bo Fang

This study investigates the mechanism of the TRPV1 channel in neuropathic pain (NP), focusing on the c/EBPβ/Uchl3/TRPV1 axis and mitochondrial dynamics. Using male rats chronic constriction injury (CCI) model and an LPS-induced dorsal root ganglion (DRG) cell model, we measured paw withdrawal mechanical threshold (PWMT) and paw withdrawal thermal latency (PWTL), assessed expression changes of related molecules via Real-time quantitative reverse transcription PCR (RT-qPCR) and Western blot, observed mitochondrial fission via transmission electron microscopy (TEM) and Tomm20 immunofluorescence, evaluated mitochondrial function via JC-1 and MitoSOX, and examined neuronal excitability via calcium imaging.Co-immunoprecipitation (Co-IP) confirmed Uchl3-TRPV1 binding, and ubiquitination assay combined with Cycloheximide (CHX) chase and proteasome inhibition assays demonstrated that Uchl3 inhibits TRPV1 degradation via deubiquitination. Luciferase and Chromatin immunoprecipitation (ChIP) assays verified c/EBPβ as a transcriptional activator of Uchl3. RESULTS: showed that TRPV1 activation promoted mitochondrial fission, dysfunction, and neuronal excitability, driving NP. Uchl3 stabilized TRPV1 by removing its ubiquitination, altering mitochondrial dynamics. c/EBPβ transcriptionally upregulated Uchl3, forming a regulatory cascade. Intrathecal si-c/EBPβ in CCI rats downregulated c/EBPβ, Uchl3, and TRPV1, restored mitochondrial homeostasis, and alleviated pain behavior. IN CONCLUSION: the c/EBPβ/Uchl3/TRPV1 pathway regulates NP through mitochondrial dynamics in male rats, presenting a novel therapeutic target for NP treatment.

本研究探讨了TRPV1通道在神经性疼痛（NP）中的作用机制，重点研究了c/EBPβ/Uchl3/TRPV1轴和线粒体动力学。利用雄性大鼠慢性收缩损伤（CCI）模型和lps诱导的背根节（DRG）细胞模型，测定足部退缩机械阈值（PWMT）和足部退缩热潜伏期（PWTL），利用实时定量反转录PCR （RT-qPCR）和Western blot检测相关分子的表达变化，利用透射电镜（TEM）和Tomm20免疫荧光观察线粒体裂变。通过JC-1和MitoSOX评估线粒体功能，并通过钙成像检测神经元兴奋性。共免疫沉淀（Co-IP）证实了Uchl3-TRPV1的结合，泛素化实验联合环己亚胺（CHX）追踪和蛋白酶体抑制实验表明Uchl3通过去泛素化抑制TRPV1的降解。荧光素酶和染色质免疫沉淀（ChIP）实验证实c/EBPβ是Uchl3的转录激活因子。结果：TRPV1激活可促进线粒体分裂、功能障碍和神经元兴奋性，驱动NP。Uchl3通过去除TRPV1的泛素化，改变线粒体动力学来稳定TRPV1。c/EBPβ通过转录上调Uchl3，形成调控级联。CCI大鼠鞘内si-c/EBPβ下调c/EBPβ、Uchl3和TRPV1，恢复线粒体稳态，减轻疼痛行为。结论：c/EBPβ/Uchl3/TRPV1通路通过线粒体动力学调节雄性大鼠NP，为NP治疗提供了新的治疗靶点。

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引用次数: 0

Aggression after intermittent ethanol intoxication in mice: Sex differences and modulation via medial amygdala relaxin-3/RXFP3 signaling. 小鼠间歇性乙醇中毒后的攻击行为：性别差异和内侧杏仁核松弛素-3/RXFP3信号的调节

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2026-03-17 DOI: 10.1016/j.neuropharm.2026.110924

Mohamed Aly Zahran, Aroa Mañas-Ojeda, Mónica Navarro Sánchez, Andrew L Gundlach, Francisco E Olucha-Bordonau, Esther Castillo-Gómez

Alcohol consumption is strongly associated with aggression and violence in humans, yet the underlying neurobiological mechanisms within key aggression circuits remain poorly understood. In this preclinical study, we examined the effects of intermittent alcohol intoxication on dominance and aggressive behaviors in mice, focusing on sex differences and the potential involvement of the nucleus incertus relaxin-3/relaxin-family peptide receptor 3 (RXFP3) signaling pathway. Using an intermittent ethanol-intoxication protocol, we observed that male mice displayed a transient increase in dominance and aggressive behaviors during acute abstinence, as measured by the tube-dominance and resident-intruder tests, whereas female mice displayed heightened defensive responses. Distinct patterns of neural activation across brain regions, reflected by c-Fos protein expression, were associated with aggression in males, including decreased expression in the medial amygdala (MeA) and increased expression in the ventromedial hypothalamus (VMH), consistent with an established MeA-VMH based aggression circuit. Additionally, the levels of relaxin-3 immunoreactivity in MeA nerve fibers increased in parallel with behavioral recovery, suggesting a modulatory role of relaxin-3/RXFP3 signaling. To test this hypothesis, we bilaterally injected an adeno-associated viral (AAV) vector expressing the selective RXFP3 agonist, R3/I5, into the MeA of male mice. Notably, this chronic localized R3/I5 treatment significantly reduced dominance and aggressive behaviors both before and after alcohol intoxication. Together, these data demonstrate that relaxin-3/RXFP3 signaling in the MeA counteracts alcohol-related aggression in male mice, pointing to this pathway as a potential target for treating impulsive violence associated with alcohol intoxication in humans.

酒精消费与人类的攻击性和暴力行为密切相关，但在关键的攻击回路中潜在的神经生物学机制仍然知之甚少。在这项临床前研究中，我们研究了间歇性酒精中毒对小鼠优势和攻击行为的影响，重点关注性别差异和细胞核松弛素-3/松弛素家族肽受体3 （RXFP3）信号通路的潜在参与。使用间歇性乙醇中毒方案，我们观察到雄性小鼠在急性戒断期间表现出短暂的优势和攻击行为增加，通过管优势和常驻入侵者测试来测量，而雌性小鼠表现出增强的防御反应。通过c-Fos蛋白表达反映的不同脑区神经激活模式与雄性的攻击行为有关，包括内侧杏仁核（MeA）表达减少，腹内侧下丘脑（VMH）表达增加，这与已建立的基于MeA-VMH的攻击回路一致。此外，MeA神经纤维中的松弛素-3免疫反应性水平与行为恢复平行增加，表明松弛素-3/RXFP3信号的调节作用。为了验证这一假设，我们将表达选择性RXFP3激动剂R3/I5的腺相关病毒（AAV）载体注射到雄性小鼠的MeA中。值得注意的是，这种慢性局部R3/I5治疗显著减少了酒精中毒前后的优势和攻击行为。总之，这些数据表明，MeA中的松弛素-3/RXFP3信号通路抵消了雄性小鼠的酒精相关攻击，指出这一途径是治疗人类酒精中毒相关冲动暴力的潜在靶点。

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引用次数: 0

2-Phenyl-3-(phenylselanyl)benzofuran attenuates depressive-like behavior and memory deficits induced by subchronic glucocorticoid exposure in female Swiss mice: role of redox and neurochemical mechanisms. 2-苯基-3-（苯selanyl）苯并呋喃减轻瑞士雌性小鼠亚慢性糖皮质激素暴露引起的抑郁样行为和记忆缺陷：氧化还原和神经化学机制的作用

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2026-03-17 DOI: 10.1016/j.neuropharm.2026.110930

Dianer Nornberg Strelow, Mariana Parron Paim, Taís da Silva Teixeira Rech, Larissa Sander Magalhães, Julia Eisenhardt de Mello, Roselia Spanevello, José Sebastião Santos Neto, César Augusto Brüning, Cristiani Folharini Bortolatto

Preclinical studies are valuable tools for screening new drugs, and reports suggest that the administration of glucocorticoids, such as dexamethasone (DEX), can induce neurochemical and behavioral changes linked to depression and memory deficits. The organoselenium compound 2-phenyl-3-(phenylselanyl)benzofuran (SeBZF1) has demonstrated antidepressant-like effects and protection against memory impairments in previous studies. The present study investigated the impact of repeated SeBZF1 administration on a subchronic DEX administration protocol in female Swiss mice. The animals received daily intraperitoneal injections of DEX (2 mg/kg) or its vehicle for 21 days. In the last 7 days of the protocol, the compound SeBZF1 (1 or 5 mg/kg) or its vehicle was administered intragastrically. The 1st set revealed that SeBZF1 attenuated the increase in immobility time in the tail suspension test and the memory decline in the Y-maze test induced by DEX. The 2nd set confirmed the actions of SeBZF1 by the forced swimming test and through the object recognition test. Furthermore, SeBZF1 reduced the reactive oxygen species (ROS) and thiobarbituric acid reactive substances (TBARS) levels induced by DEX administration in the prefrontal cortex and reduced ROS levels in the hippocampus. In addition, treatment with the compound modulated the monoamine oxidase A activity in the hypothalamus and acetylcholinesterase in the hippocampus. In summary, the present study elucidates the promising action of repeated SeBZF1 treatment in an experimental model of subchronic DEX administration in female Swiss mice.

临床前研究是筛选新药的宝贵工具，报告表明，糖皮质激素，如地塞米松（DEX），可以诱导与抑郁和记忆缺陷有关的神经化学和行为改变。有机硒化合物2-苯基-3-（苯selanyl）苯并呋喃（SeBZF1）在先前的研究中已证明具有抗抑郁样作用和对记忆障碍的保护作用。本研究调查了重复SeBZF1给药对瑞士雌性小鼠亚慢性右美托咪唑给药方案的影响。每天腹腔注射DEX （2 mg/kg）或DEX的对照剂，持续21天。在方案的最后7天，化合物SeBZF1（1或5 mg/kg）或其载体灌胃。第1组结果显示，SeBZF1对大鼠悬尾静止时间的增加和DEX诱导的y型迷宫记忆下降有减弱作用。第二组通过强迫游泳测试和物体识别测试来确认SeBZF1的动作。此外，SeBZF1降低了DEX诱导的前额皮质活性氧（ROS）和硫代巴比妥酸活性物质（TBARS）水平，并降低了海马中的ROS水平。此外，用该化合物治疗可以调节下丘脑的单胺氧化酶A活性和海马的乙酰胆碱酯酶。综上所述，本研究阐明了SeBZF1在瑞士雌性小鼠亚慢性DEX给药实验模型中有希望的作用。

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引用次数: 0

Dorsal raphe serotonergic neurons facilitate arousal from sevoflurane anesthesia by heterogeneously modulating neuronal activity in the basolateral amygdala 背中叶5 -羟色胺能神经元通过异质调节杏仁核基底外侧的神经元活动促进七氟醚麻醉后的觉醒。

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2026-03-15 Epub Date: 2025-12-23 DOI: 10.1016/j.neuropharm.2025.110815

Cen Yang , Yuting He , Min Cai , Sa Wang , Yuhao Wang , Miao Wang , Huaning Wang , Yanyan Sun , Jiannan Li

Background

Although the dorsal raphe nucleus (DRN) serotonergic neurons—which play a key role in consciousness—send dense projections to the basolateral amygdala (BLA), the electrophysiological mechanisms underlying their role in general anesthesia regulation remain elusive.

Methods

Fiber photometry was used to monitor DRN serotonergic activity changes in the BLA during sevoflurane anesthesia and arousal process. Optogenetics and neuropharmacology were taken advantage to study the effects and receptor mechanisms. Additionally, in vivo electrophysiology was applied to elucidate the neurophysiological mechanisms underlying DRN serotonergic modulating BLA during sevoflurane anesthesia and arousal process.

Results

DRN serotonergic afferents in the BLA exhibited decreased activity during sevoflurane anesthesia compared to wakefulness. Optogenetic activation of DRN serotonergic terminals in BLA accelerated arousal from sevoflurane anesthesia, as evidenced by electroencephalographic (EEG) signatures and behavioral recovery. Microinjection of 5-hydroxytryptamine (5-HT)1A receptors agonist (but not 5-HT2A or 5-HT2C agonists) into the BLA similarly promoted anesthetic emergence. Mechanistically, DRN serotonergic input inhibited GABAergic neurons while exciting glutamatergic neurons in the BLA, with these effects persisting across both wakefulness and anesthetic states.

Conclusions

Our findings establish a functional role for the DRN serotonergic-BLA neural pathway in promoting arousal from sevoflurane general anesthesia. These results provide novel mechanistic insights into the neural circuitry underlying consciousness recovery.

背景：虽然中隔背核（DRN）的5 -羟色胺能神经元（在意识中起关键作用）向基底外侧杏仁核（BLA）发送密集的投射，但其在全身麻醉调节中的作用的电生理机制尚不清楚。方法：采用纤维光度法监测七氟醚麻醉和觉醒过程中DRN - 5 -羟色胺能活性的变化。利用光遗传学和神经药理学研究其作用和受体机制。此外，体内电生理学应用于阐明在七氟醚麻醉和觉醒过程中DRN - 5 -羟色胺能调节BLA的神经生理机制。结果：与清醒时相比，七氟醚麻醉时BLA中DRN - 5 -羟色胺能事件的活性降低。脑电图和行为恢复证明，光遗传激活BLA中DRN - 5 -羟色胺能末端加速了七氟醚麻醉后的觉醒。微量注射5-羟色胺（5-HT）1A受体激动剂（但不是5-HT2A或5-HT2C激动剂）进入BLA同样促进麻醉出现。从机制上讲，DRN的5 -羟色胺能输入抑制gaba能神经元，同时刺激BLA中的谷氨酸能神经元，这些影响在清醒和麻醉状态下都持续存在。结论：我们的研究结果确定了DRN - 5 -羟色胺能- bla神经通路在促进七氟醚全身麻醉唤醒中的功能作用。这些结果为意识恢复背后的神经回路提供了新的机制见解。

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引用次数: 0

Teneurin-4 knockdown disrupts dopamine dynamics and attenuates methamphetamine-induced behaviors tenneurin -4敲低扰乱多巴胺动力学并减弱甲基苯丙胺诱导的行为。

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2026-03-15 Epub Date: 2025-12-23 DOI: 10.1016/j.neuropharm.2025.110817

Wenbing Chen , Jun Yokose , Naotaka Izuo , Yusuke Yano , Tomoya Kaigawa , Nobuyuki Kai , Chikako Kamiyoshihara , Noriaki Ohkawa , Yuki Shigetsura , Shin-ichi Muramatsu , Atsumi Nitta

Methamphetamine (METH) addiction is a major global public health issue with significant societal consequences. Dopamine (DA) plays a central role in the neurobiological mechanisms of METH addiction, particularly by reinforcing reward pathways and modulating neuronal plasticity. Teneurin-4 (TENM4), a type II transmembrane protein, is essential for neural development and for establishing precise synaptic connectivity. However, the specific role of TENM4 in the nucleus accumbens (NAc) during METH-induced reward remains unclear. Here, we found that repeated METH exposure selectively increased TENM4 protein expression in the nucleus accumbens (NAc), prompting us to investigate its function using an AAV-CRISPR-mediated knockdown (TENM4KD) targeted to the NAc in mice. TENM4KD significantly attenuated the development of METH-induced conditioned place preference, without altering METH-induced hyperlocomotion. This behavioral deficit was paralleled by blunted dopamine dynamics; fiber photometry revealed impaired predictive DA signals during conditioning, and microdialysis confirmed a reduction in both basal and METH-evoked DA levels. Mechanistically, this impairment was not due to damage to dopaminergic neurons themselves but was linked to a loss of local GABAergic neurons within the medial NAc and a compensatory upregulation of the dopamine transporter (DAT). These findings uncover a critical role for TENM4 in maintaining the integrity of local NAc circuits that govern reward learning. Thus, TENM4 emerges as a potential molecular target for therapeutic intervention, as manipulating its expression in the NAc disrupts local inhibitory signaling and reduces METH-induced addictive behaviors.

甲基苯丙胺（冰毒）成瘾是一个具有重大社会后果的重大全球公共卫生问题。多巴胺（DA）在甲基苯丙胺成瘾的神经生物学机制中起着核心作用，特别是通过加强奖赏通路和调节神经元可塑性。tenneurin -4 （TENM4）是一种II型跨膜蛋白，对神经发育和建立精确的突触连接至关重要。然而，在冰毒诱导的奖赏过程中，TENM4在伏核（NAc）中的具体作用尚不清楚。在这里，我们发现反复暴露于甲基安非他明选择性地增加了TENM4蛋白在伏隔核（NAc）中的表达，这促使我们使用aav - crispr介导的针对小鼠NAc的敲低（TENM4KD）来研究其功能。TENM4KD显著减弱了甲基醚诱导的条件位置偏好的发展，但没有改变甲基醚诱导的过度运动。这种行为缺陷与多巴胺动力减弱相平行；纤维光度法显示，在调节过程中，预测性DA信号受损，微透析证实，基础和甲基安非他明诱发的DA水平都有所降低。从机制上讲，这种损伤不是由于多巴胺能神经元本身的损伤，而是与内侧NAc内局部gaba能神经元的丧失和多巴胺转运体（DAT）的代偿上调有关。这些发现揭示了TENM4在维持控制奖励学习的局部NAc回路的完整性方面的关键作用。因此，TENM4成为治疗干预的潜在分子靶点，因为操纵其在NAc中的表达会破坏局部抑制信号并减少冰毒诱导的成瘾行为。

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引用次数: 0

Age-dependent transcriptomic effects of morphine in the frontal cortex of female mice 吗啡在雌性小鼠额叶皮层的年龄依赖性转录组效应。

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2026-03-15 Epub Date: 2025-12-16 DOI: 10.1016/j.neuropharm.2025.110809

Jarvis Savage , Anupama Rai , Jonathan D. Lee , Jane Banahan , Kristina Dujic , Masiel Nunez , Barbara Caldarone , Sarbani Ghoshal , Frank J. Slack , Maria Mavrikaki

Increasing lifespans make health problems in the elderly such as opioid misuse a more prominent concern. Understanding the effects that opioids may have on the aged brain can help us address age-related concerns of opioid exposure. This study aimed to assess potential interactions between aging and opioid exposure. Three-month-old (young adult) and 19-month-old (aged) C57BL/6JN mice were assigned to either a morphine (3 mg/kg, i.p.) or saline group. A conditioned placed preference (CPP) task was used to assess reward sensitivity, while rotarod and beam walk tests were used to assess sensorimotor coordination. To assess for potential age-dependent effects of morphine on gene expression, we performed RNA sequencing in the prefrontal cortex (PFC). We found that morphine induced CPP in both age groups. Our results indicate impaired motor coordination in aged mice; however, morphine did not significantly affect motor coordination in either age group, although a trend toward an increased number of slips was observed in morphine-treated aged mice. Transcriptomic analysis revealed more robust effects of morphine on gene expression in the aged brain compared to the young brain. Interestingly, we found limited overlap between morphine-regulated genes in young and old mice, suggesting that the molecular effects of morphine are age-dependent. Taken together, while we found no significant interactions between morphine (at the tested dose) and aging in the behavioral assays, morphine caused age-dependent gene expression changes. Our findings suggest that age should be considered when prescribing opioids and that age-specific therapeutics may help address opioid use disorder in the elderly.

寿命的延长使老年人的健康问题，如阿片类药物滥用，成为一个更加突出的问题。了解阿片类药物对老年大脑的影响可以帮助我们解决与年龄相关的阿片类药物暴露问题。本研究旨在评估衰老与阿片类药物暴露之间的潜在相互作用。将3月龄和19月龄C57BL/6JN小鼠分为吗啡组（3mg/kg, ig）和生理盐水组。条件放置偏好（CPP）任务用于评估奖励敏感性，而旋转棒和梁行走测试用于评估感觉运动协调。为了评估吗啡对基因表达的潜在年龄依赖性影响，我们在前额皮质（PFC）中进行了RNA测序。我们发现吗啡在两个年龄组中均可诱发CPP。我们的研究结果表明，老年小鼠的运动协调功能受损；然而，吗啡并没有显著影响两个年龄组的运动协调，尽管在吗啡治疗的老年小鼠中观察到滑移次数增加的趋势。转录组学分析显示，与年轻大脑相比，吗啡对老年大脑基因表达的影响更强。有趣的是，我们在年轻和年老的老鼠身上发现了吗啡调控基因之间有限的重叠，这表明吗啡的分子效应是年龄依赖性的。综上所述，虽然我们在行为分析中发现吗啡（在测试剂量下）与衰老之间没有显著的相互作用，但吗啡引起了年龄依赖性基因表达的变化。我们的研究结果表明，在处方阿片类药物时应考虑年龄，针对年龄的治疗方法可能有助于解决老年人阿片类药物使用障碍。

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引用次数: 0

Targeting treatment-resistant social anxiety with sitagliptin: Effects on social fear and comorbid depressive-like behavior in a preclinical model 西格列汀治疗难治性社交焦虑：临床前模型中对社交恐惧和共病抑郁样行为的影响

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2026-03-15 Epub Date: 2025-12-23 DOI: 10.1016/j.neuropharm.2025.110812

Iulia Zoicas, Johannes Kornhuber

Social anxiety disorder (SAD) is often complicated by comorbid depression and resistance to standard treatments, yet therapeutic strategies that effectively address both core and comorbid symptoms remain limited. We previously demonstrated that sitagliptin, a dipeptidyl peptidase-4 (DPP4) inhibitor commonly used in the treatment of type 2 diabetes mellitus, effectively reduces social fear in mice subjected to social fear conditioning (SFC), an ethologically valid model of SAD. In the present study, we extend these findings by evaluating the efficacy of sitagliptin in reducing social fear and preventing the development of comorbid depressive-like behavior in acid sphingomyelinase-deficient (ASM−/−) mice, a genetically defined model of antidepressant-resistant emotional behavior. Chronic oral administration of sitagliptin (100 mg/kg/day) significantly reduced social fear in both male and female ASM+/+ and ASM−/− mice following SFC. Notably, sitagliptin also prevented the emergence of depressive-like behavior in both genotypes, as well as the increase in anxiety-like behavior observed specifically in ASM−/− mice, two hallmark comorbidities in the SFC model. These findings indicate that sitagliptin exerts dual-action effects on both primary and comorbid behavioral symptoms of SAD, including in individuals resistant to conventional antidepressant treatment. Given its established clinical use and safety profile, sitagliptin may represent a promising candidate for repurposing as an early intervention in complex, treatment-resistant forms of SAD.

社交焦虑障碍（SAD）通常伴有共病性抑郁和对标准治疗的抵抗，但有效解决核心症状和共病症状的治疗策略仍然有限。我们之前证明了西格列汀，一种二肽基肽酶-4 （DPP4）抑制剂，通常用于治疗2型糖尿病，可以有效地减少社交恐惧条件作用（SFC）小鼠的社交恐惧，SFC是一种行为学上有效的SAD模型。在本研究中，我们通过评估西格列汀在酸性鞘磷脂酶缺乏（ASM-/-）小鼠（一种抗抑郁情绪行为的遗传定义模型）中减少社交恐惧和预防共病抑郁样行为发展的功效来扩展这些发现。长期口服西格列汀（100 mg/kg/天）显著降低了SFC后雄性和雌性ASM+/+和ASM-/-小鼠的社交恐惧，值得注意的是，西格列汀还阻止了两种基因型中出现的抑郁样行为，以及ASM-/-小鼠中观察到的焦虑样行为的增加，这是SFC模型中的两种标志性合并症。这些发现表明西格列汀对SAD的原发性和共病行为症状具有双重作用，包括对常规抗抑郁药物治疗有抵抗力的个体。鉴于其已确立的临床用途和安全性，西格列汀可能是一个有希望的候选药物，可作为复杂的、治疗抵抗型SAD的早期干预手段。

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引用次数: 0

Cftr nominates a novel therapeutic target for Alzheimer's disease: Evidence from integrative omics and in vitro validation Cftr提名一种治疗阿尔茨海默病的新靶点：来自综合组学和体外验证的证据。

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2026-03-15 Epub Date: 2025-12-14 DOI: 10.1016/j.neuropharm.2025.110808

Hao-Ran Li , Jun-Zhuo Shi , Meng-Jie Zhang , Lu-Yao Yun , Yun-Feng Zhou , Yang-Yang He , Xi Li , Guan-Hua Du , Xiao-Bin Pang , Meng-Wei Wang , Xin-Mei Xie , Jie-Jian Kou

Alzheimer's disease (AD), among the most prevalent neurodegenerative disorders, poses substantial challenges for therapeutic development due to its complex pathophysiology, necessitating novel treatment strategies. This study applied an integrated transcriptomics and untargeted metabolomics approach to hippocampal tissues from wild-type and 3 × Tg-AD mice to identify AD-associated molecular alterations and key pathways. KEGG pathway enrichment analysis of significantly differentially expressed genes and metabolites identified several core candidate genes, including C5ar1, Gabrg1, Ptger1, Tac1, Lpar2, Pnp2, Cftr, and Sstr3. PCR-based validation in both in vivo and in vitro models confirmed Cftr as the most promising candidate for further investigation. In Aβ₂₅-₃₅-induced cellular AD models, Cftr knockdown or pharmacological inhibition activated the NLRP3 inflammasome pathway, exacerbating neuroinflammation and oxidative stress, whereas enhancing Cftr activity attenuated these pathological processes. These results establish Cftr as a potential therapeutic target for AD and reveal that its modulation of NLRP3 inflammasome signaling represents a strategic avenue for mitigating neuroinflammation and oxidative stress, suggesting a promising direction for intervening in AD progression.

阿尔茨海默病（AD）是最常见的神经退行性疾病之一，由于其复杂的病理生理，对治疗发展提出了重大挑战，需要新的治疗策略。本研究采用整合转录组学和非靶向代谢组学方法对野生型和3×Tg-AD小鼠海马组织进行研究，以鉴定ad相关的分子改变和关键通路。KEGG通路富集分析显著差异表达的基因和代谢物鉴定出几个核心候选基因，包括C5ar1、Gabrg1、Ptger1、Tac1、Lpar2、Pnp2、Cftr和Sstr3。基于pcr的体内和体外模型验证证实Cftr是最有希望进一步研究的候选药物。在a - β25-35诱导的细胞AD模型中，Cftr敲低或药物抑制激活NLRP3炎症小体途径，加剧神经炎症和氧化应激，而增强Cftr活性则减弱这些病理过程。这些结果证实了Cftr作为AD的潜在治疗靶点，并揭示了其对NLRP3炎症小体信号的调节是缓解神经炎症和氧化应激的一种策略途径，为干预AD的进展提供了一个有希望的方向。

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引用次数: 0

Cell models to probe the biological bases of antipsychotic-induced metabolic Syndrome: towards an individual specific approach 细胞模型探索抗精神病诱导代谢综合征的生物学基础：迈向个体特异性途径

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2026-03-15 Epub Date: 2025-12-24 DOI: 10.1016/j.neuropharm.2025.110814

Maria Fiore , Silvia Saltarelli , Laura De Mastro , Enrico D'Ambrosio , Antonia Ianniello , Alessandro Bertolino , Giulio Pergola , Maria Favia , Antonio Rampino

Background

Individuals with major psychiatric disorders are at an increased risk of developing Metabolic Syndrome (MetS), partly attributed to the dysmetabolic side effects of Second-Generation Antipsychotics (SGAs). In vitro cell models of peripheral tissues provide a valid platform to investigate the biochemical and molecular alterations induced by SGAs at the peripheral level in conjunction with their effects on the central nervous system. This scoping review summarizes two decades of studies utilizing established cell lines and primary rodent cells to examine the direct dysmetabolic effects of antipsychotics (APs) on lipid and glucose metabolism, inflammatory pathways, and mitochondrial function.

Methods

We identified published scientific literature in the PubMed database using the following search strategy: (“antipsychotic” OR “olanzapine” OR “clozapine” OR “risperidone” OR “quetiapine” OR “haloperidol”) AND (“metabolic syndrome” OR “insulin action” OR “insulin resistance” OR “up-regulation” OR “down-regulation” OR “dyslipidemia”) AND (cell models).

Results

Out of 121 articles identified, 21 met the eligibility criteria and were included in the review, with their methods and findings organized according to the AP-affected biological processes implicated in MetS.

Conclusions

Independent studies on cell models confirm the AP-pathogenic role on gene and protein expression regulation involved in lipid and glucose metabolism, inflammatory processes, and impairments at the mitochondrial level.

In the final section of the manuscript, we highlight the potential of individual-specific stem-cell–based models, like induced pluripotent stem cells, to investigate gene-by-medication interactions relevant to AP-induced MetS. However, these stem-cell approaches fall outside the scope of the present review and were not included in our literature search.

背景：患有严重精神疾病的个体发生代谢综合征（MetS）的风险增加，部分原因是第二代抗精神病药物（SGAs）的代谢不良副作用。体外外周组织细胞模型为研究SGAs在外周水平诱导的生化和分子改变及其对中枢神经系统的影响提供了一个有效的平台。本综述总结了二十年来利用已建立的细胞系和原代啮齿动物细胞来研究抗精神病药物（APs）对脂质和葡萄糖代谢、炎症途径和线粒体功能的直接代谢不良影响的研究。方法我们使用以下搜索策略在PubMed数据库中识别已发表的科学文献：（抗精神病药）或“奥氮平”或“氯氮平”或“利培酮”或“喹硫平”或“氟哌啶醇”)和（代谢综合征”或“胰岛素作用”或“胰岛素抵抗”或“上调”或“下调”或“血脂异常”）和（细胞模型）。结果在121篇文章中，21篇符合入选标准，纳入了本综述，他们的方法和发现是根据与MetS相关的ap影响的生物学过程组织的。对细胞模型的独立研究证实了ap在脂质和糖代谢、炎症过程和线粒体水平损伤的基因和蛋白质表达调控中的致病作用。在论文的最后部分，我们强调了基于个体特异性干细胞模型的潜力，如诱导多能干细胞，研究与ap诱导的MetS相关的基因-药物相互作用。然而，这些干细胞方法不在本综述的范围之内，也没有包括在我们的文献检索中。

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引用次数: 0

Osthole ameliorates cognitive impairment in ovariectomized rats via estrogen-mediated enhancement of cholinergic function and regulation of neurotransmitter homeostasis 蛇床子素通过雌激素介导的增强胆碱能功能和调节神经递质稳态改善去卵巢大鼠认知功能障碍。

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2026-03-15 Epub Date: 2025-12-12 DOI: 10.1016/j.neuropharm.2025.110806

Yanman Liu , Jimei Zhang , Wenjuan Li , Qingwen Qu , Zhengxing Shan , Chunwei Liu , Ke Jiao , Xueqin Hou

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive dysfunction that is closely associated with cholinergic system damage. Estrogen deficiency is a well-established risk factor for AD in women. Osthole (OST), a phytoestrogen with mild, bidirectional regulatory properties, has been proposed as a potential estrogen replacement. This study aimed to investigate the mechanisms by which OST ameliorates cognitive impairment. Cognitive deficits were induced in female Sprague-Dawley rats by bilateral ovariectomy (OVX), and OST was subsequently administered by oral gavage. Behavioral tests revealed that OST significantly improved learning and memory and reduced anxiety-like and depression-like behaviors in OVX rats. H&E staining and Nissl staining demonstrated that OST reversed neuronal damage in the hippocampus and cortex. Western blotting, ELISA, and immunofluorescence staining indicated that OST treatment restored the estrogen–cholinergic–NGF axis: E₂, ERα, and ERβ expression were upregulated; Ach, ChAT, NGF, and TrkA levels were increased, whereas AChE activity was decreased. Moreover, OST inhibited neuronal apoptosis by elevating Bcl-2 and reducing Bax expression, enhanced the expression of markers of synaptic plasticity (PSD95, SYN, and BDNF), and modulated neurotransmitter release (GABA and E). Collectively, these multi-target effects identify OST as a promising candidate for treating AD in women.

阿尔茨海默病（AD）是一种以认知功能障碍为特征的进行性神经退行性疾病，与胆碱能系统损伤密切相关。雌激素缺乏是女性AD的一个公认的危险因素。蛇草素（OST）是一种温和的植物雌激素，具有双向调节特性，被认为是一种潜在的雌激素替代品。本研究旨在探讨OST改善认知障碍的机制。雌性Sprague-Dawley大鼠双侧卵巢切除术（OVX）诱导认知障碍，OST随后灌胃。行为测试显示，OST显著改善OVX大鼠的学习和记忆，减少焦虑样和抑郁样行为。H&E染色和Nissl染色表明，OST逆转了海马和皮层的神经元损伤。Western blotting、ELISA和免疫荧光染色显示，OST处理恢复了雌激素-胆碱能- ngf轴：E2、ERα和ERβ表达上调；Ach、ChAT、NGF和TrkA水平升高，AChE活性降低。此外，OST通过提高Bcl-2和降低Bax的表达，增强突触可塑性标志物（PSD95、SYN和BDNF）的表达，调节神经递质释放（GABA和E）来抑制神经元凋亡。总的来说，这些多靶点效应确定OST是治疗女性AD的有希望的候选药物。

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引用次数: 0