Neurochemistry international最新文献

Neuroprotective and anti-inflammatory effects of the RIPK3 inhibitor GSK872 in an MPTP-induced mouse model of Parkinson's disease RIPK3 抑制剂 GSK872 在 MPTP 诱导的帕金森病小鼠模型中的神经保护和抗炎作用。

IF 4.4 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Neurochemistry international

Pub Date : 2024-11-02 DOI: 10.1016/j.neuint.2024.105896

Parkinson's disease (PD) is a neurodegenerative disorder triggered by the loss of dopaminergic neurons in the substantia nigra (SN). Recent studies have demonstrated that necroptosis is involved in dopaminergic neuronal cell death and the resulting neuroinflammation. During the process of necroptosis, a necrosome complex is formed consisting of the proteins receptor-interacting protein kinase 1 (RIPK1), RIPK3, and mixed lineage kinase domain-like protein (MLKL). Although the neuroprotective effects of the RIPK1-specific inhibitor necrostatin-1, as well as RIPK3 and MLKL knockout in mice, have been described, the effects of RIPK3 pharmacological inhibitors have not yet been reported in animal models of PD. In the present study, we investigated the neuroprotective effects of GSK872, a specific RIPK3 inhibitor, in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of PD. GSK872 rescued MPTP-induced motor impairment and inhibited tyrosine hydroxylase-positive dopaminergic cell death in the SN and striatum. Additionally, GSK872 inhibited the MPTP-induced increase in the expression of p-RIPK3 and p-MLKL in both the dopaminergic neurons and microglia, as assessed by biochemical and histological analyses. GSK872 further inhibited microglial activation and the expression of inflammatory mediators including NLRP3, interleukin (IL)-1β, IL-6, tumor necrosis factor-alpha, and inducible nitric oxide synthase in the SN region of MPTP mice. Using in vitro experiments, we validated the effects of GSK872 on necroptosis in SH-SY5Y neuronal and BV2 microglial cells. Overall, our results suggest that GSK872 exerts neuroprotective and anti-inflammatory effects, and may thus have therapeutic potential for PD.

帕金森病（Parkinson's disease，PD）是一种神经退行性疾病，由黑质（substantia nigra，SN）中多巴胺能神经元的丧失引发。最近的研究表明，坏死蛋白沉积参与了多巴胺能神经细胞的死亡和由此引发的神经炎症。在坏死过程中，会形成一个由受体相互作用蛋白激酶 1（RIPK1）、RIPK3 和混合系激酶结构域样蛋白（MLKL）组成的坏死体复合物。虽然RIPK1特异性抑制剂necrostatin-1以及小鼠RIPK3和MLKL基因敲除具有神经保护作用，但RIPK3药理抑制剂在帕金森病动物模型中的作用尚未见报道。在本研究中，我们研究了特异性 RIPK3 抑制剂 GSK872 在 1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）诱导的帕金森病小鼠模型中的神经保护作用。GSK872 可挽救 MPTP 诱导的运动障碍，并抑制 SN 和纹状体中酪氨酸羟化酶阳性多巴胺能细胞的死亡。此外，根据生化和组织学分析，GSK872 还抑制了 MPTP 诱导的 p-RIPK3 和 p-MLKL 在多巴胺能神经元和小胶质细胞中的表达增加。GSK872 进一步抑制了 MPTP 小鼠 SN 区域的小胶质细胞活化和炎症介质（包括 NLRP3、白细胞介素 (IL)-1β、IL-6、肿瘤坏死因子-α 和诱导型一氧化氮合酶）的表达。通过体外实验，我们验证了 GSK872 对 SH-SY5Y 神经元和 BV2 小胶质细胞坏死的影响。总之，我们的研究结果表明，GSK872 具有神经保护和抗炎作用，因此可能具有治疗帕金森病的潜力。

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引用次数: 0

Altered sex differences related to food intake, hedonic preference, and FosB/deltaFosB expression within central neural circuit involved in homeostatic and hedonic food intake regulation in Shank3B mouse model of autism spectrum disorder 自闭症谱系障碍 Shank3B 小鼠模型中与食物摄入量、享乐偏好和 FosB/deltaFosB 表达有关的性别差异，这些神经回路参与食物摄入量的平衡调节和享乐调节。

IF 4.4 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Neurochemistry international

Pub Date : 2024-10-24 DOI: 10.1016/j.neuint.2024.105895

Autism spectrum disorder (ASD) is a neurodevelopmental disorder accompanied by narrow interests, difficulties in communication and social interaction, and repetitive behavior. In addition, ASD is frequently associated with eating and feeding problems. Although the symptoms of ASD are more likely to be observed in boys, the prevalence of eating disorders is more common in females. The ingestive behavior is regulated by the integrative system of the brain, which involves both homeostatic and hedonic neural circuits. Sex differences in the physiology of food intake depend on sex hormones regulating the expression of the ASD-associated Shank genes. Shank3 mutation leads to ASD-like traits and Shank3B −/− mice have been established as an animal model to study the neurobiology of ASD. Therefore, the long-lasting neuronal activity in the central neural circuit related to the homeostatic and hedonic regulation of food intake was evaluated in both sexes of Shank3B mice, followed by the evaluation of the food intake and preference. In the Shank3B +/+ genotype, well-preserved relationships in the tonic activity within the homeostatic neural network together with the relationships between ingestion and hedonic preference were observed in males but were reduced in females. These interrelations were partially or completely lost in the mice with the Shank3B −/− genotype. A decreased hedonic preference for the sweet taste but increased total food intake was found in the Shank3B −/− mice. In the Shank3B −/− group, there were altered sex differences related to the amount of tonic cell activity in the hedonic and homeostatic neural networks, together with altered sex differences in sweet and sweet-fat solution intake. Furthermore, the Shank3B −/− females exhibited an increased intake and preference for cheese compared to the Shank3B +/+ ones. The obtained data indicate altered functional crosstalk between the central homeostatic and hedonic neural circuits involved in the regulation of food intake in ASD.

自闭症谱系障碍（ASD）是一种神经发育障碍，伴有兴趣狭窄、沟通和社交困难以及重复行为。此外，自闭症还经常伴有进食和喂养问题。虽然男孩更容易出现 ASD 的症状，但进食障碍在女性中更为常见。进食行为受大脑综合系统的调节，该系统涉及平衡神经回路和享乐神经回路。食物摄入生理上的性别差异取决于性激素对 ASD 相关 Shank 基因表达的调控。Shank3 基因突变会导致类似 ASD 的特征，Shank3B -/- 小鼠已被确立为研究 ASD 神经生物学的动物模型。因此，我们评估了雌雄Shank3B小鼠中枢神经回路中与食物摄入的平衡性和享乐性调节相关的神经元长效活动，然后评估了食物摄入量和偏好。在 Shank3B +/+ 基因型小鼠中，可以观察到雄性小鼠平衡神经网络内的强直活动关系以及摄入与享乐偏好之间的关系，但雌性小鼠的这种关系有所减弱。在 Shank3B -/- 基因型的小鼠中，这些相互关系部分或完全消失。Shank3B -/-小鼠对甜味的享乐偏好降低，但总食物摄入量增加。在 Shank3B -/-组中，与享乐神经网络和平衡神经网络中的强直性细胞活动量有关的性别差异发生了改变，同时甜味和甜脂溶液摄入量的性别差异也发生了改变。此外，与 Shank3B +/+ 雌性相比，Shank3B -/- 雌性对奶酪的摄入量和偏好都有所增加。所获得的数据表明，参与 ASD 食物摄入调节的中枢平衡神经回路和享乐神经回路之间的功能串扰发生了改变。

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引用次数: 0

Discriminating fingerprints of chronic neuropathic pain following spinal cord injury using artificial neural networks and mass spectrometry analysis of female mice serum 利用人工神经网络和雌性小鼠血清质谱分析鉴别脊髓损伤后慢性神经病理性疼痛的指纹。

IF 4.4 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Neurochemistry international

Pub Date : 2024-10-23 DOI: 10.1016/j.neuint.2024.105890

Spinal cord injury (SCI) often leads to central neuropathic pain, a condition associated with significant morbidity and is challenging in terms of the clinical management. Despite extensive efforts, identifying effective biomarkers for neuropathic pain remains elusive. Here we propose a novel approach combining matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) with artificial neural networks (ANNs) to discriminate between mass spectral profiles associated with chronic neuropathic pain induced by SCI in female mice. Functional evaluations revealed persistent chronic neuropathic pain following mild SCI as well as minor locomotor disruptions, confirming the value of collecting serum samples. Mass spectra analysis revealed distinct profiles between chronic SCI and sham controls. On applying ANNs, 100% success was achieved in distinguishing between the two groups through the intensities of m/z peaks. Additionally, the ANNs also successfully discriminated between chronic and acute SCI phases. When reflexive pain response data was integrated with mass spectra, there was no improvement in the classification. These findings offer insights into neuropathic pain pathophysiology and underscore the potential of MALDI-TOF MS coupled with ANNs as a diagnostic tool for chronic neuropathic pain, potentially guiding attempts to discover biomarkers and develop treatments.

脊髓损伤（SCI）通常会导致中枢神经病理痛，这种病症与严重的发病率有关，而且在临床治疗方面具有挑战性。尽管做出了大量努力，但确定神经病理性疼痛的有效生物标记物仍然遥遥无期。在这里，我们提出了一种结合基质辅助激光解吸/电离飞行时间质谱（MALDI-TOF MS）和人工神经网络（ANNs）的新方法，用于区分与雌性小鼠因脊髓损伤诱发的慢性神经性疼痛相关的质谱图谱。功能评估显示，轻度 SCI 后会出现持续性慢性神经病理性疼痛以及轻微的运动障碍，这证实了采集血清样本的价值。质谱分析揭示了慢性 SCI 和假对照组之间的不同特征。在应用 ANNs 时，通过 m/z 峰的强度区分两组的成功率达到了 100%。此外，ANN 还成功区分了慢性和急性 SCI 阶段。当反射性疼痛反应数据与质谱数据整合时，分类效果没有改善。这些发现提供了对神经病理性疼痛病理生理学的见解，并强调了 MALDI-TOF MS 与 ANNs 结合作为慢性神经病理性疼痛诊断工具的潜力，有可能为发现生物标记物和开发治疗方法提供指导。

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引用次数: 0

Neuron-selective and activity-dependent splicing of BDNF exon I–IX pre-mRNA BDNF外显子I-IX前mRNA的神经元选择性和活动依赖性剪接。

IF 4.4 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Neurochemistry international

Pub Date : 2024-10-23 DOI: 10.1016/j.neuint.2024.105889

Brain-derived neurotrophic factor (BDNF) is essential for numerous neuronal functions, including learning and memory. The expression of BDNF is regulated by distinctive transcriptional and post-transcriptional mechanisms. The Bdnf gene in mice and rats comprises eight untranslated exons (exons I–VIII) and one exon (exon IX) that contains the pre-proBDNF coding sequence. Multiple splice donor sites on the untranslated exons and a single acceptor site upstream of the coding sequence result in the characteristic exon skipping patterns that generate multiple Bdnf mRNA variants, which are essential for the spatiotemporal regulation of BDNF expression, mRNA localization, mRNA stability, and translational control. However, the regulation of Bdnf pre-mRNA splicing remains unclear. Here, we focused on the splicing of Bdnf exon I–IX pre-mRNA. We first constructed a minigene to evaluate Bdnf exon I–IX pre-mRNA splicing. Compared with Bdnf exon I–IX pre-mRNA splicing in non-neuronal NIH3T3 cells, splicing was preferentially observed in primary cultures of cortical neurons. Additionally, a series of overexpression and knockdown experiments suggested that neuro-oncological ventral antigen (NOVA) 2 is involved in the neuron-selective splicing of Bdnf exon I–IX pre-mRNA. Supporting this finding, endogenous Nova2 mRNA expression was markedly higher in neurons, and a strong correlation between endogenous Bdnf exon I–IX and Nova2 mRNA was observed across several brain regions. Furthermore, Bdnf exon I–IX pre-mRNA splicing was facilitated by Ca²⁺ signals evoked via L-type voltage-dependent Ca²⁺ channels. Notably, among the Bdnf pre-mRNA splicing investigated in the current study, neuron-selective and activity-dependent splicing was observed in Bdnf exon I–IX pre-mRNA. In conclusion, Bdnf exon I-IX pre-mRNA splicing is preferentially observed in neurons and is facilitated in an activity-dependent manner. The neuron-selective and activity-dependent splicing of Bdnf exon I–IX pre-mRNA may contribute to the efficient induction of Bdnf exon I–IX expression in neurons.

脑源性神经营养因子（BDNF）对包括学习和记忆在内的多种神经元功能至关重要。BDNF 的表达受独特的转录和转录后机制调控。小鼠和大鼠的 Bdnf 基因由八个非翻译外显子（外显子 I-VIII）和一个包含前前导 BDNF 编码序列的外显子（外显子 IX）组成。非翻译外显子上的多个剪接供体位点和编码序列上游的一个受体位点导致了特征性的外显子跳接模式，从而产生了多个 Bdnf mRNA 变体，这些变体对于 BDNF 的表达、mRNA 定位、mRNA 稳定性和翻译控制的时空调控至关重要。然而，Bdnf前mRNA剪接的调控仍不清楚。在这里，我们重点研究了Bdnf外显子-I-IX前mRNA的剪接。我们首先构建了一个迷你基因来评估Bdnf外显子I-IX前mRNA的剪接。与非神经元NIH3T3细胞中的Bdnf外显子I-IX前mRNA剪接相比，在皮层神经元的原代培养物中更容易观察到剪接。此外，一系列过表达和基因敲除实验表明，神经肿瘤腹侧抗原（NOVA）2参与了Bdnf外显子I-IX前mRNA的神经元选择性剪接。支持这一发现的是，内源性 Nova2 mRNA 在神经元中的表达明显较高，而且在多个脑区观察到内源性 Bdnf 外显子-I-X 和 Nova2 mRNA 之间存在很强的相关性。此外，通过 L 型电压依赖性 Ca2+ 通道诱发的 Ca2+ 信号促进了 Bdnf 外显子-I-X 预 mRNA 的剪接。值得注意的是，在本研究调查的Bdnf前mRNA剪接中，在Bdnf外显子I-IX前mRNA中观察到了神经元选择性和活动依赖性剪接。总之，Bdnf外显子I-IX前mRNA剪接优先在神经元中观察到，并以活动依赖的方式促进。Bdnf外显子I-IX前mRNA的神经元选择性和活动依赖性剪接可能有助于有效诱导Bdnf外显子I-IX在神经元中的表达。

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引用次数: 0

Supplemental oxygen alters the pentose phosphate pathway in the developing mouse brain through SIRT signaling 补充氧气可通过 SIRT 信号改变发育中小鼠大脑中的五糖磷酸途径

IF 4.4 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Neurochemistry international

Pub Date : 2024-10-20 DOI: 10.1016/j.neuint.2024.105886

Oxygen support plays a critical role in the management of preterm infants in neonatal intensive care units. On the other hand, the possible effects of oxygen supplementation on cellular functions, specifically glucose metabolism, have been less understood.

Purpose

of the study is to investigate whether supplemental oxygen alters glucose metabolism and pentose phosphate pathway (PPP) activity in the brain tissue and its relevance with silent information regulator proteins (SIRT) pathway. For this purpose, newborn C57BL/6 pups were exposed to 90% oxygen from birth until postnatal day 7 (PN7) and metabolites of glysolysis and PPP were investigated through metabolomics analysis. SIRT1, glucose-6-phosphate dehydrogenase (G6PD) and transaldolase (TALDO) proteins were examined immunohistochemically and molecularly in the prefrontal and hippocampus regions of the brain. Later on, SIRT1 inhibition was carried out.

Our results indicate that supplemental oxygen causes an increase in PPP metabolites as well as activation of G6PD enzyme in the brain tissue, which is reversed by SIRT1 inhibition. Our study underlines a connection between supplemental oxygen, glucose metabolism, PPP pathway and the SIRT signaling. Understanding these intricate relationships not only deepens our knowledge of cellular physiology but also holds promise for therapeutic interventions for creating neuroprotective strategies in preterm brain.

氧气支持在新生儿重症监护室早产儿的管理中起着至关重要的作用。另一方面，人们对补氧对细胞功能，特别是葡萄糖代谢可能产生的影响了解较少。目的：本研究旨在探讨补充氧气是否会改变脑组织中的葡萄糖代谢和磷酸戊糖途径（PPP）活性及其与沉默信息调节蛋白（SIRT）途径的相关性。为此，新生 C57BL/6 幼崽从出生到出生后第 7 天（PN7）一直暴露在 90% 的氧气环境中，并通过代谢组学分析研究糖酵解和磷酸戊糖途径的代谢物。通过免疫组化和分子学方法检测了大脑前额叶和海马区的 SIRT1、葡萄糖-6-磷酸脱氢酶（G6PD）和转醛酸酶（TALDO）蛋白。随后进行了 SIRT1 抑制实验。我们的研究结果表明，补充氧气会导致 PPP 代谢物的增加以及脑组织中 G6PD 酶的激活，而抑制 SIRT1 则会逆转这种情况。我们的研究强调了补氧、葡萄糖代谢、PPP 途径和 SIRT 信号转导之间的联系。了解这些错综复杂的关系不仅能加深我们对细胞生理学的认识，还能为早产儿大脑神经保护策略的治疗干预带来希望。

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引用次数: 0

Reassessment of capsaicin desensitization in the rodent spinal dorsal horn 重新评估啮齿类动物脊髓背角的辣椒素脱敏。

IF 4.4 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Neurochemistry international

Pub Date : 2024-10-20 DOI: 10.1016/j.neuint.2024.105887

Capsaicin activates primary afferent transient receptor potential vanilloid 1 (TRPV1) in the spinal dorsal horn and induces exaggerated glutamate release. This capsaicin action is followed by a lasting refractory state referred to as “capsaicin desensitization”, which is considered a presynaptic event. In this study, using whole-cell recordings and holographic photostimulation, we reassessed this notion by investigating presynaptic glutamate release and the postsynaptic glutamate response during capsaicin administration. We found that both presynaptic synchronous glutamate release and the postsynaptic glutamate response were largely attenuated in this refractory state; in contrast, asynchronous release was exaggerated. Further behavioral studies revealed a quick increase in the mechanical pain threshold with intrathecal capsaicin administration. Taken together, both presynaptic synchronous glutamate release and the postsynaptic response are downregulated during capsaicin desensitization, and this desensitization may transiently increase the pain threshold. Since both presynaptic synchronous release and postsynaptic glutamate responses are attenuated, the traditional electrophysiological evidence supporting capsaicin desensitization as a presynaptic event should be reassessed.

辣椒素可激活脊髓背角的初级传入瞬时受体电位类香草素 1（TRPV1），并诱导谷氨酸的大量释放。这种辣椒素作用之后会出现一种持久的折射状态，被称为 "辣椒素脱敏"，它被认为是一种突触前事件。在本研究中，我们使用全细胞记录和全息光刺激，通过研究辣椒素给药期间突触前谷氨酸释放和突触后谷氨酸反应，重新评估了这一概念。我们发现，在这种难治性状态下，突触前同步谷氨酸释放和突触后谷氨酸反应在很大程度上被削弱；相反，异步释放被夸大。进一步的行为学研究表明，鞘内注射辣椒素可迅速提高机械痛阈。综上所述，在辣椒素脱敏过程中，突触前同步谷氨酸释放和突触后反应都被下调，这种脱敏可能会短暂提高痛阈。由于突触前同步释放和突触后谷氨酸反应都会减弱，支持辣椒素脱敏是突触前事件的传统电生理学证据应该重新评估。

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引用次数: 0

Apelin regulates mitochondrial dynamics by inhibiting Mst1-JNK-Drp1 signaling pathway to reduce neuronal apoptosis after spinal cord injury Apelin通过抑制Mst1-JNK-Drp1信号通路调节线粒体动力学，从而减少脊髓损伤后的神经细胞凋亡。

IF 4.4 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Neurochemistry international

Pub Date : 2024-10-19 DOI: 10.1016/j.neuint.2024.105885

In the secondary injury stage of spinal cord injury, mitochondrial dysfunction leads to decreased ATP production, increased ROS production, and activation of the mitochondria-mediated apoptosis signaling pathway. This ultimately intensifies neuronal death and promotes the progression of the injury. Apelin, a peptide produced by the APLN gene, has demonstrated promise in the treatment of spinal cord injury. The aim of this study was to investigate how Apelin protects neurons after spinal cord injury by influencing the mitochondrial dynamics. The results showed that Apelin has the ability to reduce mitochondrial fission, enhance the mitochondrial membrane potential, improve antioxidant capacity, facilitate the clearance of excess ROS, and ultimately decrease apoptosis in PC12 cells. Moreover, Apelin is overexpressed in neurons in the damaged part of the spinal cord, contributing to reduce mitochondrial fission, improve antioxidant capacity, increase ATP production, decrease apoptosis, promote spinal cord morphological repair, maintain the number of nissl bodies, and enhance signal transduction in the descending spinal cord pathway. Apelin exerts its protective effect by inhibiting the Mst1-JNK-Drp1 signaling pathway. In summary, our study further improved the effect of Apelin in the treatment of spinal cord injury, revealed the mechanism of Apelin in protecting damaged neurons after spinal cord injury by maintaining mitochondrial homeostasis, and provided a new therapeutic mechanism for Apelin in spinal cord injury.

在脊髓损伤的继发性损伤阶段，线粒体功能障碍会导致 ATP 生成减少、ROS 生成增加，并激活线粒体介导的细胞凋亡信号通路。这最终会加剧神经元的死亡，促进损伤的发展。Apelin是一种由APLN基因产生的多肽，在治疗脊髓损伤方面前景看好。本研究旨在探讨 Apelin 如何通过影响线粒体动力学来保护脊髓损伤后的神经元。结果表明，Apelin 能够减少 PC12 细胞线粒体分裂，增强线粒体膜电位，提高抗氧化能力，促进过量 ROS 的清除，并最终减少细胞凋亡。此外，Apelin 在脊髓受损部位的神经元中过表达，有助于减少线粒体分裂、提高抗氧化能力、增加 ATP 生成、减少细胞凋亡、促进脊髓形态修复、维持 nissl 体的数量以及增强脊髓下降通路的信号转导。Apelin通过抑制Mst1-JNK-Drp1信号通路发挥保护作用。综上所述，我们的研究进一步提高了Apelin治疗脊髓损伤的效果，揭示了Apelin通过维持线粒体平衡保护脊髓损伤后受损神经元的机制，为Apelin治疗脊髓损伤提供了新的治疗机制。

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引用次数: 0

Ras, RhoA, and vascular pharmacology in neurodevelopment and aging 神经发育和衰老中的 Ras、RhoA 和血管药理学。

IF 4.4 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Neurochemistry international

Pub Date : 2024-10-18 DOI: 10.1016/j.neuint.2024.105883

Small GTPases Ras, Rac, and RhoA are crucial regulators of cellular functions. They also act in dysregulated cell proliferation and transformation. Multiple publications have focused on illuminating their roles and mechanisms, including in immune system pathologies. Their functions in neurology-related diseases, neurodegeneration and neurodevelopment, are also emerging, as well as their potential as pharmacological targets in both pathologies. Observations increasingly suggest that these pathologies may relate to activation (or suppression) of signaling by members of the Ras superfamily, especially Ras, Rho, and Rac isoforms, and components of their signaling pathways. Germline (or embryonic) mutations that they harbor are responsible for neurodevelopmental disorders, such as RASopathies, autism spectrum disorder, and dilated cardiomyopathy. In aging, they promote neurodegenerative diseases, with Rho GTPase featuring in their pharmacology, as in the case of Alzheimer's disease (AD). Significantly, drugs with observed anti-AD activity, particularly those involved in cardiovascular systems, are associated with the RhoA signaling, as well as cerebral vasculature in brain development and aging. This leads us to suggest that anti-AD drugs could inform neurodevelopmental disorders, including pediatric low-grade gliomas pharmacology. Neurodevelopmental disorders associated with RhoA, like autism, are also connected with vascular systems, thus could be targets of vascular system-connected drugs.

小 GTP 酶 Ras、Rac 和 RhoA 是细胞功能的关键调节因子。它们还在细胞增殖和转化失调中发挥作用。已有多篇论文集中阐明了它们的作用和机制，包括在免疫系统病理学中的作用和机制。它们在神经系统相关疾病、神经变性和神经发育中的功能以及作为这两种病症的药物靶点的潜力也在不断涌现。越来越多的观察结果表明，这些病理现象可能与 Ras 超家族成员（尤其是 Ras、Rho 和 Rac 异构体）及其信号通路成分的信号激活（或抑制）有关。它们所携带的种系（或胚胎）突变是神经发育疾病的罪魁祸首，如 RAS 病、自闭症谱系障碍和扩张型心肌病。在衰老过程中，它们会促进神经退行性疾病的发生，Rho GTPase 在这些疾病的药理学中占有重要地位，阿尔茨海默病（AD）就是一例。值得注意的是，已观察到具有抗 AD 活性的药物，尤其是那些涉及心血管系统的药物，都与 RhoA 信号转导以及大脑发育和衰老过程中的脑血管有关。这使我们认为，抗 AD 药物可以为神经发育疾病（包括小儿低级别胶质瘤）的药理学提供信息。与RhoA有关的神经发育障碍，如自闭症，也与血管系统有关，因此可能成为与血管系统有关的药物的靶点。

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引用次数: 0

LASP1 in the nucleus accumbens modulates methamphetamine-induced conditioned place preference in mice 小鼠伏隔核中的 LASP1 可调节甲基苯丙胺诱导的条件性位置偏好。

IF 4.4 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Neurochemistry international

Pub Date : 2024-10-16 DOI: 10.1016/j.neuint.2024.105884

Methamphetamine (METH) is a highly addictive and widely abused drug that causes complex adaptive changes in the brain's reward system, such as the nucleus accumbens (NAc). LASP1 (LIM and SH 3 domain protein 1) as an actin-binding protein, regulates synaptic plasticity. However, the role and mechanism by which NAc LASP1 contributes to METH addiction remains unclear. In this study, adult male C57BL/6J mice underwent repeated METH exposure or METH-induced conditioned place preference (CPP). Western blotting and immunohistochemistry were used to determine LASP1 expression in the NAc. Furthermore, LASP1 knockdown or overexpression using adeno-associated virus (AAV) administration via stereotactic injection into the NAc was used to observe the corresponding effects on CPP. We found that repeated METH exposure and METH-induced CPP upregulated LASP1 expression in the NAc. LASP1 silencing in the NAc reversed METH-induced CPP and reduced PSD95, NR2A, and NR2B expression, whereas LASP1 overexpression in the NAc enhanced CPP acquisition, accompanied by increased PSD95, NR2A, and NR2B expression. Our findings demonstrate an important role of NAc LASP1 in modulating METH induced drug-seeking behavior and the underlying mechanism may be related to regulate the expression of synapse-associated proteins in the NAc. These results reveal a novel molecular regulator of the actions of METH on the NAc and provide a new strategy for treating METH addiction.

甲基苯丙胺（METH）是一种极易上瘾且被广泛滥用的药物，它会导致大脑奖赏系统（如纳氏核）发生复杂的适应性变化。LASP1（LIM 和 SH 3 结构域蛋白 1）是一种肌动蛋白结合蛋白，可调节突触的可塑性。然而，NAc LASP1在METH成瘾中的作用和机制仍不清楚。在这项研究中，成年雄性 C57BL/6J 小鼠接受了反复的 METH 暴露或 METH 诱导的条件性位置偏好（CPP）。研究采用了 Western 印迹和免疫组织化学方法来确定 LASP1 在 NAc 中的表达。此外，我们还使用腺相关病毒（AAV）通过立体定向注射到 NAc 来敲除或过表达 LASP1，以观察其对 CPP 的相应影响。我们发现，重复暴露 METH 和 METH 诱导的 CPP 会上调 NAc 中 LASP1 的表达。在NAc中沉默LASP1可逆转METH诱导的CPP，并减少PSD95、NR2A和NR2B的表达，而在NAc中过表达LASP1可增强CPP的获得，同时增加PSD95、NR2A和NR2B的表达。我们的研究结果表明，NAc LASP1 在调节 METH 诱导的觅药行为中起着重要作用，其潜在机制可能与调节 NAc 中突触相关蛋白的表达有关。这些结果揭示了 METH 对 NAc 作用的新型分子调节因子，为治疗 METH成瘾提供了新策略。

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引用次数: 0

Changes in reactive oxygen species and autofluorescence under hypoxia at the hippocampal CA3 area: Role of calcium and zinc influxes 缺氧条件下海马 CA3 区活性氧和自发荧光的变化：钙和锌流入的作用

IF 4.4 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Neurochemistry international

Pub Date : 2024-10-15 DOI: 10.1016/j.neuint.2024.105882

Reactive oxygen species (ROS) have an important role in cellular biology, being involved, in a way that depends on their levels, in cell signaling processes or in oxidative stress, probably associated with neurodegenerative and other diseases. Most of the studies about ROS formation were performed in ischemic conditions, and thus, there is limited knowledge about ROS formation in less severe hypoxic conditions. This study investigates neuronal ROS generation and autofluorescence changes in hypoxic conditions, focusing on the involvement of calcium and zinc. Using hippocampal slices from Wistar rats, ROS production was monitored by the permeant fluorescent indicator H₂DCFDA under different oxygenation levels. Moderate hypoxia (40% O₂) led to a small ROS increase, while severe hypoxia (0% O₂) showed a more pronounced rise. KCl-induced depolarization significantly enhanced ROS formation, particularly under severe hypoxia. Inhibition of NMDA receptors reduced ROS generation without affecting autofluorescence, while chelation of zinc ions decreased ROS production and increased flavin adenine dinucleotide (FAD) autofluorescence. These findings suggest that, in hypoxic conditions, ROS formation is mediated by calcium entry through NMDA receptors and also by zinc influxes. Thus, these ions play a crucial role in oxidative stress, which may be related with neurodegenerative diseases associated with ROS dysregulation.

活性氧（ROS）在细胞生物学中发挥着重要作用，根据其含量参与细胞信号传导过程或氧化应激，可能与神经退行性疾病和其他疾病有关。大多数有关 ROS 形成的研究都是在缺血条件下进行的，因此对缺氧程度较轻条件下的 ROS 形成了解有限。本研究调查了缺氧条件下神经元 ROS 的生成和自发荧光的变化，重点关注钙和锌的参与。使用 Wistar 大鼠的海马切片，在不同氧合水平下通过渗透性荧光指示剂 H2DCFDA 监测 ROS 的产生。中度缺氧（40% O2）导致 ROS 少量增加，而严重缺氧（0% O2）则导致 ROS 明显增加。KCl 诱导的去极化显著增强了 ROS 的形成，尤其是在严重缺氧的情况下。抑制 NMDA 受体可减少 ROS 的产生，但不会影响自发荧光，而锌离子螯合可减少 ROS 的产生并增加黄素腺嘌呤二核苷酸（FAD）的自发荧光。这些发现表明，在缺氧条件下，ROS 的形成是通过 NMDA 受体的钙离子进入和锌离子流入介导的。因此，这些离子在氧化应激中起着至关重要的作用，而氧化应激可能与 ROS 失调相关的神经退行性疾病有关。

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