Neurochemistry international最新文献_第9页

Aerobic exercise rescues synaptic plasticity in early-stage Alzheimer's disease by suppressing miR-3473e to activate EphB2-dependent NMDA/AMPA receptor signaling 有氧运动通过抑制miR-3473e激活ephb2依赖性NMDA/AMPA受体信号通路，挽救早期阿尔茨海默病的突触可塑性

IF 4.4 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Neurochemistry international

Pub Date : 2025-07-26 DOI: 10.1016/j.neuint.2025.106023

Xiangli Tong , Zhen Tong , Weijia Wu , Jialun Yang , Juan Wang , Yang Wang , Dandan Chen , Yiyang Wang , Fanqi Zeng , Qiyan Du , Yishan Chen , Wenfeng Liu

Cognitive dysfunction in early-stage Alzheimer's disease (AD) involves significant impairments in synaptic plasticity and dendritic spines integrity. Intriguingly, exercise interventions have demonstrated efficacy in enhancing cognitive function. However, the precise molecular mechanisms, particularly the upstream endogenous regulators (such as miRNAs) through which exercise mediates this synaptic improvement, remain unclear. Our findings indicated that 12 weeks of aerobic exercise effectively increased learning and memory, promoted amyloid beta (Aβ) and cerebral amyloid angiopathy (CAA) clearance in early-stage AD. Furthermore, aerobic exercise markedly enhanced dendritic spines density of pyramidal neurons in cortical layers II/III and the hippocampal CA1 region, as well as the expression of synapse-associated proteins such as cAMP response element-binding protein (CREB), synaptophysin (SYN), and postsynaptic density protein 95 (PSD95). Whole genome RNA sequencing (RNA-Seq) and bioinformatics analysis was performed to identify miR-3473e, a target closely related to AD and also a response factor that serves as a key mediator of aerobic exercise benefits. Subsequent findings revealed that miR-3473e was overexpressed in the brains of APP/PS1 mice, whereas aerobic exercise led to a decrease in its expression. Moreover, aerobic exercise enhanced its downstream targets, EPH receptor B2 (EphB2) and solute carrier family 1 member 1 gene (Slc1a1) as well as increased downstream GluN1, GRIA1 and p-GluN2B/GluN2B protein expression levels. In summary, we demonstrate that aerobic exercise can improve synaptic plasticity, and these effects are mediated via suppression of miR-3473e and regulation EphB2-NMDA/AMPA receptor signaling pathway, underscoring the potential of aerobic exercise to enhance cognitive function in early-stage of AD.

早期阿尔茨海默病（AD）的认知功能障碍涉及突触可塑性和树突棘完整性的显著损伤。有趣的是，运动干预已被证明对增强认知功能有效。然而，确切的分子机制，特别是运动介导突触改善的上游内源性调节因子（如mirna），仍不清楚。我们的研究结果表明，12周的有氧运动有效地提高了早期AD患者的学习和记忆能力，促进了β淀粉样蛋白（Aβ）和脑淀粉样血管病（CAA）的清除。此外，有氧运动显著增强皮质II/III层和海马CA1区锥体神经元的树突棘密度，以及cAMP反应元件结合蛋白（CREB）、突触素（SYN）和突触后密度蛋白95 （PSD95）等突触相关蛋白的表达。通过全基因组RNA测序（RNA- seq）和生物信息学分析来鉴定miR-3473e，这是一个与AD密切相关的靶标，也是一个反应因子，是有氧运动益处的关键中介。随后的研究结果显示，miR-3473e在APP/PS1小鼠的大脑中过表达，而有氧运动导致其表达降低。此外，有氧运动增强了其下游靶点EPH受体B2 （EphB2）和溶质载体家族1成员1基因（Slc1a1），增加了下游GluN1、GRIA1和p-GluN2B/GluN2B蛋白的表达水平。综上所述，我们证明有氧运动可以改善突触可塑性，这些作用是通过抑制miR-3473e和调节EphB2-NMDA/AMPA受体信号通路介导的，强调了有氧运动在AD早期增强认知功能的潜力。

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引用次数: 0

Probing impact of sleep deprivation on hippocampal neurochemistry in rats using CEST imaging and 1H-MRS at 7.0T MRI 利用CEST成像和7.0T MRI 1H-MRS探查睡眠剥夺对大鼠海马神经化学的影响

IF 4.4 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Neurochemistry international

Pub Date : 2025-07-15 DOI: 10.1016/j.neuint.2025.106020

Zhihong Zhao , Lvhao Wang , Xiaolei Zhang , Yue Chen , Xinhui Zheng , Renhua Wu

Purpose

Sleep is a physiological process that plays a crucial role in maintaining cognitive functions. The hippocampus, a key brain region implicated in cognition, is particularly sensitive to sleep deprivation. we aim to investigate impact of sleep deprivation on hippocampal neurochemistry in rats using CEST imaging and ¹H-MRS.

Methods

Twelve female Sprague-Dawley rats were randomly divided into sleep deprivation and control groups. All rats experienced Morris water maze training and testing from Day 1 to Day 6 and underwent MRI scans including CEST imaging and ¹H-MRS on Days 1 and Day 3. Lastly, rats were euthanized for Nissl staining.

Results

Sleep deprivation led to a significant decrease in CEST signals across various frequency offsets (0.5–3.5 ppm) in the hippocampus (P < 0.05). Meanwhile, sleep deprivation caused an increase in glutamate (P < 0.0001) with no alterations in other metabolites (P > 0.05). Behaviorally, sleep deprivation impaired learning-memory abilities, evidenced by reduced target quadrant distance (P < 0.001) and time (P < 0.01) in the Morris water maze. Histologically, sleep deprivation caused a decline of surviving neurons in the hippocampal CA1 and CA3 regions (P < 0.001). These indicators correlated negatively with the concentrations of glutamate (P < 0.05) and positively with most of the CEST signals (P < 0.05) in the hippocampus.

Conclusion

The integration of CEST imaging and ¹H-MRS offers a promising approach for identifying imaging biomarkers that aid in the assessment and management of sleep deprivation's impact on hippocampal neurochemistry.

目的：睡眠是一个生理过程，对维持认知功能起着至关重要的作用。海马体是大脑中与认知有关的关键区域，对睡眠不足特别敏感。我们的目的是利用CEST成像和1H-MRS研究睡眠剥夺对大鼠海马神经化学的影响。方法：将12只雌性Sprague-Dawley大鼠随机分为睡眠剥夺组和对照组。所有大鼠在第1天至第6天进行Morris水迷宫训练和测试，并在第1天和第3天进行MRI扫描，包括CEST成像和1H-MRS。最后对大鼠实施安乐死，进行尼氏染色。结果：睡眠剥夺导致海马不同频率偏移（0.5-3.5 ppm）的CEST信号显著减少（P0.05）。结论：CEST成像和1H-MRS的结合为识别成像生物标志物提供了一种很有前途的方法，有助于评估和管理睡眠剥夺对海马神经化学的影响。

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引用次数: 0

Refinement of TSLP expression mediates chronic allodynia associated with IL22/STAT3 axis TSLP表达的改善介导与IL22/STAT3轴相关的慢性异常性痛

IF 4.4 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Neurochemistry international

Pub Date : 2025-07-10 DOI: 10.1016/j.neuint.2025.106022

Chun-Ching Lu , Ying-Yi Lu , Hung-Pei Tsai , Chieh-Hsin Wu

Chronic allodynia is a painful response to an innocuous stimulus because of maladaptive neuroplasticity within the central nervous system. IL22 is a pleiotropic mediator owing to its proinflammatory and immunosuppressive effects. In this study, we aimed to investigate the potential of modulating TSLP expressions to treat chronic allodynia and elucidate the underlying mechanisms associated with IL22. TSLP^−/− mice were generated, and four mouse groups were created as follows: wild-type (WT) + PBS, TSLP knockout (KO) + PBS, WT + bleomycin, and TSLP KO + bleomycin. Repeated bleomycin administration reduced the IL22/STAT3 pathway to trigger chronic allodynia in C57BL/6 mice. The degree of gliosis and neuron loss were significantly greater in the somatosensory cortex and spinal cord dorsal horn of the bleomycin-treated mice compared with those in the PBS-treated mice. Compared with those in WT mice treated with bleomycin, in TSLP-deficient mice, the degree of gliosis and neuron loss were significantly lower in the somatosensory cortex and spinal cord dorsal horn and the mechanical withdrawal threshold was altered. Differentiated human SH-SY5Y cells were created to investigate the neuroprotective effects of TSLP refinement against hydrogen peroxide (H₂O₂)-induced neurotoxicity. The deficiency of TSLP protected differentiated SH-SY5Y cells against H₂O₂-induced neurotoxicity. IL22 stimulator not only rescued the H₂O₂-induced neurotoxicity but augmented the protective effect of si-TSLP on differentiated SH-SY5Y cells. Our data confirmed that a lack of TSLP decreased the expression of TSLPR/STAT5, the bleomycin-induced chronic allodynia and the H₂O₂-induced neurotoxicity. In addition, inhibiting TSLP rescued the IL22/STAT3-mediated effect, which regulated neuroglial interactions to relieve chronic allodynia. Targeting TSLP/TSLPR is a potential therapeutic approach for relieving chronic allodynia by regulating gliosis, neuron loss, and the IL22/STAT3 axis.

慢性异常性疼痛是由于中枢神经系统的神经可塑性不适应而引起的对无害刺激的疼痛反应。由于其促炎和免疫抑制作用，IL22是一种多效介质。在这项研究中，我们旨在研究调节TSLP表达治疗慢性异常性疼痛的潜力，并阐明与IL22相关的潜在机制。生成TSLP−/−小鼠，并创建四组小鼠：野生型(WT) + PBS， TSLP敲除(KO) + PBS， WT +博来霉素，TSLP KO +博来霉素。在C57BL/6小鼠中，反复给予博来霉素可降低IL22/STAT3通路触发慢性异位性疼痛。与pbs组相比，博莱霉素组小鼠体感觉皮层和脊髓背角的胶质细胞增生和神经元丢失程度显著增加。与博来霉素处理的WT小鼠相比，tslp缺陷小鼠体感觉皮层和脊髓背角的胶质细胞增生程度和神经元损失明显降低，机械戒断阈值发生改变。建立分化的人SH-SY5Y细胞，研究TSLP精制对过氧化氢（H2O2）诱导的神经毒性的神经保护作用。缺乏TSLP可保护分化的SH-SY5Y细胞免受h2o2诱导的神经毒性。IL22刺激剂不仅可以挽救h2o2诱导的神经毒性，还可以增强si-TSLP对SH-SY5Y分化细胞的保护作用。我们的数据证实，缺乏TSLP会降低TSLPR/STAT5的表达、博莱霉素诱导的慢性异常性疼痛和h2o2诱导的神经毒性。此外，抑制TSLP恢复了IL22/ stat3介导的作用，其调节神经胶质相互作用以缓解慢性异常性疼痛。靶向TSLP/TSLPR是一种通过调节胶质细胞增生、神经元丢失和IL22/STAT3轴来缓解慢性异位性疼痛的潜在治疗方法。

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引用次数: 0

Combined administration of cocaine and alcohol alters the expression of brain peptide/protein profiles in rats: a MALDI imaging mass spectrometry approach 可卡因和酒精的联合施用改变了大鼠脑肽/蛋白质谱的表达：MALDI成像质谱法

IF 4.4 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Neurochemistry international

Pub Date : 2025-07-10 DOI: 10.1016/j.neuint.2025.106015

Alberto Marcos , Pilar Alberdi , Carlos A. Castillo-Sarmiento , Emilio Ambrosio , Inmaculada Ballesteros-Yáñez

While the concurrent use of alcohol and cocaine is common in patterns of polysubstance use, little is known about the combined effects of these substances on the brain. Proteomics approaches enable the identification of potential biomarkers and new pharmacological targets for the diagnosis and treatment of addiction and related psychiatric disorders. The main goal of this study was to explore how the combination of cocaine and alcohol affects brain peptide/protein signatures in the mesolimbic dopaminergic pathway.

To this end, we used a chronic and simultaneous intravenous administration of these substances in a Wistar rat animal model. Peptide/protein profiles in five brain regions (ventral hippocampus, dorsal hippocampus, amygdala, nucleus accumbens and prefrontal cortex) from individual animals were characterised by means of matrix-assisted laser desorption/ionisation imaging mass spectrometry (MALDI-IMS).

Our results showed that, compared to exposure to cocaine or alcohol separately, the combination of cocaine and alcohol has a synergistic effect on the number of differentially expressed peptides/proteins (DEPs) detected in all regions, particularly the amygdala. ANOVA reveals 13 DEPs, corresponding to 12 peptides/proteins, that vary significantly between all groups. Gene ontology (GO) analysis indicated that most of the DEPs found for the combined treatment are enriched in neuropeptide receptor binding, neuropeptide signalling and regulation of circadian sleep/wake process pathways.

Our findings demonstrate that the combination of cocaine and alcohol significantly exacerbates the effects of each substance separately on the expression of peptides and proteins with multiple physiological functions, including the opioid- and GABA-ergic neurotransmission systems. This study therefore provides the basis for future research on biomarkers and substance recovery therapies.

These insights underscore the importance of examining the interactions between cocaine and alcohol in terms of their effects on neurotransmitter systems in the context of polysubstance use, particularly when addressing issues related to cocaine and alcohol co-use.

虽然同时使用酒精和可卡因在多种物质使用模式中很常见，但人们对这些物质对大脑的综合影响知之甚少。蛋白质组学方法能够识别潜在的生物标志物和新的药物靶点，用于成瘾和相关精神疾病的诊断和治疗。本研究的主要目的是探索可卡因和酒精的结合如何影响中脑边缘多巴胺能通路中的脑肽/蛋白质特征。为此，我们在Wistar大鼠动物模型中长期同时静脉注射这些物质。采用基质辅助激光解吸/电离成像质谱法（MALDI-IMS）对个体动物大脑5个区域（海马腹侧、海马背侧、杏仁核、伏隔核和前额叶皮质）的肽/蛋白谱进行了表征。我们的研究结果表明，与单独暴露于可卡因或酒精相比，可卡因和酒精的组合对所有区域，特别是杏仁核中检测到的差异表达肽/蛋白（DEPs）的数量具有协同效应。方差分析显示13个dep，对应12个肽/蛋白，在所有组之间差异显著。基因本体（GO）分析表明，大多数联合治疗的dep都富含神经肽受体结合、神经肽信号传导和昼夜睡眠/觉醒过程通路的调节。我们的研究结果表明，可卡因和酒精的组合显著加剧了每种物质分别对具有多种生理功能的肽和蛋白质表达的影响，包括阿片和gaba能神经传递系统。因此，该研究为未来生物标志物和物质恢复疗法的研究提供了基础。这些见解强调了在多种物质使用的情况下，特别是在处理与可卡因和酒精共同使用有关的问题时，研究可卡因和酒精之间的相互作用对神经递质系统的影响的重要性。

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引用次数: 0

Repetitive transcranial magnetic stimulation as a universal modulator of synaptic plasticity: Bridging the gap between functional and structural plasticity 重复经颅磁刺激作为突触可塑性的普遍调节剂：弥合功能和结构可塑性之间的差距

IF 4.4 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Neurochemistry international

Pub Date : 2025-07-08 DOI: 10.1016/j.neuint.2025.106021

Danica Popovic , Milorad Dragic

Repetitive transcranial magnetic stimulation (rTMS) is a painless and non-invasive technique for neuromodulation that has shown great potential in therapy of several neurodegenerative and neuropsychiatric disorders both in patients and animal models. In addition to its non-invasiveness, the main rationale for using it for these disorders is that the positive effects extend beyond the stimulation period and can last up to several minutes, hours or even days after the last application. While the mechanisms underlying these long-lasting positive effects have not yet been fully deciphered, current literature supports hypothesis of modulation of both functional and structural plasticity. Dendritic spines are structures on dendritic branches that regulate synaptic transmission at the level of postsynapse and represent one of the structural and functional carriers of synaptic plasticity. Since rTMS has been proposed to induce long-term potentiation/long-term depression-like effects, based on the existing literature in animal studies, we suggest several molecular mechanisms which could underpin rTMS-induced structural plasticity manifested at the level of dendritic spines that include processes starting from spinogenesis to gradual spine maturation and eventual spine shrinkage and loss. The results gathered in this review postulate rTMS as a universal modulator of synaptic plasticity, which could guide future research and help in optimizing appropriate protocols of transcranial magnetic stimulation for adequate disorders and pathologies.

重复经颅磁刺激（rTMS）是一种无痛、无创的神经调节技术，在多种神经退行性疾病和神经精神疾病的治疗中显示出巨大的潜力，无论是在患者还是动物模型中。除了它的非侵入性之外，使用它治疗这些疾病的主要理由是，积极的效果超出了刺激期，可以在最后一次应用后持续几分钟、几小时甚至几天。虽然这些长期积极影响的机制尚未完全破译，但目前的文献支持功能和结构可塑性调节的假设。树突棘是树突分支上在突触后水平调节突触传递的结构，是突触可塑性的结构和功能载体之一。由于rTMS已被提出诱导长期增强/长期抑郁样效应，基于现有的动物研究文献，我们提出了几种支持rTMS诱导树突棘水平结构可塑性的分子机制，包括从脊柱形成到逐渐脊柱成熟和最终脊柱萎缩和丧失的过程。本综述的结果表明，rTMS是突触可塑性的一种普遍调节剂，可以指导未来的研究，并有助于优化经颅磁刺激治疗适当疾病和病理的方案。

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引用次数: 0

Circular RNAs from the MAPT and TARDBP genes: Novel players in neurodegeneration? 来自MAPT和TARDP基因的环状rna：神经变性的新参与者？

IF 4.4 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Neurochemistry international

Pub Date : 2025-07-07 DOI: 10.1016/j.neuint.2025.106019

Naghme Bagheri , Giorgi Margvelani , Tai-Wei Chiang , Peter T. Nelson , Trees-Juen Chuang , Stefan Stamm

The microtubule associated protein tau (MAPT) and TAR DNA binding protein (TARDBP) genes play crucial roles in neurodegeneration. The tau protein encoded by MAPT is the main component of tau tangles, a pathologic hallmark of “tauopathies” such as Alzheimer's disease (AD). Cytosolic accumulations of TDP-43, encoded by TARDBP are characteristic for LATE (Limbic-predominant age-related TDP-43 encephalopathy) and other TDPopathies. In addition to the well-characterized mRNA splicing isoforms, both genes generate a multitude of circular RNAs (circRNAs). Both MAPT and TARDBP express circular RNA-specific exons characterized by suboptimal splice sites and lengths and are frequently derived from Alu-elements. Most circTau and to date all circTARDBP RNAs expressed in brain are human-specific, suggesting a possible unique contribution to human brain disease. TARDBP and MAPT circRNAs harbor open reading frames and circTau RNAs were shown to be translated into polypeptides in cells. Thus, circRNAs from the MAPT and TARDBP genes should be considered in molecular analysis of AD, LATE and other neurological diseases.

微管相关蛋白tau （MAPT）和TAR DNA结合蛋白（TARDBP）基因在神经变性中起着至关重要的作用。由MAPT编码的tau蛋白是tau缠结的主要成分，tau缠结是阿尔茨海默病（AD）等“tau病”的病理标志。由TARDBP编码的TDP-43的细胞质积累是LATE（边缘区显性年龄相关性TDP-43脑病）和其他tdp病变的特征。除了具有良好特征的mRNA剪接异构体外，这两个基因还产生大量环状rna （circRNAs）。MAPT和TARDBP都表达环状rna特异性外显子，这些外显子的剪接位点和长度都不理想，并且通常来源于alu元件。在大脑中表达的大多数circTau和可能所有circTARDBP rna都是人类特异性的，这表明可能对人类脑部疾病有独特的贡献。TARDBP和MAPT环状rna携带开放阅读框，circTau rna在细胞中被翻译成多肽。因此，在AD、LATE和其他神经系统疾病的分子分析中，应该考虑来自MAPT和TARDBP基因的环状rna。

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引用次数: 0

The potentiating activity of benzodiazepine site of the GABA(A) receptor is inhibited by competitive antagonists of orthosteric site GABA(A)受体苯二氮平的增强活性被正构位的竞争性拮抗剂所抑制

IF 4.4 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Neurochemistry international

Pub Date : 2025-07-05 DOI: 10.1016/j.neuint.2025.106018

Elena I. Solntseva, Julia V. Bukanova, Rodion V. Kondratenko

Benzodiazepines (BDZs) are widely-prescribed drugs that act as positive allosteric modulators of GABA_A receptor, enhancing the GABA-elicited chloride current (I_GABA). In this work, we studied the influence of competitive antagonists of the GABA_A receptor gabazine (GBZ), bicuculline (Bic), and amiloride (Ami) on the potentiating effect of the agonist of BDZ site zolpidem (Zolp). These antagonists bind to their own sites, which partially overlap with the orthosteric site. The experiments were carried out on native GABA_A receptors in isolated Purkinje cells of the rat cerebellum. The I_GABA was measured using the patch-clamp technique and a system of fast application. The effects of the drugs on I_GABA were assessed by the change in the EC₅₀ value for GABA dose-effect curve constructed in the ranges of 0.5–100 μM GABA. Changes in EC₅₀ values as a percentage relative to the control were calculated. 0.5 μM Zolp shifted the GABA curve to the left and decreased the EC₅₀ by 54 % (from 4.8 μM to 2.2 μM). Competitive antagonists shifted the GABA curve to the right and increased the EC₅₀ to 72.6 μM (0.5 μM GBZ), 25.5 μM (500 μM Ami) and 28.8 μM (5 μM Bic). With the addition of Zolp, these EC₅₀ values decreased by 21–25 % and were 56.8 μM (GBZ), 19.2 μM (Ami), and 22.7 μM (Bic), respectively. The results show that the potentiating effect of Zolp is reduced by half in the presence of competitive GABA_A receptor antagonists (p < 0. 001).

苯二氮卓类药物（BDZs）作为GABAA受体的正变构调节剂，增强gaba诱导的氯离子电流（IGABA），被广泛使用。在这项工作中，我们研究了GABAA受体的竞争拮抗剂gabazine (GBZ), bicuculline （Bic）和amiloride （Ami）对BDZ部位激动剂唑吡坦（Zolp）增强作用的影响。这些拮抗剂与它们自己的位点结合，这些位点与正位位点部分重叠。实验采用大鼠小脑浦肯野细胞天然GABAA受体进行。采用膜片钳技术和快速应用系统测量IGABA。在0.5 ~ 100 μM GABA范围内，通过构建GABA剂量效应曲线EC50值的变化来评价药物对IGABA的影响。计算EC50值相对于对照组的百分比变化。0.5 μM Zolp使GABA曲线左移，EC50降低54%（从4.8 μM降至2.2 μM）。竞争拮抗剂使GABA曲线右移，EC50分别升高至72.6 μM （0.5 μM GBZ）、25.5 μM （500 μM Ami）和28.8 μM （5 μM Bic）。Zolp的加入使EC50值降低了21 ~ 25%，分别为56.8 μM （GBZ）、19.2 μM （Ami）和22.7 μM （Bic）。结果表明，在竞争性GABAA受体拮抗剂存在时，Zolp的增强作用降低了一半(p <；0. 001)。

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引用次数: 0

N-acetyltransferase 10 in the nucleus accumbens participates in methamphetamine-induced conditioned place preference and hyperlocomotion in mice 伏隔核n -乙酰转移酶10参与甲基苯丙胺诱导的小鼠条件性位置偏好和过度运动

IF 4.4 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Neurochemistry international

Pub Date : 2025-07-03 DOI: 10.1016/j.neuint.2025.106017

Ze-Hao Zeng , Lin-Xuan Zhang , Meng-Qing Li, Xue-Qin Wang, Guang-Jing Zou, Jia-Yu Yao, Chang-Qi Li, Yan-Hui Cui, Fang Li

Drug addiction is characterized by compulsive drug use despite significant negative consequences. N-acetyltransferase 10 (NAT10), a member of the Gcn5-related N-acetyltransferases (GNAT) family, has been associated with depression, anxiety-like behaviors, and cognitive dysfunction. However, its role in addiction remains largely unknown. In the present study, we observed increased expression of NAT10 in the nucleus accumbens (NAc) of mice treated either singly or repeatedly with 2 mg/kg methamphetamine (METH). To assess the role of NAT10 in addiction-related behaviors, we established mouse models of conditioned place preference (CPP) and hyperlocomotion. Using intraperitoneal administration of 0.1 mg/kg SCH23390, a dopamine D1 receptor (D1R) antagonist, we found that D1R antagonism significantly suppressed the METH-induced upregulation of NAT10 in the NAc and inhibited hyperlocomotion. Furthermore, stereotaxic delivery of a short hairpin RNA (shRNA)-based adeno-associated virus (AAV-shNAT10) into the NAc reduced both METH-induced hyperlocomotion and CPP. AAV-shNAT10 also inhibited METH-induced upregulation of PSD95 and preserved dendritic morphology in the NAc. These findings suggest that NAT10 contributes to the development of METH-induced reward-related behaviors by modulating dendritic plasticity in the NAc.

药物成瘾的特征是尽管有显著的负面后果，但仍强迫性地使用药物。n -乙酰转移酶10 （NAT10）是gcn5相关n -乙酰转移酶（GNAT）家族的一员，与抑郁、焦虑样行为和认知功能障碍有关。然而，它在成瘾中的作用在很大程度上仍然未知。在本研究中，我们观察到单独或反复给予2 mg/kg甲基苯丙胺（METH）的小鼠伏隔核（NAc）中NAT10的表达增加。为了评估NAT10在成瘾相关行为中的作用，我们建立了小鼠条件位置偏好（CPP）和过度运动模型。通过腹腔注射0.1 mg/kg多巴胺D1受体（D1R）拮抗剂SCH23390，我们发现D1R拮抗剂可显著抑制甲基甲醚诱导的NAc中NAT10的上调，并抑制过度运动。此外，立体定向递送短发夹RNA （shRNA）为基础的腺相关病毒（AAV-shNAT10）进入NAc可减少甲基甲醚诱导的过度运动和CPP。AAV-shNAT10还能抑制meth诱导的PSD95上调，并保留NAc中的树突形态。这些发现表明，NAT10通过调节NAc中的树突可塑性，促进了甲基甲醚诱导的奖励相关行为的发展。

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引用次数: 0

Acute ketamine enhances social behavior and dendritic plasticity in the amygdala by increasing BDNF, GAP43, and TRKB presence following excitotoxic neonatal ibotenic acid lesion 急性氯胺酮通过增加BDNF、GAP43和TRKB的存在，增强兴奋性新生儿伊博滕酸损伤后杏仁核的社交行为和树突可塑性。

IF 4.4 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Neurochemistry international

Pub Date : 2025-07-01 DOI: 10.1016/j.neuint.2025.106016

Nestor I. Martínez-Torres , Jhonathan Cárdenas-Bedoya , Blanca Miriam Torres-Mendoza

Schizophrenia is a highly disabling psychopathology that is a significant burden on public health systems and is characterized by both positive and negative symptoms. One of these negative symptoms is social isolation, which responds poorly to available treatments. Ketamine (KET) has been shown to enhance social behavior in various preclinical models, accompanied by neurobiological changes. In this study, we used a preclinical model of schizophrenia involving neonatal ventral hippocampal (NVHL) bilateral lesions induced by excitotoxicity with ibotenic acid (IA) at postnatal day 7 (PD). Thirty male Sprague-Dawley rats, aged 7 PD, were assigned to one of the following groups: Intact, Sham, Intact + KET, IA + Saline, and IA + KET, with n = 6 per group. Rats in the Sham, IA + Saline, and IA + KET groups underwent stereotaxic surgery and were administered with either 0.3 % saline or IA at 7 PD. At 35 PD, the rats received either saline or ketamine (15 mg/kg) and were assessed using the three-chamber social test. A Golgi-modified technique was then employed to evaluate neuronal changes in the amygdala with Sholl analysis. Also, immunohistochemistry was conducted to measure brain-derived neurotrophic factor (BDNF), tyrosine receptor kinase B (TRKB), and growth-associated protein 43 (GAP43). Acute KET treatment rescued social behavior, increased dendritic tree complexity, and elevated BDNF, TRKB, and GAP43 protein presence. Our results suggest that acute sub-anesthetic administration of KET may help alleviate social isolation symptoms. This dose could provide a window of opportunity to encourage individuals with schizophrenia to initiate and continue their treatment.

精神分裂症是一种高度致残的精神病理学，是公共卫生系统的重大负担，其特征是阳性和阴性症状。这些负面症状之一是社会孤立，对现有治疗效果不佳。氯胺酮（KET）已被证明在各种临床前模型中增强社会行为，并伴有神经生物学变化。在这项研究中，我们使用了一个临床前精神分裂症模型，该模型涉及出生后第7天（PD）由伊博tenic酸（IA）兴奋性毒性引起的新生儿腹侧海马（NVHL）双侧病变。30只雄性sd - dawley大鼠，年龄7 PD，随机分为：完整组、假手术组、完整+KET组、IA+生理盐水组和IA+KET组，每组n = 6。Sham， IA+Saline和IA+KET组的大鼠进行立体定向手术，并在7 PD时给予0.3%生理盐水或IA。在35 PD时，大鼠接受生理盐水或氯胺酮（15 mg/kg），并使用三室社会测试进行评估。然后采用高尔基改良技术与Sholl分析来评估杏仁核中的神经元变化。免疫组化检测脑源性神经营养因子（BDNF）、酪氨酸受体激酶B （TRKB）和生长相关蛋白43 （GAP43）。急性KET治疗挽救了社会行为，增加了树突树的复杂性，并提高了BDNF、TRKB和GAP43蛋白的存在。我们的研究结果表明，急性亚麻醉给药可以帮助减轻社会隔离症状。这个剂量可以提供一个机会窗口，鼓励精神分裂症患者开始并继续他们的治疗。

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引用次数: 0

Thiamet-G ameliorates Parkinson's disease-associated cognitive impairment via increasing O-GlcNAcylation of STING in the microglia Thiamet-G通过增加小胶质细胞中STING的o - glcn酰化来改善帕金森病相关的认知障碍

IF 4.4 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Neurochemistry international

Pub Date : 2025-06-26 DOI: 10.1016/j.neuint.2025.106014

Shanshan Zhu , Nan Wang , Shuyang Chen , Ju Zou , Sijie Tan

Microglia activation contributed to the development of Parkinson's disease (PD)-associated cognitive impairment and targeting microglia may be a promising strategy for improving the cognitive function in PD. O-GlcNAclytion is a novel protein post-translational modification with cognitive enhancing effects. This study aimed to investigate the effects of Thiamet-G (TMG), an O-GlcNAcase inhibitor that can increase the intracellular O-GlcNAclytion levels, on PD-associated cognitive impairment and the mechanism related to microglia activation. A PD mouse model was established using rotenone (ROT) and the cognitive functions of these mice were investigated by behavioral tests. The anti-inflammatory effects of TMG were tested in the BV2 microglia cells. TMG treatment significantly improved the cognitive function in the ROT-induced PD mouse model as evidenced by the Y-maze test and objective recognition test. Histological studies showed that TMG decreased the reactive microglia via increasing the total protein O-GlcNAclytion levels in the hippocampus of the PD mice. In the in vitro studies, TMG inhibited ROT-induced inflammation via decreasing the pro-inflammatory cytokines such as TNF-α, IL-1β and IL-6 in BV2 microglia cells. Bioinformatic analysis revealed that STING, a core protein in the innate immunity regulation, might be a novel target of O-GlcNAclytion. The immunoprecipitation experiments further confirmed that TMG inhibited STING phosphorylation via increasing O-GlcNAcylation. Taken together, TMG might ameliorate PD-associated cognitive impairment via increasing O-GlcNAcylation of STING in microglia, which provided evidence supporting that inhibiting the inflammatory response of microglia by elevating the O-GlcNAclytion levels might be an effective strategy for improving the cognitive function in PD.

小胶质细胞的激活有助于帕金森病（PD）相关认知功能障碍的发展，靶向小胶质细胞可能是改善PD认知功能的一种有希望的策略。o - glcnaclyation是一种具有认知增强作用的新型蛋白质翻译后修饰。本研究旨在探讨Thiamet-G （TMG）是一种O-GlcNAcase抑制剂，可提高细胞内O-GlcNAcase水平，对pd相关认知障碍的影响及其与小胶质细胞活化的相关机制。采用鱼藤酮（rotenone， ROT）建立PD小鼠模型，通过行为学测试观察小鼠的认知功能。在BV2小胶质细胞中检测TMG的抗炎作用。经y迷宫实验和客观识别实验证实，TMG治疗可显著改善rot诱导的PD小鼠模型的认知功能。组织学研究表明，TMG通过增加PD小鼠海马总蛋白o - glcnaclyation水平来降低反应性小胶质细胞。在体外研究中，TMG通过降低BV2小胶质细胞中促炎细胞因子TNF-α、IL-1β和IL-6来抑制rot诱导的炎症。生物信息学分析表明，作为先天免疫调控的核心蛋白，STING可能是o - glcnaclyation的新靶点。免疫沉淀实验进一步证实TMG通过增加o - glcnac酰化抑制STING磷酸化。综上所述，TMG可能通过增加小胶质细胞中STING的o - glcn酰化来改善PD相关的认知功能障碍，这为通过提高o - glcn酰化水平来抑制小胶质细胞的炎症反应可能是改善PD认知功能的有效策略提供了证据。

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引用次数: 0