Neurochemistry international最新文献_第6页

Spinal p38 MAPK/PGC-1α/SIRT3 signaling pathway mediates remifentanil-induced hyperalgesia in rats via ROS release and NR2B activation 脊髓p38 MAPK/PGC-1α/SIRT3信号通路通过ROS释放和NR2B激活介导瑞芬太尼诱导的大鼠痛觉过敏

IF 4 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Neurochemistry international

Pub Date : 2025-09-26 DOI: 10.1016/j.neuint.2025.106061

Guoyan Feng , Fengxiang Song , Aiqi Wang , Lu Wang , Haotian Zhang , Shun Wang , Haitao Hou , Lianxiang Zhang , Liqin Deng

Remifentanil-induced hyperalgesia (RIH) poses a significant clinical challenge. Our research group has previously confirmed that abnormal activation of p38 mitogen-activated protein kinase (p38 MAPK) in the spinal dorsal horn contributes to RIH, but the specific regulatory pathway remains unclear. It is known that p38 MAPK can regulate the expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), and the PGC-1α/Sirtuin 3 (SIRT3) pathway plays an important role in various pain models. However, whether this pathway is involved in RIH remains to be elucidated. In this study, an RIH model was established using male Sprague-Dawley (SD) rats, and significant hyperalgesia was observed in the RIH group. Intrathecal injection of the p38 MAPK inhibitor SB203580 or the PGC-1α agonist ZLN005 significantly alleviated this hyperalgesic response.

Mechanistic analysis further revealed that in the RIH model group, activation of p38 MAPK was increased in spinal dorsal horn microglia, while the expression of PGC-1α and SIRT3 were decreased. In neurons, reactive oxygen species (ROS) levels were increased, accompanied by increased expression of the N-methyl-d-aspartate receptor (NMDAR) subunit NR2B, synaptic structural remodeling, and an increase in the amplitude and frequency of NMDAR-mediated spontaneous excitatory postsynaptic currents (sEPSCs). All these pathological changes could be reversed by intervention with either SB203580 or ZLN005. In conclusion, this study demonstrates that remifentanil activates p38 MAPK in spinal dorsal horn microglia, inhibits the PGC-1α/SIRT3 signaling pathway, promotes ROS release, subsequently activates the neuronal NR2B subunit, and ultimately induces RIH. This mechanism provides a new potential target for the treatment of RIH.

瑞芬太尼诱发的痛觉过敏（RIH）提出了重大的临床挑战。本课课组此前已证实脊髓背角p38丝裂原活化蛋白激酶（p38 MAPK）异常激活有助于RIH，但具体调控途径尚不清楚。已知p38 MAPK可以调控过氧化物酶体增殖体激活受体γ辅助激活因子1- α (PGC-1α)的表达，PGC-1α/Sirtuin 3 （SIRT3）通路在多种疼痛模型中发挥重要作用。然而，这一途径是否参与RIH仍有待阐明。本研究以雄性SD大鼠建立RIH模型，RIH组出现明显痛觉过敏。鞘内注射p38 MAPK抑制剂SB203580或PGC-1α激动剂ZLN005可显著减轻这种过敏反应。机制分析进一步发现，RIH模型组脊髓背角小胶质细胞中p38 MAPK的激活增加，PGC-1α和SIRT3的表达降低。在神经元中，活性氧（ROS）水平升高，同时n -甲基- d -天冬氨酸受体（NMDAR）亚基NR2B的表达增加，突触结构重塑，NMDAR介导的自发兴奋性突触后电流（sEPSCs）的振幅和频率增加。SB203580或ZLN005干预均可逆转上述病理改变。综上所述，本研究表明瑞芬太尼激活脊髓背角小胶质细胞p38 MAPK，抑制PGC-1α/SIRT3信号通路，促进ROS释放，进而激活神经元NR2B亚基，最终诱导RIH。这一机制为RIH的治疗提供了一个新的潜在靶点。

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引用次数: 0

SPP1 expression after spinal cord compression injury and its effects on glial cell activation 脊髓受压损伤后SPP1的表达及其对神经胶质细胞活化的影响。

IF 4 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Neurochemistry international

Pub Date : 2025-09-26 DOI: 10.1016/j.neuint.2025.106063

Linkai Lei , Xinping Wang , Jijuan Zhao

Purpose

To study the role and mechanism of SPP1 in spinal cord injury.

Methods

We created a rat model of spinal cord compression injury (SCI) and examined the expression of SPP1 in spinal cord tissue using western blotting and immunofluorescence staining. We assessed motor function and pathological repair in SCI rats using the BBB locomotor scale, swimming tests, HE staining, Nissl staining, myelin staining, immunofluorescence, and western blot experiments. Additionally, we examined microglial activation and inflammatory phenotypes to analyze underlying mechanisms. To determine if SPP1's effects are linked to MK2, we used the MK2 inhibitor PF-364402.

Results

After spinal cord injury, the expression level of SPP1 exhibited a significant increase, peaking on the third day post-injury. A co-localization relationship was noted with Iba-1-labeled microglia. Reduced SPP1 expression enhanced motor function recovery and aided in spinal cord tissue repair after injury in mice. Low SPP1 expression modulated glial cell inflammation, reducing the iNOS-labeled pro-inflammatory phenotype and increasing the Arg-1-labeled anti-inflammatory phenotype. This modulation subsequently inhibited the activation of microglia. Furthermore, we validated the inhibitory effect of low SPP1 expression on the activation of the MK2 signaling pathway, which was associated with a reduction in the phosphorylation levels of MK2, p38, and NF-κB.

Conclusion

This study found that SPP1 was highly expressed in rats with spinal cord injury and was associated with microglial activation and inflammatory phenotype transformation. Low levels of SPP1 promoted neural repair and motor function recovery, which may be related to the MK2 pathway.

目的：探讨SPP1在脊髓损伤中的作用及其机制。方法：建立脊髓压缩性损伤大鼠模型，采用western blotting和免疫荧光染色检测脊髓组织中SPP1的表达。我们采用血脑屏障运动量表、游泳实验、HE染色、尼氏染色、髓磷脂染色、免疫荧光和western blot实验评估脊髓损伤大鼠的运动功能和病理修复。此外，我们检查了小胶质细胞激活和炎症表型来分析潜在的机制。为了确定SPP1的作用是否与MK2有关，我们使用了MK2抑制剂PF-364402。结果：脊髓损伤后，SPP1表达水平明显升高，在损伤后第3天达到峰值。与iba -1标记的小胶质细胞存在共定位关系。减少SPP1表达可促进小鼠损伤后运动功能恢复，并有助于脊髓组织修复。SPP1的低表达调节了胶质细胞的炎症，降低了inos标记的促炎表型，增加了arg -1标记的抗炎表型。这种调节随后抑制了小胶质细胞的激活。此外，我们验证了低SPP1表达对MK2信号通路激活的抑制作用，这与MK2、p38和NF-κB磷酸化水平的降低有关。结论：本研究发现SPP1在脊髓损伤大鼠中高表达，并与小胶质细胞活化和炎症表型转化有关。低水平的SPP1促进神经修复和运动功能恢复，这可能与MK2通路有关。

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引用次数: 0

Constant light exposure promotes pathogenic tau hyperphosphorylation and phenotypic manifestations in Drosophila disease models 在果蝇疾病模型中，持续的光照可促进致病性tau过度磷酸化和表型表现

IF 4 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Neurochemistry international

Pub Date : 2025-09-24 DOI: 10.1016/j.neuint.2025.106060

Prerna Aggarwal , Virender , Surajit Sarkar

Chronic sleep disruption caused by constant artificial light exposure has emerged as both a comorbidity and a precursor of several neurodegenerative disorders, including tauopathies. Tauopathies, a group of neurodegenerative disorders, are characterised by the toxic accumulation of hyperphosphorylated tau in brain neurons. While disturbance in the sleep/wake cycle is an inherent clinical feature of tauopathies, the impact of prolonged light exposure on disease progression and severity has been inadequately investigated. We utilized Drosophila models of human tauopathies to examine the impact of uninterrupted exposure to light on tau-induced phenotypic markers during pathogenesis over a short period of aging. We observed that constant light exposure causes an earlier onset and increased severity of disease-associated phenotypes in an age-dependent manner. We further noted that these aggravated phenotypes are associated with increased pathogenic hyperphosphorylation of tau, leading to the rapid accumulation of relatively larger neurotoxic aggregates in neuronal cells and their subsequent degeneration. Overall, our study demonstrates that unhealthy light exposure accelerates the early onset and severity of tauopathy-related phenotypes, highlighting its potential relevance in developing management strategies for these devastating neurodegenerative disorders.

由持续的人造光照射引起的慢性睡眠中断已经成为几种神经退行性疾病的合并症和先兆，包括牛头病。tau病是一组神经退行性疾病，其特征是大脑神经元中过度磷酸化的tau的毒性积累。虽然睡眠/觉醒周期紊乱是牛头病的固有临床特征，但长时间光照对疾病进展和严重程度的影响尚未得到充分研究。我们利用人类tau病的果蝇模型来研究在短时间衰老的发病过程中，不间断的光照对tau诱导的表型标记物的影响。我们观察到，持续的光照会导致发病早，并以年龄依赖的方式增加疾病相关表型的严重性。我们进一步注意到，这些加重的表型与tau的致病性过度磷酸化增加有关，导致神经细胞中相对较大的神经毒性聚集体的快速积累及其随后的变性。总的来说，我们的研究表明，不健康的光暴露加速了牛头病相关表型的早期发病和严重程度，强调了它在制定这些破坏性神经退行性疾病的管理策略方面的潜在相关性。

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引用次数: 0

Genetic and epigenetic architectures of stroke: Insights from GWAS to precision medicine 中风的遗传和表观遗传结构：从GWAS到精准医学的见解。

IF 4 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Neurochemistry international

Pub Date : 2025-09-24 DOI: 10.1016/j.neuint.2025.106059

Faheem Shehjar, Reetika Mahajan, Shayaan Shahnaz, Zahoor A. Shah

Stroke remains a leading cause of death and disability, driven by complex interactions among genetic, epigenetic, and environmental factors. Advances in genomic technologies have elucidated the role of common polygenic variants and rare monogenic mutations in determining susceptibility to stroke subtypes. Genome-wide association studies have identified key loci, including Histone Deacetylase 9 (HDAC9), Paired-like Homeodomain Transcription Factor 2 (PITX2), Zinc Finger Homeobox 3 (ZFHX3), and Collagen Type IV Alpha 1 Chain (COL4A1), associated with vascular inflammation, atrial fibrillation, and small vessel dysfunction. Monogenic disorders such as Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL; NOTCH3), Fabry disease (GLA), and Sickle Cell Disease (SCD; HBB) illustrate the impact of single-gene mutations on early-onset or familial stroke. Epigenetic mechanisms, including DNA methylation, histone modifications, and non-coding RNAs such as microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs) regulate pathways related to apoptosis, inflammation, angiogenesis, and blood-brain barrier dysfunction. Pharmacogenomic profiling, involving genes such as CYP2C19, VKORC1, and SLCO1B1, can guide individualized therapy with antiplatelets, anticoagulants, and statins. Collectively, these advances are steering stroke care toward precision medicine, integrating multi-omics data and gene-targeted strategies for improved prevention, diagnosis, and treatment.

由于遗传、表观遗传和环境因素之间复杂的相互作用，中风仍然是导致死亡和残疾的主要原因。基因组技术的进步已经阐明了常见的多基因变异和罕见的单基因突变在确定卒中亚型易感性中的作用。全基因组关联研究已经确定了与血管炎症、心房颤动和小血管功能障碍相关的关键位点，包括组蛋白去乙酰化酶9 （HDAC9）、配对样同源结构域转录因子2 （PITX2）、锌指同源盒3 （ZFHX3）和胶原IV型α 1链（COL4A1）。单基因疾病，如大脑常染色体显性动脉病变伴皮质下梗死和白质脑病（CADASIL; NOTCH3）、法布里病（GLA）和镰状细胞病（SCD； HBB），说明了单基因突变对早发性或家族性卒中的影响。表观遗传机制，包括DNA甲基化、组蛋白修饰和非编码rna，如microRNAs （miRNAs）、长链非编码rna （lncRNAs）和环状rna (circRNAs)，调节与凋亡、炎症、血管生成和血脑屏障功能障碍相关的途径。涉及CYP2C19、VKORC1和SLCO1B1等基因的药物基因组学分析可以指导抗血小板、抗凝血剂和他汀类药物的个体化治疗。总的来说，这些进步正在引导中风护理走向精准医学，整合多组学数据和基因靶向策略，以改进预防、诊断和治疗。

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引用次数: 0

Neuronutritional enhancement of antioxidant defense system through Nrf2/HO1/NQO1 axis in fibromyalgia Nrf2/HO1/NQO1轴对纤维肌痛患者抗氧化防御系统的神经营养增强作用

IF 4 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Neurochemistry international

Pub Date : 2025-09-23 DOI: 10.1016/j.neuint.2025.106057

Francesca Inferrera , Nicla Tranchida , Roberta Fusco , Salvatore Cuzzocrea , Daniela Impellizzeri , Rosalba Siracusa , Ramona D'Amico , Luay Rashan , Anastasiia Badaeva , Alexey Danilov , Vittorio Calabrese , Rosanna Di Paola , Marika Cordaro

Fibromyalgia (FM) is a disorder characterized by chronic widespread musculoskeletal pain, and it is often accompanied by fatigue, sleep disturbance, and cognitive dysfunction. Although pathophysiology is multifactorial, increasing evidence highlights the pivotal role of oxidative stress and mitochondrial dysfunction in the development of this condition. In particular, the Nrf2/HO-1/NQO1 antioxidant axis plays a crucial role in counteracting oxidative damage and maintaining cellular homeostasis. Boswellia (BS) is a genus of plants in the Burseraceae family, which includes around twenty species found across sub-Saharan Africa, the Arabian Peninsula, and the Indian subcontinent. In Ayurvedic medicine, it has traditionally been used in the treatment of diabetes, fever, as well as certain cardiovascular, dermatological, and neurological conditions. Boswellic acids are thought to possess anti-inflammatory, anti-rheumatic, and pain-relieving properties. The purpose of this study was to investigate the beneficial effects of BS extract in a murine model of reserpine-induced FM. Following reserpine administration, markers of oxidative stress, neuroinflammation, and behavioral changes including mechanical allodynia, hyperalgesia, anxiety, and depression-like behaviors were significantly increased. Daily oral administration of BS at a dose of 100 mg/kg effectively restored these pathological changes. BS oral supplementation, by preventing microglia and astrocyte activation, as demonstrated by decreased GFAP and Iba-1 expression, BS decreased neurological inflammation and restored neurotransmitter levels such as norepinephrine, dopamine and serotonin. Futhermore, improved antioxidant defenses by increasing nuclear translocation of Nrf2 and subsequent expression of its downstream targets, HO-1 and NQO1, limiting lipid peroxidation and ROS production. According to behavioral tests, BS significantly reduced the emotional deficit and mechanical sensitivity linked to FM. Our findings indicate that BS integration has neuroprotective effects, acting on oxidative stress and neuroinflammation, and suggesting that it is a viable natural strategy for managing FM symptoms.

纤维肌痛（FM）是一种以慢性广泛的肌肉骨骼疼痛为特征的疾病，通常伴有疲劳、睡眠障碍和认知功能障碍。虽然病理生理是多因素的，但越来越多的证据强调氧化应激和线粒体功能障碍在这种疾病的发展中的关键作用。特别是Nrf2/HO-1/NQO1抗氧化轴在对抗氧化损伤和维持细胞稳态中起着至关重要的作用。Boswellia （BS）是蕨科植物的一个属，包括大约20个物种，分布在撒哈拉以南非洲、阿拉伯半岛和印度次大陆。在阿育吠陀医学中，它传统上被用于治疗糖尿病、发烧，以及某些心血管疾病、皮肤病和神经系统疾病。乳香酸被认为具有抗炎、抗风湿和缓解疼痛的特性。本研究的目的是探讨BS提取物对利血平诱导的小鼠FM模型的有益作用。服用利血平后，氧化应激、神经炎症和行为改变（包括机械性异常性痛、痛觉过敏、焦虑和抑郁样行为）的标志物显著增加。每日口服100 mg/kg的BS可有效恢复这些病理变化。口服补充BS，通过抑制小胶质细胞和星形胶质细胞的激活，降低GFAP和Iba-1的表达，可以减少神经炎症，恢复神经递质水平，如去甲肾上腺素、多巴胺和血清素。此外，通过增加Nrf2的核易位及其随后下游靶标HO-1和NQO1的表达，限制脂质过氧化和ROS的产生，提高抗氧化防御能力。根据行为测试，BS显著降低了与FM相关的情绪缺陷和机械敏感性。我们的研究结果表明，BS整合具有神经保护作用，对氧化应激和神经炎症起作用，并表明它是治疗FM症状的一种可行的自然策略。

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引用次数: 0

Two phosphomimetic sites in the GABA transporter GAT1 C-terminus selectively regulate transporter interactions with distinct types of PDZ domains in vitro GABA转运体GAT1 c末端的两个拟磷位点选择性地调节转运体与不同类型PDZ结构域的相互作用。

IF 4 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Neurochemistry international

Pub Date : 2025-09-22 DOI: 10.1016/j.neuint.2025.106058

Iveta Koščová, Martina Baliova, Frantisek Jursky

The GABA transporter GAT1 is a membrane protein that participates in GABA signalling in the brain and certain peripheral tissues. GAT1 contains a C-terminal PDZ motif (-A⁵⁹⁷Y⁵⁹⁸I⁵⁹⁹), previously classified as a type II (ΦXΦ) motif, where PDZ interaction should depend on non-phosphorylatable hydrophobic (Φ) residues at PDZ positions 0 (I⁵⁹⁹) and −2 (A⁵⁹⁷). We recently found that a GAT1 C-terminal peptide unconventionally binds to the PDZ1 domain of syntenin-1 and to the PDZ2 domain of PSD95 by using different PDZ interaction schemes, specifically 0,-1 and 0,-3, respectively. In this work, we used phosphomimetic amino acid mutagenesis to investigate the role of phosphorylatable amino acids in the GAT1 C-terminus in binding to these two domains. The mutagenesis and molecular docking experiments suggested that phosphorylation of tyrosine 598 at PDZ position −1 might affect the interaction with the PDZ1 domain of syntenin-1, but it did not affect the interaction with the PDZ2 domain of PSD95. On the other hand, a phosphomimetic but not a neutral mutation of the remote serine residues 592 and 594 at PDZ positions −7 and −5, respectively, affected the interaction of the GAT1 PDZ motif with the PDZ2 domain of PSD95, but not with the PDZ1 domain of syntenin-1. These findings suggest the existence of at least two domain-specific GAT1 PDZ interaction modes regulated by two distinct potentially phosphorylatable serine and tyrosine residues in the GAT1 C-terminus.

GABA转运体GAT1是一种膜蛋白，参与GABA在大脑和某些外周组织中的信号传导。GAT1包含一个c端PDZ基序（-A597Y598I599），以前被归类为II型基序（ΦXΦ），其中PDZ相互作用应该依赖于PDZ位置0 （I599）和-2 （A597）上的非磷酸化疏水（Φ）残基。我们最近发现，GAT1 c端肽通过不同的PDZ相互作用方案（分别为0，-1和0，-3）非常规地结合到syntenin-1的PDZ1结构域和PSD95的PDZ2结构域。在这项工作中，我们使用拟磷氨基酸诱变来研究GAT1 c端可磷酸化氨基酸与这两个结构域结合的作用。诱变和分子对接实验表明，酪氨酸598在PDZ -1位置的磷酸化可能会影响其与syntenin-1的PDZ1结构域的相互作用，但不会影响其与PSD95的PDZ2结构域的相互作用。另一方面，位于PDZ -7和-5位置的远端丝氨酸残基592和594的同源性突变影响了GAT1 PDZ基序与PSD95的PDZ2结构域的相互作用，而不影响与syntenin-1的PDZ1结构域的相互作用。这些发现表明，至少存在两种特定于GAT1 PDZ结构域的相互作用模式，由GAT1 c端两种不同的潜在可磷酸化的丝氨酸和酪氨酸残基调节。

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引用次数: 0

The antidepressant venlafaxine induces upregulation of miR-92 and histological alterations in a chicken embryo model 在鸡胚模型中，抗抑郁药文拉法辛诱导miR-92上调和组织学改变。

IF 4 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Neurochemistry international

Pub Date : 2025-09-20 DOI: 10.1016/j.neuint.2025.106056

Oykum Kaplan-Arabaci , Denis Zosen , Diana Domanska , Sigrid Bjørnstad , Simone Santini , Umut Karaca , Jasmin Andrea Haeckel , Kristine Dolva , Zuzana Dančišinová , Fred Haugen , Jannike Mørch Andersen , Ragnhild Elisabeth Paulsen

Antidepressants are commonly prescribed for treating anxiety disorders and depression, including pregnant patients. These medications influence the absorption and metabolism of key neurotransmitters such as serotonin, norepinephrine, and dopamine. However, many aspects of antidepressant function remain unclear, especially regarding their impact on neurodevelopment when used during pregnancy. To explore this, we employed a 3R-friendly chicken embryo model to investigate the cellular and molecular implications of antidepressants use. We focused on commonly used antidepressants for the study: escitalopram, which is a selective serotonin reuptake inhibitor; and venlafaxine, a serotonin and noradrenaline reuptake inhibitor, both of which are frequently prescribed during pregnancy.

Drug distribution analysis showed that both antidepressant drugs reached clinical concentrations in the brain of developing chicken embryos and persisted for several hours. High-throughput miRNA-sequencing showed that venlafaxine upregulated 13 different miRNAs in the chicken cerebellum. Specifically, miR-92 and its human ortholog, miR-363, were significantly upregulated in chicken cerebellum and neuronally differentiated human SH-SY5Y cells, respectively. Neurite metrics showed a significant reduction in neurite outgrowth with venlafaxine, but not with escitalopram. Furthermore, venlafaxine caused histological alterations, such as increased white matter and reduced thickness of the cortical and molecular layer in the cerebellum. Both drugs reduced the thickness of the external granular layer and the number of mitotic events, impacting this crucial germinal zone of the brain.

These findings highlight distinct neurodevelopmental effects of escitalopram and venlafaxine and raise awareness for potential adverse neurological effects in offspring exposed to antidepressants in utero.

抗抑郁药通常用于治疗焦虑症和抑郁症，包括孕妇。这些药物影响关键神经递质的吸收和代谢，如血清素、去甲肾上腺素和多巴胺。然而，抗抑郁药功能的许多方面仍不清楚，特别是在怀孕期间使用它们对神经发育的影响。为了探讨这一点，我们采用了一个3r友好的鸡胚胎模型来研究抗抑郁药使用的细胞和分子意义。我们在研究中重点研究了常用的抗抑郁药：艾司西酞普兰（escitalopram，一种选择性血清素再摄取抑制剂）和文拉法辛（venlafaxine，一种血清素和去甲肾上腺素再摄取抑制剂），这两种药都是孕期常用的处方。药物分布分析表明，这两种抗抑郁药物在发育中的鸡胚胎的大脑中达到临床浓度，并持续数小时。高通量mirna测序显示，文拉法辛上调了鸡小脑中13种不同的mirna。具体来说，miR-92及其人类同源物miR-363分别在鸡小脑和神经分化的人SH-SY5Y细胞中显著上调。神经突指标显示文拉法辛组神经突生长显著减少，但艾司西酞普兰组没有。此外，文拉法辛引起组织学改变，如白质增加，小脑皮层和分子层厚度减少。这两种药物都减少了外颗粒层的厚度和有丝分裂事件的数量，影响了大脑这个关键的生发区。这些发现突出了艾司西酞普兰和文拉法辛对神经发育的独特影响，并提高了对胎儿在子宫内暴露于抗抑郁药物的潜在不良神经系统影响的认识。

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引用次数: 0

Further characterisation of the intrastriatal 6-OHDA Parkinson's disease model with non-motor symptom replication and widespread catecholamine dysfunction in male mice 具有非运动症状复制和广泛儿茶酚胺功能障碍的雄性小鼠纹状体内6-OHDA帕金森病模型的进一步表征

IF 4 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Neurochemistry international

Pub Date : 2025-09-18 DOI: 10.1016/j.neuint.2025.106054

Alisha Braun , Jessica Racz , Sanjay Garg , Larisa Bobrovskaya

The 6-OHDA mouse model of Parkinson's disease is not well characterised, with variable dosages, injection sites and timeframes. This study further characterised the unilateral intrastriatal 8 μg 6-OHDA mouse model using a four-week protocol, with replication of motor and some non-motor symptoms in male mice. Non-motor symptom replication included cognitive impairment and gastrointestinal dysfunction. Olfactory dysfunction and anxiety-like behaviour were unable to be replicated in this study. Parkinson's disease pathology, particularly non-motor pathology, was also investigated in this study which found the intrastriatal 6-OHDA lesion caused widespread catecholamine dysfunction outside of the nigrostriatal pathway, including the mesocortical and mesolimbic pathway. Proteins involved in neuroinflammation (GFAP), oxidative stress defence (SOD2) and synaptic proteins (SNAP25) were altered, as seen in Parkinson's disease pathology, in the brains of the 6-OHDA lesioned mice.

6-OHDA帕金森病小鼠模型没有很好地表征，具有可变的剂量、注射部位和时间框架。本研究采用为期四周的方案进一步表征了单侧8μg - 6-OHDA小鼠胃内模型，在雄性小鼠中复制了运动和一些非运动症状。非运动症状复制包括认知障碍和胃肠功能障碍。嗅觉功能障碍和焦虑样行为在这项研究中无法被复制。本研究还研究了帕金森病的病理，特别是非运动病理，发现纹状体内6-OHDA病变引起黑质纹状体途径外的广泛儿茶酚胺功能障碍，包括中皮层和中边缘途径。在6-OHDA损伤小鼠的大脑中，参与神经炎症（GFAP）、氧化应激防御（SOD2）和突触蛋白（SNAP25）的蛋白质发生了改变，正如在帕金森病病理中看到的那样。

引用次数: 0

Schwann cells as a therapeutic target for amyotrophic lateral sclerosis: A TDP-43 focussed review 雪旺细胞作为肌萎缩性侧索硬化症的治疗靶点：TDP-43聚焦综述

IF 4 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Neurochemistry international

Pub Date : 2025-09-18 DOI: 10.1016/j.neuint.2025.106055

Katherine N. Lewis , David G. Gonsalvez , Bradley J. Turner , Samantha K. Barton

Amyotrophic lateral sclerosis (ALS) is an incurable, lethal neurodegenerative disease and a proteinopathy with >97 % of cases characterised by pathological accumulation of TDP-43. TDP-43 is ubiquitously expressed and its pathological accumulation has now been identified in non-neuronal cells in both the central and peripheral nervous systems. Thus, the expansion to exploring other cells and their contribution to ALS pathogenesis may be the key to finding more effective treatments. Schwann cells are the myelinating cells of the peripheral nervous system, that encase neuronal axons to propagate action potentials, maintain neuronal health, and respond to neuronal activity in the extracellular environment. Despite Schwann cells being identified to exhibit aberrant TDP-43 proteinopathy in ALS patients, their role in disease remains elusive. Here, we review the potential contributions of Schwann cells to ALS as well as the prospective benefits of harnessing Schwann cells treat the disease.

肌萎缩性侧索硬化症（ALS）是一种无法治愈的、致死性的神经退行性疾病和一种伴有bbb97的蛋白质病，97%的病例以TDP-43的病理性积累为特征。TDP-43在中枢和周围神经系统的非神经元细胞中普遍表达，其病理积累现已被确定。因此，扩展到探索其他细胞及其对ALS发病机制的贡献可能是找到更有效治疗方法的关键。雪旺细胞是周围神经系统的髓鞘细胞，包裹神经元轴突传播动作电位，维持神经元健康，并在细胞外环境中对神经元活动作出反应。尽管雪旺细胞在ALS患者中表现出异常的TDP-43蛋白病变，但它们在疾病中的作用仍然难以捉摸。在这里，我们回顾了雪旺细胞对ALS的潜在贡献以及利用雪旺细胞治疗该疾病的潜在益处。

引用次数: 0

Toxic Tango in Parkinson's Disease: A dance between αSyn and iron import, export and speciation 帕金森病的毒性探戈：αSyn与铁输入、输出和形成之间的舞蹈。

IF 4 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Neurochemistry international

Pub Date : 2025-09-16 DOI: 10.1016/j.neuint.2025.106053

Tasha Cosson , Peter Faller , Dean L. Pountney

The intricate interplay between brain iron homeostasis and pathological α-Synuclein (αSyn) in Parkinson's Disease (PD) is still unclear. αSyn is the primary protein involved in disease progression and promotes cytotoxicity by impairing dopamine synthesis, mitochondrial dysfunction and disrupts brain iron homeostasis. Iron has further revealed to induce αSyn aggregation however, the exact mechanism of interaction between iron and αSyn is uncertain. Many studies have demonstrated an imbalance of iron homeostasis in PD pathogenesis, including macroautophagy related to αSyn aggregate and accumulated ferritin degradation. Inducible ferritinophagy has been suggested as a possible therapeutic to combat raised ferritin levels and reinstate iron homeostasis however this may lead to increased ferroptosis. Despite limited knowledge of ferritinophagy induced ferroptosis in PD there is a possible link to neurodegeneration. This review aims to summarise the current understanding of the chemical interactions between iron and αSyn and possible binding affinities in biologically relevant models, while further highlighting αSyn's pathological role in neurodegeneration and aberrant iron homeostasis. Developing knowledge surrounding the complex interactions between αSyn and iron in PD will aid in possible therapeutic strategies to combat PD disease progression.

帕金森病（PD）中脑铁稳态与病理性α-突触核蛋白（αSyn）之间复杂的相互作用尚不清楚。αSyn是参与疾病进展的主要蛋白，并通过损害多巴胺合成、线粒体功能障碍和破坏脑铁稳态来促进细胞毒性。铁可以诱导αSyn聚集，但铁与αSyn相互作用的确切机制尚不清楚。许多研究表明PD的发病机制中存在铁稳态失衡，包括与αSyn聚集和铁蛋白降解相关的巨噬。诱导自噬铁蛋白已被认为是一种可能的治疗方法，以对抗升高的铁蛋白水平和恢复铁稳态，但这可能导致铁下沉增加。尽管对PD中铁蛋白吞噬引起的铁下垂的了解有限，但它可能与神经退行性变有关。本文旨在总结目前对铁与αSyn之间的化学相互作用以及在生物学相关模型中可能的结合亲和力的理解，同时进一步强调αSyn在神经变性和异常铁稳态中的病理作用。围绕PD中αSyn和铁之间复杂相互作用的知识的发展将有助于可能的治疗策略来对抗PD疾病的进展。

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