Neurochemistry international最新文献_第4页

Alcohol disrupts neural differentiation through endoplasmic reticulum stress and PERK pathway activation 酒精通过内质网应激和PERK通路激活扰乱神经分化。

IF 4 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Neurochemistry international

Pub Date : 2026-01-01 Epub Date: 2025-12-29 DOI: 10.1016/j.neuint.2025.106108

Zuohui Zhang, Wen Wen, Hong Lin, Di Hu, Hui Li, Jia Luo

Prenatal alcohol exposure (PAE) can lead to fetal alcohol spectrum disorder (FASD), a condition marked by developmental brain defects that result in neurobehavioral and cognitive impairments. However, the underlying molecular mechanisms remain poorly understood. Brain development is a highly regulated process, with neurogenesis playing a crucial role. A key stage in this process is neural differentiation, which is essential for proper brain function. This study aims to investigate how alcohol disrupts neural differentiation. NE-4C cells, a neural stem cell line derived from the mouse embryonic brain, were utilized as an in vitro model. As an in vivo model, pregnant mice were exposed to alcohol between gestation days 14 and 16, after which newly formed neurons in the ventricular zone (VZ) were analyzed. To examine the role of endoplasmic reticulum (ER) stress, tunicamycin (TM), and MANF-deficient NE-4C cells were employed. Neural differentiation was assessed using immunofluorescence, immunoblotting and flow cytometry. Alcohol impaired the differentiation of NE-4C cells into neurons and astrocytes without impacting cell migration. It also induced ER stress, preferably activating the PERK pathway. Similarly, ER stress caused by TM and MANF deficiency disrupted neural differentiation and activated PERK. Inhibiting PERK mitigated alcohol-induced impairment of neuronal differentiation. PAE decreased the number of newly formed neurons in the VZ of fetal brain while having little effects on cell survival and proliferation. Inhibiting PERK partially reversed the reduction of new neurons caused by PAE. Thus, alcohol-induced ER stress, particularly PERK activation, may contribute to impaired neurogenesis linked to FASD.

产前酒精暴露（PAE）可导致胎儿酒精谱系障碍（FASD），这是一种以发育性大脑缺陷为特征的疾病，会导致神经行为和认知障碍。然而，潜在的分子机制仍然知之甚少。大脑发育是一个高度调控的过程，其中神经发生起着至关重要的作用。这个过程的一个关键阶段是神经分化，这是大脑正常功能所必需的。这项研究旨在研究酒精是如何扰乱神经分化的。NE-4C细胞是一种来源于小鼠胚胎脑的神经干细胞系，作为体外模型。作为体内模型，孕鼠在妊娠14 - 16天暴露于酒精中，分析心室区（VZ）新形成的神经元。为了研究内质网（ER）应激的作用，我们使用了tunicamycin （TM）和缺乏manf的NE-4C细胞。采用免疫荧光、免疫印迹和流式细胞术评估神经分化。酒精可抑制NE-4C细胞向神经元和星形胶质细胞的分化，但不影响细胞迁移。它还能诱导内质网应激，激活PERK通路。同样，TM和MANF缺乏引起的内质网应激破坏了神经分化，激活了PERK。抑制PERK可减轻酒精诱导的神经元分化损伤。PAE可减少胎儿脑VZ区新生神经元数量，但对细胞存活和增殖影响不大。抑制PERK部分逆转了PAE引起的新神经元减少。因此，酒精诱导的内质网应激，特别是PERK激活，可能导致与FASD相关的神经发生受损。

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引用次数: 0

Interplay and intervention of epigenetic dysregulation in traumatic brain injury pathology 外伤性脑损伤病理中表观遗传失调的相互作用与干预。

IF 4 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Neurochemistry international

Pub Date : 2026-01-01 Epub Date: 2025-11-27 DOI: 10.1016/j.neuint.2025.106094

Samuel G. Faasen, Vijay Arruri, Reid S. Alisch

Traumatic brain injury (TBI) occurs when an external mechanical force damages brain tissue, leading to temporary or lasting disturbances in brain structure and function. The heterogeneous molecular and phenotypic nature of TBI poses a major challenge to translating basic research discoveries into clinically effective interventions. Emerging evidence indicates that epigenetic and epitranscriptomic mechanisms, including histone modifications, DNA methylation, and RNA modifications, play pivotal roles in the molecular response to TBI. In this review, we discuss post-TBI epigenomic alterations with a focus on histone modifications, DNA methylation, and RNA modifications, and we highlight preclinical interventions that modulate these alterations and improve related post-TBI behavioral outcomes.

外伤性脑损伤（TBI）发生时，外部机械力损害脑组织，导致暂时或持久的大脑结构和功能紊乱。TBI的异质性分子和表型性质对将基础研究发现转化为临床有效的干预措施提出了重大挑战。新出现的证据表明，表观遗传和表转录组学机制，包括组蛋白修饰、DNA甲基化和RNA修饰，在TBI的分子反应中起着关键作用。在这篇综述中，我们讨论了脑外伤后的表观基因组改变，重点是组蛋白修饰、DNA甲基化和RNA修饰，并强调了调节这些改变和改善相关脑外伤后行为结果的临床前干预。

引用次数: 0

GDNF-AS1 mediated LHX2/METTL3/NCOA4 axis inhibits glioma progression via induction of ferroptosis GDNF-AS1介导的LHX2/METTL3/NCOA4轴通过诱导铁下垂抑制胶质瘤进展。

IF 4 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Neurochemistry international

Pub Date : 2026-01-01 Epub Date: 2025-11-21 DOI: 10.1016/j.neuint.2025.106085

Yangbo zhou, Zhongyue Liu, Wenjia Ma

Glioma, particularly glioblastoma (GBM), represents the most aggressive primary brain tumor with limited treatment options and poor prognosis. Emerging evidence highlights ferroptosis induction as a promising therapeutic strategy, while long non-coding RNAs (lncRNAs) have gained attention as potential biomarkers and regulators in glioma pathogenesis. This study aimed to investigate the molecular mechanism of lncRNA Glial Cell Line-Derived Neurotrophic Factor Antisense RNA 1 (GDNF-AS1) in glioma cell ferroptosis through the LIM Homeobox 2 (LHX2)/Methyltransferase-Like 3 (METTL3)/Nuclear Receptor Coactivator 4 (NCOA4) pathway using Normal Human Astrocytes (NHA) and glioma cell lines (U87MG, T98G, U251, and A172), along with intracranial and subcutaneous xenotransplantation models established in BALB/c nude mice. Functional experiments demonstrated that GDNF-AS1, LHX2, and NCOA4 were downregulated while METTL3 was upregulated in glioma cells. GDNF-AS1 overexpression promoted mitochondrial damage and oxidative stress by enhancing ferroptosis, ultimately impairing glioma cell biological functions. METTL3 silencing augmented GDNF-AS1's effects, further exacerbating ferroptosis and oxidative stress while inhibiting glioma progression. Mechanistically, GDNF-AS1 recruited transcription factor LHX2 to upregulate its enrichment at the METTL3 promoter, thereby suppressing METTL3 transcription, reducing N6-Methyladenosine (m6A) levels, promoting NCOA4 expression, and inducing ferroautophagy and ferroptosis in glioma cells. These findings demonstrate that GDNF-AS1 inhibits glioma development by activating ferroptosis through the LHX2/METTL3/NCOA4 axis.

胶质瘤，尤其是胶质母细胞瘤（GBM），是最具侵袭性的原发性脑肿瘤，治疗方案有限，预后差。新出现的证据表明，诱导铁下垂是一种很有前景的治疗策略，而长链非编码rna （lncRNAs）作为神经胶质瘤发病机制中的潜在生物标志物和调节因子已受到关注。本研究旨在利用正常人星状细胞（NHA）和胶质瘤细胞系（U87MG、T98G、U251和A172），以及建立BALB/c裸鼠颅内和皮下异种移植模型，通过LIM Homeobox 2 (LHX2)/甲基转移酶样3 (METTL3)/核受体共激活因子4 （NCOA4）通路，探讨lncRNA胶质细胞系衍生的神经营养因子反义RNA 1 （GDNF-AS1）在胶质瘤细胞铁凋亡中的分子机制。功能实验表明，胶质瘤细胞中GDNF-AS1、LHX2和NCOA4下调，而METTL3上调。GDNF-AS1过表达通过增强铁凋亡促进线粒体损伤和氧化应激，最终损害胶质瘤细胞的生物学功能。METTL3沉默增强GDNF-AS1的作用，进一步加剧铁下垂和氧化应激，同时抑制胶质瘤的进展。机制上，GDNF-AS1募集转录因子LHX2上调其在METTL3启动子的富集，从而抑制METTL3转录，降低n6 -甲基腺苷（m6A）水平，促进NCOA4表达，诱导胶质瘤细胞铁自噬和铁凋亡。这些发现表明GDNF-AS1通过LHX2/METTL3/NCOA4轴激活铁下垂来抑制胶质瘤的发展。

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引用次数: 0

Therapeutic potential of KATP channels in the attenuation of Parkinson's disease pathogenesis and progression – A review KATP通道在减缓帕金森病发病和进展中的治疗潜力综述

IF 4 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Neurochemistry international

Pub Date : 2026-01-01 Epub Date: 2025-11-21 DOI: 10.1016/j.neuint.2025.106091

Barbara Gundi , Hio Lam Ho , Xinyang Zhang , Amanda He , Danielle Xin , Ana Flávia F. Ferreira , Luiz Roberto Britto , Zhong-Ping Feng , Hong-Shuo Sun

Parkinson's disease (PD) is one of the most prevalent progressive neurodegenerative diseases today. However, existing treatments primarily focus on symptom management rather than attenuating disease progression and pathogenesis. ATP-sensitive potassium (K_ATP) ion channels play a significant role in motor control and coordination within the basal ganglia and have been implicated in the dopaminergic depletion mechanisms underlying PD. Recent studies have explored the potential of K_ATP channel inhibitors to slow PD pathogenesis and progression. Both pharmacological inhibition and genetic inactivation of these channels have been shown to reduce oxidative stress, dopamine (DA) depletion, and subsequent motor deficits. Contrastingly, alternative evidence suggests that K_ATP channel openers (KCOs) may elicit similar effects, highlighting the need for further exploration of K_ATP-mediated DA depletion mechanisms in PD. Future studies expanding our understanding of the mechanistic action of K_ATP in PD are essential to effectively leverage the channel's potential as a therapeutic target for combating PD pathology.

帕金森病（PD）是当今最常见的进行性神经退行性疾病之一。然而，现有的治疗主要侧重于症状管理，而不是减轻疾病的进展和发病机制。atp敏感钾离子通道在基底神经节内的运动控制和协调中起着重要作用，并与PD的多巴胺能耗竭机制有关。最近的研究已经探索了KATP通道抑制剂减缓PD发病和进展的潜力。这些通道的药理抑制和基因失活均可减少氧化应激、多巴胺（DA）消耗和随后的运动缺陷。相反，其他证据表明，KATP通道打开剂（KCOs）可能会产生类似的效果，这突出了进一步探索KATP介导的PD中DA消耗机制的必要性。未来的研究扩大了我们对KATP在PD中的机制作用的理解，对于有效利用该通道作为对抗PD病理的治疗靶点的潜力至关重要。

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引用次数: 0

Tricyclic antidepressant amitriptyline potentiates brain-derived neurotrophic factor expression mediated by PKC delta–NF–kappa B signaling in primary cultured astrocytes with connexin43-knockdown 三环抗抑郁药阿米替林在连接蛋白43敲低的原代培养星形胶质细胞中增强PKC δ - nf - κ B信号介导的脑源性神经营养因子表达。

IF 4 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Neurochemistry international

Pub Date : 2026-01-01 Epub Date: 2025-12-11 DOI: 10.1016/j.neuint.2025.106102

Nozomi Tokunaga, Rikako Fujimoto, Yoki Nakamura, Kazue Hisaoka-Nakashima, Norimitsu Morioka

Depression is a major mental illness, and its underlying mechanisms remain unclear. Emerging evidence suggests that astrocytes, which play a crucial role in brain function, may be involved in the pathophysiology of depression. We previously showed that downregulation of astrocytic connexin43 (Cx43) enhances the antidepressant effect of amitriptyline. However, the precise molecular mechanisms underlying this phenomenon remain unknown. In the present study, we investigated the signaling pathways involved in the antidepressant action of amitriptyline using an in vitro model involving Cx43-knockdown astrocytes. We found that amitriptyline potentiated the expression of brain-derived neurotrophic factor (BDNF), a key neurotrophic factor, in Cx43-knockdown astrocytes. This potentiation was mediated by the activation of Gq protein-coupled lysophosphatidic acid (LPA) receptors, a pathway that was sensitized by Cx43 downregulation. We further demonstrated that this signaling cascade involved the activation of Protein Kinase C (PKC) δ and transcription factor NF-κB, but not the conventional BDNF transcription factor CREB. We propose that Cx43 downregulation enhances the antidepressant effect of amitriptyline by specifically engaging the Gq-PKCδ–NF–κB pathway. These findings suggest that Cx43 downregulation in astrocytes, which has been considered a pathological feature of depression, may paradoxically contribute to the therapeutic efficacy of antidepressants by sensitizing a specific signaling pathway. Our study provides new insights into the molecular mechanism of antidepressant action and highlights the potential role of astrocytic Cx43 in modulating therapeutic responses.

抑郁症是一种主要的精神疾病，其潜在机制尚不清楚。新的证据表明，星形胶质细胞在大脑功能中起着至关重要的作用，可能与抑郁症的病理生理有关。我们之前的研究表明，下调星形细胞连接蛋白43 （Cx43）可增强阿米替林的抗抑郁作用。然而，这种现象背后的精确分子机制仍然未知。在本研究中，我们利用体外模型研究了阿米替林抗抑郁作用的信号通路，该模型涉及cx43敲低的星形胶质细胞。我们发现阿米替林增强了脑源性神经营养因子（BDNF）的表达，这是一种关键的神经营养因子，在cx43敲除的星形胶质细胞中。这种增强是由Gq蛋白偶联溶血磷脂酸（LPA）受体的激活介导的，这是一种被Cx43下调致敏的途径。我们进一步证明，该信号级联涉及蛋白激酶C (PKC) δ和转录因子NF-κB的激活，但不涉及传统的BDNF转录因子CREB。我们提出Cx43下调通过特异性参与Gq-PKCδ-NF-κB通路增强阿米替林的抗抑郁作用。这些发现表明，星形胶质细胞中Cx43的下调，被认为是抑郁症的病理特征，可能矛盾地通过使特定信号通路敏感来促进抗抑郁药的治疗效果。我们的研究为抗抑郁作用的分子机制提供了新的见解，并强调了星形细胞Cx43在调节治疗反应中的潜在作用。

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引用次数: 0

Characterizing stroke-related cellular changes in the surviving neurons of mouse ischemic stroke 小鼠缺血性中风存活神经元中与中风相关的细胞变化特征。

IF 4 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Neurochemistry international

Pub Date : 2025-12-01 Epub Date: 2025-11-11 DOI: 10.1016/j.neuint.2025.106086

Takeshi Ikegami , Tsutomu Sasaki , Takashi Shimbo , Tomomi Kitayama , Yukari Yamamoto , Yuya Ouchi , Sho Yamazaki , Shintaro Sugiyama , Kumiko Nishiyama , Yasufumi Gon , Shuhei Okazaki , Kenichi Todo , Shigenobu Matsumura , Katsuto Tamai , Hideki Mochizuki

Rapid restoration of cerebral blood flow through endovascular therapy is crucial for minimizing neuronal injury in ischemic stroke. This study characterized cellular and molecular alterations during the acute and subacute phases of distal middle cerebral artery occlusion (dMCAO) in mice using single-nucleus (snRNA-seq) and single-cell (scRNA-seq) RNA sequencing. C57BL/6 mice were assigned to control, sham, dMCAO 3-day, and dMCAO 14-day groups. snRNA-seq identified diverse cell populations, including neurons (glutamatergic and GABAergic), fibroblast-like cells, astrocytes, oligodendrocytes, microglia, endothelial cells, and pericytes. Microglia shifted from homeostatic (Siglech, P2ry12) to acute-phase (Lgals1, Top2a, Mki67) and disease-associated states, consistent with previous evidence confirming that our dataset captured stroke-related dynamics. snRNA-seq enabled efficient recovery and analysis of neurons, revealing stroke-induced cell state changes.; notably, glutamatergic neurons declined on day 3, while endothelial cells increased. Gene ontology analysis indicated neuronal death, autophagy, and cAMP biosynthesis pathways. Elevated Syngap1, Ikbkb, and Rock1 expression across glutamatergic subclusters suggested roles in cell death–related mechanisms and vulnerability to ischemic injury. Dissociation of SynGAP1 from PSD-95 after ischemia may enhance ERK1/2 phosphorylation, whereas ischemic preconditioning suppresses this dissociation and prevents ERK1/2 overactivation. Immunohistochemistry confirmed Syngap1 and cAMP response element-binding (CREB) pathway activation at 3 and 14 days post-ischemia, aligning with sequencing results. Suppressing CREB with pAAV-A-CREB reduced neuronal survival, underscoring its role in autophagy and neuroprotection. These findings provide mechanistic insight into stroke-induced molecular alterations and identify autophagy and cAMP pathways within the penumbra as promising therapeutic targets.

通过血管内治疗快速恢复脑血流是减少缺血性脑卒中神经元损伤的关键。本研究通过单核（snRNA-seq）和单细胞（scRNA-seq） RNA测序，表征了小鼠远端大脑中动脉闭塞（dMCAO）急性和亚急性期的细胞和分子变化。将C57BL/6小鼠分为对照组、假手术组、dMCAO 3 d组和dMCAO 14 d组。snRNA-seq鉴定了不同的细胞群，包括神经元（谷氨酸能和gaba能）、成纤维细胞样细胞、星形胶质细胞、少突胶质细胞、小胶质细胞、内皮细胞和周细胞。小胶质细胞从稳态（Siglech, P2ry12）转变为急性期（Lgals1, Top2a, Mki67）和疾病相关状态，这与先前的证据一致，证实了我们的数据集捕获了卒中相关的动态。snRNA-seq能够有效地恢复和分析神经元，揭示中风诱导的细胞状态变化。值得注意的是，第3天谷氨酸能神经元减少，内皮细胞增加。基因本体论分析提示神经元死亡、自噬和cAMP生物合成途径。谷氨酸能亚群中Syngap1、Ikbkb和Rock1表达的升高表明其在细胞死亡相关机制和缺血性损伤易感性中起作用。缺血后PSD-95的SynGAP1解离可增强ERK1/2磷酸化，而缺血预处理可抑制这种解离并防止ERK1/2过度激活。免疫组织化学证实Syngap1和cAMP反应元件结合（CREB）通路在缺血后3和14天激活，与测序结果一致。用pAAV-A-CREB抑制CREB可降低神经元存活，强调其在自噬和神经保护中的作用。这些发现为中风诱导的分子改变提供了机制，并确定了半暗带内的自噬和cAMP途径是有希望的治疗靶点。

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引用次数: 0

Astrocytic HIF-1α/VEGF induces endothelial PI3K/Akt activation to accelerate post-ischemic angiogenesis upon LCN2 inhibition 星形胶质细胞HIF-1α/VEGF诱导内皮细胞PI3K/Akt激活，在LCN2抑制下加速缺血后血管生成。

IF 4 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Neurochemistry international

Pub Date : 2025-12-01 Epub Date: 2025-10-14 DOI: 10.1016/j.neuint.2025.106078

Ning Tian , Xiaoxia Li , Yanlin Jiang , Jungang Deng , Hao Wang , Bing Guo , Meiling Chen , Rujia Liao

Therapeutic angiogenesis represents a pivotal yet underexplored avenue for functional recovery following cerebral ischemia. Although lipocalin-2 (LCN2) participates in neuropathological processes, its cell-type-specific regulation of post-ischemic vascular remodeling remains unknown. Here, we demonstrate that CRISPR/Cas9-mediated C8D1A astrocyte-like cells-specific LCN2 knockout significantly enhances vascular network formation in endothelial co-cultures under oxygen-glucose deprivation/reperfusion (OGD/R). Clinically, elevated LCN2 (GDS4521 dataset) correlates with poor stroke prognosis. Functional analyses revealed that AAV-shRNA-mediated LCN2 knockdown in photothrombotic stroke mice reduced infarct volume, attenuated peri-infarct neuronal loss, increased peri-infarct vascular density, and improved neurobehavioral outcomes at 7 days post-ischemia. Mechanistically, transcriptomic profiling identified hypoxia-inducible factor 1α (HIF-1α) as the master regulator of ischemia-induced angiogenesis. Molecular docking confirmed LCN2-HIF1α interaction. Furthermore, LCN2 ablation unleashes a HIF-1α/VEGF signaling cascade in C8D1A astrocyte-like cells, which activates endothelial phosphatidylinositol-3-kinase/protein kinase B (PI3K/Akt) via paracrine mechanisms to drive functional revascularization. These findings not only redefine ischemic pathophysiology but also pioneers LCN2 inhibition as a translational strategy to overcome the limitations of current pro-angiogenic therapies in cerebrovascular disease.

治疗性血管生成是脑缺血后功能恢复的关键但尚未充分探索的途径。尽管脂载素-2 （LCN2）参与神经病理过程，但其对缺血后血管重构的细胞类型特异性调控尚不清楚。在这里，我们证明了CRISPR/ cas9介导的C8D1A星形细胞样细胞特异性LCN2敲除显著增强了氧糖剥夺/再灌注（OGD/R）下内皮共培养血管网络的形成。临床上，升高的LCN2 （GDS4521数据集）与卒中预后不良相关。功能分析显示，在光血栓性卒中小鼠中，aav - shrna介导的LCN2敲低减少了梗死体积，减轻了梗死周围神经元的损失，增加了梗死周围血管密度，并在缺血后7天改善了神经行为结果。在机制上，转录组学分析发现缺氧诱导因子1α (HIF-1α)是缺血诱导血管生成的主要调节因子。分子对接证实LCN2-HIF1α相互作用。此外，LCN2消融在C8D1A星形细胞样细胞中释放HIF-1α/VEGF信号级联，通过旁分泌机制激活内皮磷脂酰肌醇-3激酶/蛋白激酶B (PI3K/Akt)，驱动功能性血运重建。这些发现不仅重新定义了缺血病理生理学，而且开创了LCN2抑制作为一种翻译策略来克服当前脑血管疾病促血管生成治疗的局限性。

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引用次数: 0

Striatal injection of aminochrome in Wistar rats induces early-stage behavioral changes of Parkinson's disease and dopaminergic degeneration in the caudal and medial regions of the nigra pars compacta 纹状体注射氨基色素诱导Wistar大鼠帕金森病早期行为改变及紧黑部尾部和内侧区域多巴胺能变性。

IF 4 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Neurochemistry international

Pub Date : 2025-12-01 Epub Date: 2025-11-06 DOI: 10.1016/j.neuint.2025.106083

Jéssica Teles-Souza , Juciele Valeria Ribeiro de Oliveira , Fillipe Mendes de Araújo , Flávia Santos Sanches , Lívia Bacelar de Jesus , Suzane Lopes de Souza , Amanda Dias Pinheiro Santos Brito , Camilla Melo Oliveira Leite , Gabriel de Jesus Ferrolho , Emiliano Fernandez-Villalba , Deise Souza Vilas Bôas , Rejane Conceição Santana , Silvia Lima Costa , Maria Trinidad Herrero , Victor Diogenes Amaral Silva

Most preclinical Parkinson's disease (PD) models use neurotoxic agents to cause rapid dopaminergic neuron degeneration, mimicking the late stage of PD. That creates a gap in understanding early-stage pathophysiology, critical for neuroprotective therapies and early diagnosis. To replicate the prodromal stage of PD, it is pivotal that preclinical study models promote a slow and selective death of dopaminergic neurons, triggering degenerative processes and early symptoms. In this context, we investigated behavioral and neuronal changes using a model of unilateral aminochrome injection (6 nmol/6 μL) in the striatum of adult male Wistar rats (CEUA-ICS, Protocol 3006070223), focusing on subtle changes representative of the early stages of PD. On the fourteenth day after the stereotaxic injection, we observed behavioral impairments marked by a reduction of frequency of entries, time spent and distance traveled in the central quadrants in the open field test, reduction of frequency of rearing and grooming in the open field, as well as an increase in the rate of motor asymmetry in the cylinder test. In addition, we observed a decrease in the transition of animals through the elevated plus maze, with a reduction in the number of entries into the open arm. Immunohistochemical analyses indicated that aminochrome induces cytotoxicity for tyrosine hydroxylase-positive (TH⁺) cells and induces astrogliosis and microgliosis. Our findings show that striatal injection of aminochrome induces a reduction in the density of TH⁺ fibers in the striatum, a slight reduction in the number of dopaminergic neurons in the caudal and medial regions of the nigra pars compacta (SNpc), and subtle motor deficits typical of an early stage of PD. Here, we provided evidence that aminochrome can induce a rodent model of the prodromal stages of PD.

大多数临床前帕金森病（PD）模型使用神经毒性药物引起快速多巴胺能神经元变性，模拟帕金森病的晚期。这在理解早期病理生理学方面造成了空白，而早期病理生理学对神经保护疗法和早期诊断至关重要。为了复制PD的前驱阶段，关键是临床前研究模型促进多巴胺能神经元缓慢和选择性死亡，引发退行性过程和早期症状。在这种情况下，我们使用单侧氨基色素注射（6 nmol/6μ l）的模型研究成年雄性Wistar大鼠纹状体的行为和神经元变化（CEUA-ICS，协议3006070223），重点关注具有代表性的PD早期的细微变化。在立体定向注射后的第14天，我们观察到大鼠的行为障碍，表现为在开放场地测试中进入中央象限的次数、时间和距离减少，在开放场地饲养和梳理的频率减少，以及在圆柱体测试中运动不对称率增加。此外，我们观察到动物通过高架+迷宫的过渡减少，进入张开手臂的次数减少。免疫组化分析表明，氨基色素对酪氨酸羟酶阳性（TH+）细胞具有细胞毒性，可诱导星形胶质细胞和小胶质细胞增生。我们的研究结果表明，纹状体注射氨基色素导致纹状体中TH+纤维密度降低，紧黑部（SNpc）尾侧和内侧区域多巴胺能神经元数量轻微减少，以及PD早期典型的轻微运动障碍。在这里，我们提供了证据，证明氨基色素可以诱导PD前驱期的啮齿动物模型。

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引用次数: 0

LC-MS/MS techniques for the analysis of steroid panel in human cerebrospinal fluid LC-MS/MS技术分析人脑脊液中类固醇成分。

IF 4 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Neurochemistry international

Pub Date : 2025-12-01 Epub Date: 2025-10-23 DOI: 10.1016/j.neuint.2025.106080

Tereza Skodova , Jana Vitku , Ondrej Bradac , Petr Skalicky , Adela Bubenikova , Radmila Kanceva , Lucie Kolatorova

The metabolic processes within the brain are reflected in the cerebrospinal fluid (CSF). It is in close contact with the nervous system, which is both target and source of multiple steroids. The aim of our study was to develop and validate robust, sensitive LC-MS/MS methods with and without derivatization step for the analysis of unconjugated steroids from all major steroid classes in CSF. The validation of the method without derivatization was performed for ten C19- steroids (dehydroepiandrosterone (DHEA), 7α-hydroxyDHEA, 7β-hydroxyDHEA, 7-ketoDHEA, testosterone, epitestosterone, dihydrotestosterone, 11-hydroxytestosterone, 11-ketotestosterone and androstenedione), ten C21- steroids (cortisol, 11-deoxycortisol, 21-deoxycortisol, cortisone, corticosterone, 11-deoxycorticosterone, pregnenolone, progesterone, 17-hydroxyprogesterone, aldosterone) and three C18- steroids (estrone, estradiol, estriol). The method with derivatization is validated for determination of eleven C19- steroids (testosterone, 11-ketodihydrotestosterone, 11-hydroxytestosterone, DHEA, 7α-hydroxyDHEA, 7β-hydroxyDHEA, 7-ketoDHEA, androstenedione, androsterone, epiandrosterone, 7β-hydroxyepiandrosterone) and six C21- steroids (cortisol, cortisone, corticosterone, pregnenolone, 17-hydroxypregnenolone, progesterone) in CSF. The method without derivatization is applicable for the determination of the majority of steroids in CSF, except for pregnenolone, 17-hydroxypregnenolone and DHEA, for which the derivatization method provides better sensitivity. When analyzing CSF samples of normal pressure hydrocephalus (NPH) patients, 11-ketodihydrotestosterone, epitestosterone, androsterone, epiandrosterone, 7β-hydroxyepiandrosterone, 7-ketoDHEA and 21-deoxycortisol were found to be below the LLOQ, suggesting that their presence is very limited. 17-hydroxypregnenolone, and 11-deoxycortisol were quantified for the first time, their CSF levels in NPH subjects are presented. We also observed significantly increased CSF levels of testosterone and 17-hydroxyprogesterone in men compared to women, both with NPH.

脑内的代谢过程反映在脑脊液（CSF）中。它与神经系统密切接触，是多种类固醇的靶点和来源。本研究的目的是开发和验证可靠、敏感的LC-MS/MS方法，用于分析脑脊液中所有主要类固醇类的非共轭类固醇。对10种C19-甾体（脱氢表雄酮（DHEA）、7α-羟基DHEA、7-羟基DHEA、7-酮DHEA、睾酮、表雄酮、二氢睾酮、11-羟基睾酮、11-酮睾酮和雄烯二酮）、10种C21-甾体（皮质醇、11-脱氧皮质醇、21-脱氧皮质醇、可的松、皮质酮、11-脱氧皮质酮、孕烯醇酮、孕酮、17-羟孕酮、醛固酮）和3种C18-甾体(雌酮、雌二醇、雌三醇)。验证了衍生化法测定脑脊液中11种C19-甾体（睾酮、11-酮二氢睾酮、11-羟基睾酮、DHEA、7α-羟基DHEA、7β-羟基DHEA、雄烯二酮、雄酮、表雄酮、7β-羟基雄酮）和6种C21-甾体（皮质醇、可的松、皮质酮、孕烯醇酮、17-羟基孕烯醇酮、孕酮）的含量。除孕烯醇酮、17-羟基孕烯醇酮和脱氢表雄酮外，不衍生化法适用于脑脊液中大部分类固醇的测定，衍生化法对这些类固醇的灵敏度更高。在分析常压脑积水（NPH）患者脑脊液样本时，发现11-酮二氢睾酮、表甾酮、雄酮、表雄酮、7- β-羟基雄酮、7-酮脱氢表雄酮和21-脱氧皮质醇低于LLOQ，表明它们的存在非常有限。首次定量测定了17-羟基孕烯醇酮和11-脱氧皮质醇，并给出了它们在NPH受试者脑脊液中的水平。我们还观察到，与NPH患者相比，男性脑脊液中睾酮和17-羟孕酮水平显著升高。

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引用次数: 0

Food restriction and amphetamine exposure synergistically enhance accumbal dopamine D1 receptor-mediated locomotor activity 食物限制和安非他明暴露协同增强伏隔多巴胺D1受体介导的运动活动。

IF 4 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Neurochemistry international

Pub Date : 2025-12-01 Epub Date: 2025-10-27 DOI: 10.1016/j.neuint.2025.106081

Seohyeon Lee , Hyung Shin Yoon , Jeong-Hoon Kim

Natural rewards such as food and drugs of abuse share the mesolimbic dopamine system, including the nucleus accumbens (NAcc), as a common neural pathway that influences appetite and addictive behavior. Ghrelin, an orexigenic hormone, acts synergistically with mesolimbic dopamine in this process. In the present study, we examined the effects of food restriction (FR) on plasma ghrelin levels and amphetamine (AMPH)-induced locomotor activity. Chronic FR (cFR) significantly enhanced AMPH-induced locomotor activity compared to normal feeding and acute FR (aFR), which was associated with increased plasma ghrelin and dopamine D1 receptor (D1R) expression levels in the NAcc. These effects were inhibited by either systemic or NAcc-specific administration of D1R or ghrelin receptor antagonists. Furthermore, rats under the aFR condition showed enhanced locomotor activity in response to intra-accumbal microinjection of the D1R agonist when pre-exposed to AMPH, whereas rats in the cFR condition showed these effects regardless of pre-exposures to either AMPH or saline. These results demonstrate that FR conditions interact with drugs of abuse via the accumbal ghrelin and D1R systems, thereby contributing to the expression of addictive behaviors. Notably, these findings suggest that dietary status should be considered during addiction treatment.

自然奖励，如食物和药物滥用共享中脑边缘多巴胺系统，包括伏隔核（NAcc），作为一个共同的神经通路，影响食欲和成瘾行为。胃饥饿素是一种促氧激素，在这一过程中与中脑边缘多巴胺协同作用。在本研究中，我们研究了食物限制（FR）对血浆胃饥饿素水平和安非他明（AMPH）诱导的运动活动的影响。与正常喂养和急性FR （aFR）相比，慢性FR （cFR）显著增强了amph诱导的运动活性，这与NAcc血浆胃饥饿素和多巴胺D1受体（D1R）表达水平升高有关。这些作用可被D1R或胃饥饿素受体拮抗剂的全身或nac特异性施用所抑制。此外，aFR条件下的大鼠在预先暴露于AMPH时，对伏隔区内微量注射D1R激动剂的运动活动表现出增强的反应，而cFR条件下的大鼠无论预先暴露于AMPH还是生理盐水都表现出这些作用。这些结果表明FR条件通过伏隔胃饥饿素和D1R系统与药物滥用相互作用，从而促进成瘾行为的表达。值得注意的是，这些发现表明在成瘾治疗期间应考虑饮食状况。

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引用次数: 0