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Targeting harmful effects of non-excitatory amino acids as an alternative therapeutic strategy to reduce ischemic damage. 将非兴奋性氨基酸的有害作用作为减少缺血性损伤的替代治疗策略。
IF 5.9 2区 医学 Q2 CELL BIOLOGY Pub Date : 2025-09-01 Epub Date: 2024-09-24 DOI: 10.4103/NRR.NRR-D-24-00536
Victoria Jiménez Carretero, Iris Álvarez-Merz, Jorge Hernández-Campano, Sergei A Kirov, Jesús M Hernández-Guijo

The involvement of the excitatory amino acids glutamate and aspartate in cerebral ischemia and excitotoxicity is well-documented. Nevertheless, the role of non-excitatory amino acids in brain damage following a stroke or brain trauma remains largely understudied. The release of amino acids by necrotic cells in the ischemic core may contribute to the expansion of the penumbra. Our findings indicated that the reversible loss of field excitatory postsynaptic potentials caused by transient hypoxia became irreversible when exposed to a mixture of just four non-excitatory amino acids (L-alanine, glycine, L-glutamine, and L-serine) at their plasma concentrations. These amino acids induce swelling in the somas of neurons and astrocytes during hypoxia, along with permanent dendritic damage mediated by N-methyl-D-aspartate receptors. Blocking N-methyl-D-aspartate receptors prevented neuronal damage in the presence of these amino acids during hypoxia. It is likely that astroglial swelling caused by the accumulation of these amino acids via the alanine-serine-cysteine transporter 2 exchanger and system N transporters activates volume-regulated anion channels, leading to the release of excitotoxins and subsequent neuronal damage through N-methyl-D-aspartate receptor activation. Thus, previously unrecognized mechanisms involving non-excitatory amino acids may contribute to the progression and expansion of brain injury in neurological emergencies such as stroke and traumatic brain injury. Understanding these pathways could highlight new therapeutic targets to mitigate brain injury.

兴奋性氨基酸谷氨酸和天冬氨酸在脑缺血和兴奋性毒性中的作用已得到充分证实。然而,非兴奋性氨基酸在中风或脑外伤后脑损伤中的作用在很大程度上仍未得到充分研究。缺血核心坏死细胞释放的氨基酸可能会导致半影扩大。我们的研究结果表明,当暴露于四种非兴奋性氨基酸(L-丙氨酸、甘氨酸、L-谷氨酰胺和 L-丝氨酸)的血浆浓度混合物时,瞬时缺氧引起的场兴奋性突触后电位的可逆性丧失变得不可逆。缺氧时,这些氨基酸会诱发神经元和星形胶质细胞的体细胞肿胀,并由 N-甲基-D-天冬氨酸受体介导造成永久性树突损伤。阻断 N-甲基-D-天冬氨酸受体可防止神经元在缺氧时因这些氨基酸的存在而受损。这些氨基酸通过丙氨酸-丝氨酸-半胱氨酸转运体 2 交换器和 N 系统转运体积聚引起的星形胶质细胞肿胀可能激活了体积调节阴离子通道,导致兴奋性毒素的释放,进而通过 N-甲基-D-天冬氨酸受体的激活造成神经元损伤。因此,以前未认识到的涉及非兴奋性氨基酸的机制可能会导致中风和创伤性脑损伤等神经系统急症中脑损伤的进展和扩大。了解这些途径可以突出减轻脑损伤的新治疗目标。
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引用次数: 0
Decreased levels of phosphorylated synuclein in plasma are correlated with poststroke cognitive impairment. 血浆中磷酸化突触核蛋白水平的降低与脑卒中后的认知障碍有关。
IF 5.9 2区 医学 Q2 CELL BIOLOGY Pub Date : 2025-09-01 Epub Date: 2024-06-03 DOI: 10.4103/NRR.NRR-D-23-01348
Yi Wang, Yuning Li, Yakun Gu, Wei Ma, Yuying Guan, Mengyuan Guo, Qianqian Shao, Xunming Ji, Jia Liu

JOURNAL/nrgr/04.03/01300535-202509000-00022/figure1/v/2024-11-05T132919Z/r/image-tiff Poststroke cognitive impairment is a major secondary effect of ischemic stroke in many patients; however, few options are available for the early diagnosis and treatment of this condition. The aims of this study were to (1) determine the specific relationship between hypoxic and α-synuclein during the occur of poststroke cognitive impairment and (2) assess whether the serum phosphorylated α-synuclein level can be used as a biomarker for poststroke cognitive impairment. We found that the phosphorylated α-synuclein level was significantly increased and showed pathological aggregation around the cerebral infarct area in a mouse model of ischemic stroke. In addition, neuronal α-synuclein phosphorylation and aggregation were observed in the brain tissue of mice subjected to chronic hypoxia, suggesting that hypoxia is the underlying cause of α-synuclein-mediated pathology in the brains of mice with ischemic stroke. Serum phosphorylated α-synuclein levels in patients with ischemic stroke were significantly lower than those in healthy subjects, and were positively correlated with cognition levels in patients with ischemic stroke. Furthermore, a decrease in serum high-density lipoprotein levels in stroke patients was significantly correlated with a decrease in phosphorylated α-synuclein levels. Although ischemic stroke mice did not show significant cognitive impairment or disrupted lipid metabolism 14 days after injury, some of them exhibited decreased cognitive function and reduced phosphorylated α-synuclein levels. Taken together, our results suggest that serum phosphorylated α-synuclein is a potential biomarker for poststroke cognitive impairment.

摘要:脑卒中后认知功能障碍是缺血性脑卒中对许多患者造成的主要继发性影响;然而,对这种情况的早期诊断和治疗却鲜有可选方案。本研究的目的是:(1)确定脑卒中后认知障碍发生过程中缺氧与α-突触核蛋白之间的具体关系;(2)评估血清磷酸化α-突触核蛋白水平是否可用作脑卒中后认知障碍的生物标志物。我们发现,在缺血性脑卒中小鼠模型中,磷酸化α-突触核蛋白水平显著升高,并在脑梗死区周围出现病理性聚集。此外,在长期缺氧的小鼠脑组织中观察到神经元α-突触核蛋白磷酸化和聚集,这表明缺氧是缺血性脑卒中小鼠脑中α-突触核蛋白介导的病理变化的根本原因。缺血性中风患者的血清磷酸化α-突触核蛋白水平明显低于健康人,并且与缺血性中风患者的认知水平呈正相关。此外,中风患者血清中高密度脂蛋白水平的降低与磷酸化α-突触核蛋白水平的降低呈显著相关。虽然缺血性脑卒中小鼠在损伤 14 天后未表现出明显的认知功能障碍或脂质代谢紊乱,但其中一些小鼠表现出认知功能下降和磷酸化 α-突触核蛋白水平降低。综上所述,我们的研究结果表明,血清磷酸化α-突触核蛋白是中风后认知障碍的潜在生物标志物。
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引用次数: 0
Small molecule inhibitor DDQ-treated hippocampal neuronal cells show improved neurite outgrowth and synaptic branching. 小分子抑制剂 DDQ 处理的海马神经元细胞显示神经元突起生长和突触分支得到改善。
IF 5.9 2区 医学 Q2 CELL BIOLOGY Pub Date : 2025-09-01 Epub Date: 2024-06-19 DOI: 10.4103/NRR.NRR-D-24-00157
Jangampalli Adi Pradeepkiran, Priyanka Rawat, Arubala P Reddy, Erika Orlov, P Hemachandra Reddy

JOURNAL/nrgr/04.03/01300535-202509000-00024/figure1/v/2024-11-05T132919Z/r/image-tiff The process of neurite outgrowth and branching is a crucial aspect of neuronal development and regeneration. Axons and dendrites, sometimes referred to as neurites, are extensions of a neuron's cellular body that are used to start networks. Here we explored the effects of diethyl (3,4-dihydroxyphenethylamino)(quinolin-4-yl) methylphosphonate (DDQ) on neurite developmental features in HT22 neuronal cells. In this work, we examined the protective effects of DDQ on neuronal processes and synaptic outgrowth in differentiated HT22 cells expressing mutant Tau (mTau) cDNA. To investigate DDQ characteristics, cell viability, biochemical, molecular, western blotting, and immunocytochemistry were used. Neurite outgrowth is evaluated through the segmentation and measurement of neural processes. These neural processes can be seen and measured with a fluorescence microscope by manually tracing and measuring the length of the neurite growth. These neuronal processes can be observed and quantified with a fluorescent microscope by manually tracing and measuring the length of the neuronal HT22. DDQ-treated mTau-HT22 cells (HT22 cells transfected with cDNA mutant Tau) were seen to display increased levels of synaptophysin, MAP-2, and β-tubulin. Additionally, we confirmed and noted reduced levels of both total and p-Tau, as well as elevated levels of microtubule-associated protein 2, β-tubulin, synaptophysin, vesicular acetylcholine transporter, and the mitochondrial biogenesis protein-peroxisome proliferator-activated receptor-gamma coactivator-1α. In mTau-expressed HT22 neurons, we observed DDQ enhanced the neurite characteristics and improved neurite development through increased synaptic outgrowth. Our findings conclude that mTau-HT22 (Alzheimer's disease) cells treated with DDQ have functional neurite developmental characteristics. The key finding is that, in mTau-HT22 cells, DDQ preserves neuronal structure and may even enhance nerve development function with mTau inhibition.

摘要:神经元的生长和分支过程是神经元发育和再生的一个重要方面。轴突和树突有时被称为神经元,是神经元细胞体的延伸,用于启动网络。在这里,我们探讨了(3,4-二羟基苯乙胺)(喹啉-4-基)甲基膦酸二乙酯(DDQ)对 HT22 神经元细胞神经元发育特征的影响。在这项工作中,我们研究了 DDQ 对表达突变型 Tau(mTau)cDNA 的分化 HT22 细胞的神经元过程和突触生长的保护作用。为了研究 DDQ 的特性,我们使用了细胞活力、生化、分子、Western 印迹和免疫细胞化学等方法。神经元生长是通过神经过程的分割和测量来评估的。使用荧光显微镜可通过手动追踪和测量神经元生长的长度来观察和测量这些神经过程。通过手动追踪和测量神经元 HT22 的长度,可以用荧光显微镜观察和量化这些神经元过程。经 DDQ 处理的 mTau-HT22 细胞(转染了 cDNA 突变体 Tau 的 HT22 细胞)显示突触素、MAP-2 和 β-tubulin 水平升高。此外,我们还证实并注意到总 Tau 和 p-Tau 水平降低,微管相关蛋白 2、β-tubulin、突触素、囊泡乙酰胆碱转运体和线粒体生物生成蛋白-过氧化物酶体增殖激活受体-gamma 辅激活剂-1α 水平升高。在表达 mTau 的 HT22 神经元中,我们观察到 DDQ 通过增加突触生长增强了神经元特征并改善了神经元发育。我们的研究结果表明,经 DDQ 处理的 mTau-HT22(阿尔茨海默病)细胞具有功能性神经元发育特征。关键的发现是,在 mTau-HT22 细胞中,DDQ 可保护神经元结构,甚至可能通过抑制 mTau 增强神经发育功能。
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引用次数: 0
Apples to oranges: environmentally derived, dynamic regulation of serotonin neuron subpopulations in adulthood? 苹果与橘子:成年期血清素神经元亚群的环境衍生动态调控?
IF 5.9 2区 医学 Q2 CELL BIOLOGY Pub Date : 2025-09-01 Epub Date: 2024-09-24 DOI: 10.4103/NRR.NRR-D-24-00507
Christopher J O'Connell, Matthew J Robson
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引用次数: 0
Soluble epoxide hydrolase: a next-generation drug target for Alzheimer's disease and related dementias. 可溶性环氧化物水解酶:治疗阿尔茨海默病和相关痴呆症的新一代药物靶点。
IF 5.9 2区 医学 Q2 CELL BIOLOGY Pub Date : 2025-09-01 Epub Date: 2024-09-06 DOI: 10.4103/NRR.NRR-D-24-00503
Andrew Gregory, Chengyun Tang, Fan Fan
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引用次数: 0
Syndecans in Alzheimer's disease: pathogenetic mechanisms and potential therapeutic targets. 阿尔茨海默病中的突变蛋白:发病机制和潜在治疗目标。
IF 5.9 2区 医学 Q2 CELL BIOLOGY Pub Date : 2025-09-01 Epub Date: 2024-09-24 DOI: 10.4103/NRR.NRR-D-24-00659
Carmela Rita Balistreri, Roberto Monastero
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引用次数: 0
Spinal cord injury regenerative therapy development: integration of design of experiments. 脊髓损伤再生疗法的开发:实验设计的整合。
IF 5.9 2区 医学 Q2 CELL BIOLOGY Pub Date : 2025-09-01 Epub Date: 2024-07-29 DOI: 10.4103/NRR.NRR-D-24-00553
Yuji Okano, Hideyuki Okano, Yoshitaka Kase
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引用次数: 0
Glucocorticoid receptor signaling in the brain and its involvement in cognitive function. 大脑中的糖皮质激素受体信号转导及其在认知功能中的参与。
IF 5.9 2区 医学 Q2 CELL BIOLOGY Pub Date : 2025-09-01 Epub Date: 2024-09-06 DOI: 10.4103/NRR.NRR-D-24-00355
Chonglin Su, Taiqi Huang, Meiyu Zhang, Yanyu Zhang, Yan Zeng, Xingxing Chen

The hypothalamic-pituitary-adrenal axis regulates the secretion of glucocorticoids in response to environmental challenges. In the brain, a nuclear receptor transcription factor, the glucocorticoid receptor, is an important component of the hypothalamic-pituitary-adrenal axis's negative feedback loop and plays a key role in regulating cognitive equilibrium and neuroplasticity. The glucocorticoid receptor influences cognitive processes, including glutamate neurotransmission, calcium signaling, and the activation of brain-derived neurotrophic factor-mediated pathways, through a combination of genomic and non-genomic mechanisms. Protein interactions within the central nervous system can alter the expression and activity of the glucocorticoid receptor, thereby affecting the hypothalamic-pituitary-adrenal axis and stress-related cognitive functions. An appropriate level of glucocorticoid receptor expression can improve cognitive function, while excessive glucocorticoid receptors or long-term exposure to glucocorticoids may lead to cognitive impairment. Patients with cognitive impairment-associated diseases, such as Alzheimer's disease, aging, depression, Parkinson's disease, Huntington's disease, stroke, and addiction, often present with dysregulation of the hypothalamic-pituitary-adrenal axis and glucocorticoid receptor expression. This review provides a comprehensive overview of the functions of the glucocorticoid receptor in the hypothalamic-pituitary-adrenal axis and cognitive activities. It emphasizes that appropriate glucocorticoid receptor signaling facilitates learning and memory, while its dysregulation can lead to cognitive impairment. This provides clues about how glucocorticoid receptor signaling can be targeted to overcome cognitive disability-related disorders.

下丘脑-垂体-肾上腺轴调节糖皮质激素的分泌,以应对环境挑战。在大脑中,核受体转录因子糖皮质激素受体是下丘脑-垂体-肾上腺轴负反馈环路的重要组成部分,在调节认知平衡和神经可塑性方面起着关键作用。糖皮质激素受体通过基因组和非基因组机制的结合影响认知过程,包括谷氨酸神经传递、钙信号传导和脑源性神经营养因子介导途径的激活。中枢神经系统内的蛋白质相互作用可改变糖皮质激素受体的表达和活性,从而影响下丘脑-垂体-肾上腺轴和与压力有关的认知功能。适当水平的糖皮质激素受体表达可改善认知功能,而过多的糖皮质激素受体或长期暴露于糖皮质激素可导致认知功能损害。与认知障碍相关的疾病,如阿尔茨海默病、衰老、抑郁症、帕金森氏病、亨廷顿氏病、中风和成瘾等,患者通常表现为下丘脑-垂体-肾上腺轴和糖皮质激素受体表达失调。本综述全面概述了糖皮质激素受体在下丘脑-垂体-肾上腺轴和认知活动中的功能。它强调,适当的糖皮质激素受体信号传导有利于学习和记忆,而其失调则会导致认知障碍。这为如何针对糖皮质激素受体信号传递克服认知障碍相关疾病提供了线索。
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引用次数: 0
Cellular models of stress resistance may pave ways to fight neurodegenerative diseases. 抗应激的细胞模型可为抗击神经退行性疾病铺平道路。
IF 5.9 2区 医学 Q2 CELL BIOLOGY Pub Date : 2025-09-01 Epub Date: 2024-09-24 DOI: 10.4103/NRR.NRR-D-24-00476
Thu Nguyen Minh Pham, Christian Behl
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引用次数: 0
Treadmill exercise in combination with acousto-optic and olfactory stimulation improves cognitive function in APP/PS1 mice through the brain-derived neurotrophic factor- and Cygb-associated signaling pathways. 跑步机运动与声光和嗅觉刺激相结合,可通过脑源性神经营养因子和Cygb相关信号通路改善APP/PS1小鼠的认知功能。
IF 5.9 2区 医学 Q2 CELL BIOLOGY Pub Date : 2025-09-01 Epub Date: 2024-07-29 DOI: 10.4103/NRR.NRR-D-23-01681
Biao Xiao, Chaoyang Chu, Zhicheng Lin, Tianyuan Fang, Yuyu Zhou, Chuxia Zhang, Jianghui Shan, Shiyu Chen, Liping Li
<p><p>JOURNAL/nrgr/04.03/01300535-202509000-00031/figure1/v/2024-11-05T132919Z/r/image-tiff A reduction in adult neurogenesis is associated with behavioral abnormalities in patients with Alzheimer's disease. Consequently, enhancing adult neurogenesis represents a promising therapeutic approach for mitigating disease symptoms and progression. Nonetheless, non-pharmacological interventions aimed at inducing adult neurogenesis are currently limited. Although individual non-pharmacological interventions, such as aerobic exercise, acousto-optic stimulation, and olfactory stimulation, have shown limited capacity to improve neurogenesis and cognitive function in patients with Alzheimer's disease, the therapeutic effect of a strategy that combines these interventions has not been fully explored. In this study, we observed an age-dependent decrease in adult neurogenesis and a concurrent increase in amyloid-beta accumulation in the hippocampus of amyloid precursor protein/presenilin 1 mice aged 2-8 months. Amyloid deposition became evident at 4 months, while neurogenesis declined by 6 months, further deteriorating as the disease progressed. However, following a 4-week multifactor stimulation protocol, which encompassed treadmill running (46 min/d, 10 m/min, 6 days per week), 40 Hz acousto-optic stimulation (1 hour/day, 6 days/week), and olfactory stimulation (1 hour/day, 6 days/week), we found a significant increase in the number of newborn cells (5'-bromo-2'-deoxyuridine-positive cells), immature neurons (doublecortin-positive cells), newborn immature neurons (5'-bromo-2'-deoxyuridine-positive/doublecortin-positive cells), and newborn astrocytes (5'-bromo-2'-deoxyuridine-positive/glial fibrillary acidic protein-positive cells). Additionally, the amyloid-beta load in the hippocampus decreased. These findings suggest that multifactor stimulation can enhance adult hippocampal neurogenesis and mitigate amyloid-beta neuropathology in amyloid precursor protein/presenilin 1 mice. Furthermore, cognitive abilities were improved, and depressive symptoms were alleviated in amyloid precursor protein/presenilin 1 mice following multifactor stimulation, as evidenced by Morris water maze, novel object recognition, forced swimming test, and tail suspension test results. Notably, the efficacy of multifactor stimulation in consolidating immature neurons persisted for at least 2 weeks after treatment cessation. At the molecular level, multifactor stimulation upregulated the expression of neuron-related proteins (NeuN, doublecortin, postsynaptic density protein-95, and synaptophysin), anti-apoptosis-related proteins (Bcl-2 and PARP), and an autophagy-associated protein (LC3B), while decreasing the expression of apoptosis-related proteins (BAX and caspase-9), in the hippocampus of amyloid precursor protein/presenilin 1 mice. These observations might be attributable to both the brain-derived neurotrophic factor-mediated signaling pathway and antioxidant pathways. Furthermore,
成体神经发生的减少与阿尔茨海默病患者的行为异常有关。因此,增强成体神经发生是缓解疾病症状和进展的一种很有前景的治疗方法。然而,目前旨在诱导成体神经发生的非药物干预措施还很有限。虽然有氧运动、声光刺激和嗅觉刺激等单独的非药物干预措施在改善阿尔茨海默病患者的神经发生和认知功能方面显示出了有限的能力,但将这些干预措施结合起来的策略的治疗效果尚未得到充分探索。在这项研究中,我们观察到,2-8 个月大的淀粉样前体蛋白/淀粉样前体蛋白 1 小鼠海马中,成年神经发生的减少与年龄有关,同时淀粉样蛋白-β的积累也在增加。淀粉样蛋白沉积在小鼠4个月大时开始显现,而神经发生在6个月大时开始下降,并随着病情的发展而进一步恶化。然而,经过为期4周的多因素刺激方案,包括跑步机跑步(46分钟/天,10米/分钟,每周6天)、40赫兹声光刺激(1小时/天,6天/周)和嗅觉刺激(1小时/天,6天/周)、我们发现新生细胞(5'-溴-2'-脱氧尿苷阳性细胞)、未成熟神经元(双皮质素阳性细胞)、新生未成熟神经元(5'-溴-2'-脱氧尿苷阳性/双皮质素阳性细胞)和新生星形胶质细胞(5'-溴-2'-脱氧尿苷阳性/胶质纤维酸性蛋白阳性细胞)的数量明显增加。此外,海马中的淀粉样蛋白-β负荷也有所下降。这些研究结果表明,多因素刺激可以增强淀粉样前体蛋白/presenilin 1小鼠的成年海马神经发生,减轻淀粉样蛋白-β神经病理学。此外,通过莫里斯水迷宫、新物体识别、强迫游泳测试和悬尾测试结果,淀粉样前体蛋白/前体蛋白1小鼠的认知能力得到了改善,抑郁症状也得到了缓解。值得注意的是,多因素刺激在巩固未成熟神经元方面的疗效在治疗停止后至少持续两周。在分子水平上,多因素刺激可上调淀粉样前体蛋白/早老素1小鼠海马中神经元相关蛋白(NeuN、双皮质素、突触后密度蛋白-95和突触素)、抗凋亡相关蛋白(Bcl-2和PARP)以及自噬相关蛋白(LC3B)的表达,同时降低凋亡相关蛋白(BAX和caspase-9)的表达。这些观察结果可能归因于脑源性神经营养因子介导的信号通路和抗氧化通路。此外,血清代谢组学分析表明,多因素刺激调节了与细胞凋亡、氧化损伤和认知相关的不同表达代谢物。总之,这些研究结果表明,多因素刺激是预防和治疗阿尔茨海默病的一种新型非侵入性方法。
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引用次数: 0
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Neural Regeneration Research
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