Experimental Neurology最新文献_第9页

Novel PREP ligand, HUP-46, ameliorates behavioral deficits in an alpha-synuclein based Parkinson's disease model 新型PREP配体HUP-46改善了基于α -突触核蛋白的帕金森病模型中的行为缺陷。

IF 4.2 2区医学 Q1 NEUROSCIENCES

Experimental Neurology

Pub Date : 2025-12-11 DOI: 10.1016/j.expneurol.2025.115593

Tommi Kilpeläinen , Rui Yang , Jyri Toivio , Tony Eteläinen , Francesca De Lorenzo , Bianca Fastré , Cheng Zuo , Johanna K. Uhari-Väänänen , Ulrika Julku , Hengjing Cui , Timo T. Myöhänen

Parkinson's disease (PD) is the most common neurodegenerative movement disorder, and current therapies cannot stop or delay the neuronal death. Therefore, novel therapies having disease-modifying effects are urgently needed. Small-molecular ligands for prolyl oligopeptidase (PREP) have shown disease-modifying effects in various α-synuclein (aSyn) based PD mouse models. We have recently developed novel, more effective PREP ligand series that aim to regulate PREP-related protein-protein interactions, such as with aSyn and protein phosphatase 2 A (PP2A). The most promising novel PREP ligand, HUP-46, was now tested in a PD mouse model based on unilateral AAV-A53T-aSyn virus vector injection on substantia nigra. Our results show that HUP-46, but not reference PREP inhibitor, KYP-2047, was able to restore the behavioral deficit caused by the virus vector injection in the cylinder test. 4-week treatment with PREP ligands reduced the soluble and insoluble aSyn oligomers, and iNOS-positive microglial cells in the substantia nigra. When the effect on microglial activity was further studied in the BV2 microglial cell culture activated by lipopolysaccharide and interferon-γ, the results revealed that HUP-46 but not KYP-2047 significantly reduced TNF-α production. Analysis revealed that HUP-46 reduced p38 phosphorylation and restored autophagic flux in the activated BV2 cells that may contribute to the reduced pro-inflammatory activation of BV2 cells. Taken together, our results suggest that novel PREP ligands, such as HUP-46, can have disease-modifying effect on PD mouse model.

帕金森病（PD）是最常见的神经退行性运动障碍，目前的治疗方法不能阻止或延缓神经元的死亡。因此，迫切需要具有疾病修饰作用的新疗法。脯氨酸寡肽酶（PREP）小分子配体在多种α-突触核蛋白（aSyn）为基础的PD小鼠模型中显示出疾病改善作用。我们最近开发了新的，更有效的PREP配体系列，旨在调节PREP相关蛋白-蛋白相互作用，如与aSyn和蛋白磷酸酶2 A （PP2A）。目前，最具前景的新型PREP配体HUP-46在PD小鼠模型中进行了测试，该模型基于单侧黑质注射AAV-A53T-aSyn病毒载体。结果表明，在柱体试验中，HUP-46能够恢复病毒载体注射引起的行为缺陷，而参考PREP抑制剂KYP-2047则不能。4周的PREP配体治疗减少了黑质中可溶性和不可溶性的aSyn低聚物和inos阳性的小胶质细胞。在脂多糖和干扰素-γ激活的BV2小胶质细胞培养中进一步研究其对小胶质细胞活性的影响，结果表明，HUP-46而非kypp -2047显著降低TNF-α的产生。分析显示，HUP-46降低了活化BV2细胞的p38磷酸化并恢复了自噬通量，这可能有助于降低BV2细胞的促炎激活。综上所述，我们的研究结果表明，新型PREP配体，如HUP-46，可以对PD小鼠模型产生疾病改善作用。

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引用次数: 0

Noninvasive deep brain stimulation using theta-burst transcranial magnetic-acoustic coupling to modulate cortical rhythms in Parkinsonian mice 利用经颅磁声耦合无创深部脑刺激来调节帕金森小鼠的皮质节律。

IF 4.2 2区医学 Q1 NEUROSCIENCES

Experimental Neurology

Pub Date : 2025-12-10 DOI: 10.1016/j.expneurol.2025.115592

Ruixu Liu , Ruru Wang , Xiaoqing Zhou , Fangxuan Chu , Yuheng Wang , Kai Zhu , Shunqi Zhang , Ren Ma , Zhipeng Liu

Modulating the subthalamic nucleus (STN) through neural circuits can suppress abnormal discharge rhythms in the primary motor cortex (M1) in Parkinson's disease (PD), thereby enhancing motor function. However, a clinically viable noninvasive deep brain stimulation method for PD has yet to be realized. We developed a noninvasive transcranial magnetic-acoustic coupling stimulation (TMAS) system, employing a theta burst stimulation (TBS) mode, to examine its effects of simulated electrical parameters on cortical rhythms in PD. The theta burst-TMAS (TBTMAS) system was established, and its physical performance parameters were evaluated. The STN of MPTP-induced Parkinsonian mice was targeted using both continuous TBTMAS (cTBTMAS) and intermittent TBTMAS (iTBTMAS) modes. Local field potentials (LFPs) in the M1 were recorded before and after stimulation to assess pathological biomarkers associated with PD. Results showed that both TBTMAS protocols significantly suppressed abnormal beta oscillations and reduced beta power spectral density (PSD) in the M1 of PD mice. In addition, both modes decreased the beta–ripple phase–amplitude coupling (PAC) index and disrupted PAC locking. Notably, the iTBTMAS mode exhibited a more substantial inhibitory effect on beta PSD and enhanced the downmodulation and decoupling of beta–high gamma PAC phase-locking. These findings suggest that TBTMAS can effectively regulate pathological oscillatory activity in the M1 of PD models, offering a promising non-invasive approach for deep brain stimulation therapy.

通过神经回路调节丘脑下核（STN）可以抑制帕金森病（PD）原发性运动皮层（M1）异常放电节律，从而增强运动功能。然而，一种临床可行的无创PD深部脑刺激方法尚未实现。我们开发了一种无创经颅磁声耦合刺激（TMAS）系统，采用θ波爆发刺激（TBS）模式，研究其模拟电参数对PD皮质节律的影响。建立了theta burst-TMAS （TBTMAS）系统，并对其物理性能参数进行了评价。采用连续TBTMAS （cTBTMAS）和间歇TBTMAS （iTBTMAS）两种模式靶向mptp诱导的帕金森小鼠STN。在刺激前后记录M1的局部场电位（LFPs），以评估PD相关的病理生物标志物。结果表明，两种TBTMAS方案均能显著抑制PD小鼠M1中β振荡异常，降低β功率谱密度（PSD）。此外，两种模式都降低了β纹波相幅耦合（PAC）指数，并破坏了PAC锁定。值得注意的是，iTBTMAS模式对β - PSD表现出更明显的抑制作用，并增强了β -高γ - PAC锁相的降调制和去耦。这些发现表明TBTMAS可以有效调节PD模型M1的病理振荡活动，为深部脑刺激治疗提供了一种有前途的无创方法。

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引用次数: 0

Hydrogen gas promotes neuroprotection and upregulates ATF5 expression in neonatal hypoxic-ischemic brain injury 在新生儿缺氧缺血性脑损伤中，氢气促进神经保护并上调ATF5表达。

IF 4.2 2区医学 Q1 NEUROSCIENCES

Experimental Neurology

Pub Date : 2025-12-10 DOI: 10.1016/j.expneurol.2025.115590

Shinji Nakamura , Yasuhisa Nakamura , Hideo Jinnou , Yasuhiro Nakao , Htun Yinmon , Tsutomu Mitsuie , Kosuke Koyano , Masaki Ueno , Takanori Miki , Kazunobu Sawamoto , Shinji Saitoh , Takashi Kusaka

Neonatal brain injury, typically caused by hypoxia-ischemia (HI), results in irreversible cortical and white matter damage, leading to severe neurological sequelae. Therapeutic hypothermia, the only available clinical intervention, has limited effectiveness and is not suitable for all patients. Molecular hydrogen gas exerts neuroprotective effects due to its antioxidant properties and is gaining attention as a potential therapeutic strategy. However, its cellular and molecular effects in the injured neonatal brain are poorly understood. Using a robust HI brain injury model in neonatal piglets, whose brain structure and development closely resemble those of human neonates, we investigated the cell type-specific impact of hydrogen gas following neonatal HI injury and examined the potential molecular mediators underlying its neuroprotective effects. Hydrogen gas treatment significantly attenuated HI-induced apoptosis in both cortical neurons and white matter oligodendrocytes, thereby preserving their cell densities to levels comparable to uninjured controls. These neuroprotective effects were accompanied by reduced microglial activation, astrocyte expansion and myelin loss. RNAscope analyses revealed that hydrogen gas upregulated the expression of the anti-apoptotic factor activating transcription factor 5 (ATF5) in both neurons and mature oligodendrocytes, suggesting a cell-specific protective mechanism. These findings demonstrate that hydrogen gas exerts robust neuroprotection for cortical neurons and white matter oligodendrocytes following neonatal HI injury, and ATF5 is a potential mediator of its anti-apoptotic effects. Our study highlights the clinical feasibility of hydrogen gas as a novel therapeutic strategy for neonatal brain injury.

新生儿脑损伤通常由缺氧缺血（HI）引起，可导致不可逆的皮质和白质损伤，导致严重的神经系统后遗症。治疗性低温是唯一可用的临床干预措施，其有效性有限，并不适用于所有患者。分子氢气由于其抗氧化特性而具有神经保护作用，作为一种潜在的治疗策略正受到关注。然而，其在新生儿脑损伤中的细胞和分子作用尚不清楚。利用脑结构和发育与人类新生儿非常相似的新生儿仔猪脑损伤模型，我们研究了新生儿HI损伤后氢气对细胞类型的特异性影响，并研究了其神经保护作用的潜在分子介质。氢气处理显著减弱了hi诱导的皮质神经元和白质少突胶质细胞的凋亡，从而使它们的细胞密度保持在与未损伤对照相当的水平。这些神经保护作用伴随着小胶质细胞激活减少、星形胶质细胞扩张和髓磷脂损失。RNAscope分析显示，氢气上调了神经元和成熟少突胶质细胞中抗凋亡因子激活转录因子5 （ATF5）的表达，提示细胞特异性保护机制。这些发现表明，新生儿HI损伤后，氢气对皮质神经元和白质少突胶质细胞具有强大的神经保护作用，而ATF5是其抗凋亡作用的潜在介质。我们的研究强调了氢气作为新生儿脑损伤新治疗策略的临床可行性。

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引用次数: 0

Azeliragon attenuates cerebral infarction aggravation in diabetic rats: Receptor for advanced glycation end-product as a novel therapeutic target azelagon减轻糖尿病大鼠脑梗死加重：晚期糖基化终产物受体作为一种新的治疗靶点。

IF 4.2 2区医学 Q1 NEUROSCIENCES

Experimental Neurology

Pub Date : 2025-12-09 DOI: 10.1016/j.expneurol.2025.115588

Jin Soo Lee , Bok Seon Yoon , Seong-Joon Lee , So Young Park , Eun Hye Joe , Young J. Oh , Eui-Ju Choi

Diabetes mellitus contributes to neurological deterioration in acute ischemic stroke; nonetheless, rapid glucose control strategies have proven ineffective in clinical trials. We investigated whether targeting the receptor for advanced glycation end products (RAGE) could prevent infarction worsening in diabetic cerebral ischemia. To generate a diabetic model, streptozotocin (50 mg/kg) was intraperitoneally injected into male Sprague–Dawley rats (7–8 weeks old). A transient 30-min middle cerebral artery occlusion was performed at 34 days after diabetes induction. Azeliragon (10 mg/kg), a RAGE antagonist, was administered as a single intraperitoneal injection immediately after reperfusion. Total infarct volume, neurological severity, and mechanistic analyses were compared between vehicle and azeliragon groups. The 9.4 T animal magnetic resonance imaging analysis demonstrated that total infarct volume was significantly lower in the azeliragon group compared with the vehicle group (125.3 ± 26.2 mm³ vs. 240.5 ± 21.6 mm³; p = 0.003). Additionally, the modified neurological severity scores were significantly lower in the azeliragon group compared with the vehicle group (6.4 ± 1.7 vs. 11.1 ± 0.7; p = 0.012). The neuroprotective effect was consistently observed in a 4-day hyperglycemic model. Mechanistic analyses, including immunohistochemistry and Western blotting, revealed that azeliragon treatment significantly reduced the levels of reactive oxygen species, apoptotic markers, and key inflammatory mediators. Specifically, the phosphorylated to total NF-κB p65 ratio was significantly lower (p = 0.030), along with the levels of tumor necrosis factor-α and interleukin-1β, in the azeliragon group compared with the vehicle group (p < 0.001 for each). Therefore, RAGE antagonism significantly reduced ischemic brain damage and neuroinflammation in diabetic cerebral ischemia, offering a promising therapeutic strategy.

糖尿病对急性缺血性脑卒中患者神经功能恶化的影响然而，快速血糖控制策略在临床试验中被证明是无效的。我们研究了靶向晚期糖基化终产物受体（RAGE）是否可以预防糖尿病性脑缺血梗死恶化。采用链脲佐菌素（50 mg/kg）腹腔注射7-8 周龄雄性Sprague-Dawley大鼠，建立糖尿病模型。糖尿病诱导后34 天短暂性大脑中动脉闭塞30分钟。Azeliragon（10 mg/kg）是一种RAGE拮抗剂，在再灌注后立即单次腹腔注射。总梗死面积、神经系统严重程度和机制分析比较了两组间的差异。9.4 T动物磁共振成像分析表明,梗塞总量显著低于azeliragon组相比,车辆组(125.3 ±26.2  mm3 vs 240.5 ±21.6  mm3; p = 0.003)。此外，与载药组相比，杜鹃花组改良神经系统严重程度评分显著降低（6.4 ± 1.7 vs 11.1 ± 0.7;p = 0.012）。在为期4天的高血糖模型中持续观察到神经保护作用。机制分析，包括免疫组织化学和Western blotting，显示azelagon治疗显著降低活性氧、凋亡标志物和关键炎症介质的水平。具体而言，与载药组相比，鸢尾素组磷酸化的NF-κB p65与总NF-κB p65之比显著降低（p = 0.030），肿瘤坏死因子-α和白细胞介素-1β水平也显著降低（p . 0.05）

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引用次数: 0

Loss of presenilin 2 function age-dependently increases susceptibility to kainate-induced acute seizures and blunts hippocampal kainate-type glutamate receptor expression 早老素2功能的丧失与年龄相关，增加了对盐酸盐诱导的急性癫痫发作的易感性，并使海马盐酸盐型谷氨酸受体表达减弱。

IF 4.2 2区医学 Q1 NEUROSCIENCES

Experimental Neurology

Pub Date : 2025-12-09 DOI: 10.1016/j.expneurol.2025.115586

Larissa Robinson-Cooper , Stephanie Davidson , Rami Koutoubi , Kangni Zhang , Hannah Park , Melissa Barker-Haliski

Presenilin 2 (PSEN2) variants increase risk of Alzheimer's disease (AD) and unprovoked seizures. Yet, age-related PSEN2 contributions to seizure susceptibility are understudied. Critically, PSEN proteolytic capacity may regulate hippocampal kainate-type glutamate receptor (KAR) availability. Kainic acid (KA) is a KAR agonist that evokes severe seizures in mice. We hypothesized that PSEN2 knockout (KO) mice would show reduced latency to KA-induced seizures, increased seizure burden, worsened 7-day survival, and altered hippocampal KAR expression compared to wild-type (WT) controls. Using repeated low-dose systemic KA administration to 3–4- and 12–15-month-old PSEN2 KO versus WT mice, we quantified acute seizure latency and neuropathology. GluK2 and GluK5 KAR subunit expression was colocalized in astrocytes 7 days after seizures or sham to assess the impact of PSEN2 loss and seizures on hippocampal KARs. Young PSEN2 KO mice were more seizure-prone than WT mice, while genotype did not change latency to first seizure in aged mice. Aged females seized faster than young females and experienced greater mortality, unlike males. There was no difference in KAR subunit expression between young mouse genotypes and regardless of seizure history. In both genotypes, hippocampal CA3 astrocytes expressed GluK5 after seizures, however, astrocytic GluK2 upregulation only occurred in WT mice. GluK5 expression was significantly reduced in aged seizure-naïve PSEN2 KO versus WT mice, while total GluK2 expression did not differ. Seizure-induced astrocytic GluK5 expression only occurred in WT mice in CA3, while astrocytic GluK2 expression occurred in both. Thus, PSEN2 loss may impair age-related hippocampal KAR expression, implicating KARs as understudied contributors to AD-related seizures.

早老素2 （PSEN2）变异体增加阿尔茨海默病（AD）和非诱发性癫痫发作的风险。然而，与年龄相关的PSEN2对癫痫易感性的影响尚未得到充分研究。关键的是，PSEN蛋白水解能力可能调节海马盐型谷氨酸受体（KARs）的可用性。Kainic acid （KA）是一种能引起小鼠严重癫痫发作的Kainic激动剂。我们假设，与野生型（WT）对照相比，PSEN2基因敲除（KO）小鼠会表现出ka诱发癫痫发作的潜伏期降低、癫痫发作负担增加、7天生存率恶化以及海马KAR表达改变。我们对3-4个月和12-15个月大的PSEN2 KO和WT小鼠重复使用低剂量全身KA，量化急性发作潜伏期和神经病理学。癫痫或假发作后7 天，在星形胶质细胞中共定位GluK2和GluK5 KAR亚基表达，以评估PSEN2丢失和癫痫发作对海马KAR的影响。年轻的PSEN2 KO小鼠比WTs更容易发作，而基因型不改变首次发作的潜伏期。与男性不同，老年女性比年轻女性发作得更快，死亡率也更高。幼鼠基因型和癫痫发作史之间的KAR亚基表达没有差异。在两种基因型中，海马CA3星形胶质细胞在癫痫发作后表达GluK5，然而星形胶质细胞GluK2上调仅发生在WTs中。老年seizure-naïve PSEN2 KO小鼠与WT小鼠相比，GluK5表达显著降低，而GluK2总表达没有差异。癫痫诱导的星形细胞GluK5表达仅发生在CA3的WT小鼠中，而星形细胞GluK2表达在两者中均有发生。因此，PSEN2缺失可能损害与年龄相关的海马KAR表达，暗示KAR是ad相关癫痫发作的尚未研究的因素。

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引用次数: 0

HMGB1 Box A gene therapy reverses cognitive and neuropathological features in AlCl₃/D-galactose rat model of Alzheimer's disease HMGB1 Box A基因治疗逆转AlCl₃/ d -半乳糖大鼠阿尔茨海默病模型的认知和神经病理特征。

IF 4.2 2区医学 Q1 NEUROSCIENCES

Experimental Neurology

Pub Date : 2025-12-08 DOI: 10.1016/j.expneurol.2025.115583

Suangsuda Supasai , Pakawat Suntaratti , Mingkwan Odton , Tasneem Longji , Thararat Karananan , Sakawdaurn Yasom , Sumate Ampawong , Yanin Limpanont , Apiwat Mutirangura

Alzheimer's disease (AD), the leading cause of dementia, is pathologically defined by the accumulation of amyloid-β and tau pathology, resulting in progressive cognitive decline. Our previous work demonstrated that high mobility group box 1 (HMGB1) Box A plasmids alleviated cellular senescence and restored cognitive performance in aged rat models, supporting their therapeutic potential for neurodegenerative disorders such as AD. In this study, we investigated the efficacy of HMGB1 Box A gene therapy in an AD-like rat model chronically induced by AlCl₃ and D-galactose. Following the onset of AD pathology, Box A plasmids were administered weekly at varying doses over eight weeks. Box A treatment significantly improved behavioral outcomes, including responsiveness, locomotor activity, and learning and memory performance. At the neuropathological level, Box A reduced hippocampal Aβ accumulation and tau pathology, restored neuronal density, and attenuated synaptic degeneration. Moreover, it suppressed hippocampal microgliosis, astrogliosis, and the expression of proinflammatory mediators. Box A also diminished markers of cellular senescence in the hippocampus. These findings demonstrate that HMGB1 Box A gene therapy confers multi-level neuroprotective effects in AD, from molecular and cellular restoration to behavioral recovery. This strategy holds strong promise as a disease-modifying treatment for AD, contributing to improved well-being by advancing therapeutic innovation to promote healthy aging and combat age-related neurodegenerative diseases.

阿尔茨海默病（AD）是痴呆症的主要原因，其病理定义是淀粉样蛋白-β和tau蛋白的积累，导致进行性认知能力下降。我们之前的研究表明，HMGB1 box a质粒可以缓解衰老大鼠模型中的细胞衰老，恢复认知能力，支持其治疗神经退行性疾病（如AD）的潜力。在本研究中，我们研究HMGB1 Box A基因治疗慢性AlCl3和d -半乳糖诱导的ad样大鼠模型的疗效。在AD病理发作后，Box A质粒在8周内以不同剂量每周给药。盒子A治疗显著改善了行为结果，包括反应性、运动活动、学习和记忆表现。在神经病理水平上，Box A减少了海马Aβ积累和tau病理，恢复了神经元密度，减轻了突触变性。此外，它还能抑制海马小胶质细胞增生、星形胶质细胞增生和促炎介质的表达。框A也减少了海马细胞衰老的标记。这些发现表明HMGB1 Box A基因治疗在AD中具有多层次的神经保护作用，从分子和细胞恢复到行为恢复。这一策略有望成为一种阿尔茨海默病的疾病改善治疗方法，通过推进治疗创新来促进健康老龄化和对抗与年龄相关的神经退行性疾病，从而改善人们的福祉。

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引用次数: 0

Molecular regulation of exercise training on hippocampal neuroprotection in post-traumatic brain injury: A systematic review 运动训练对创伤后脑损伤海马神经保护的分子调控：系统综述。

IF 4.2 2区医学 Q1 NEUROSCIENCES

Experimental Neurology

Pub Date : 2025-12-06 DOI: 10.1016/j.expneurol.2025.115587

Farhan Yousaf , Sean Kao , Shahid Ishaq , Shin-Da Lee

Objective

Traumatic brain injury (TBI) induces oxidative stress, neuroinflammation, programmed cell death, mitochondrial dysfunction, impaired neurotrophic signaling, and neurogenesis, contributing to hippocampal dysfunction. Exercise training is a promising non-pharmacological intervention with potential neuroprotective effects. This systematic review aimed to evaluate the effectiveness of exercise training on the neurobiological mechanisms and cognitive function post-TBI.

Methods

PubMed, Embase, and Web of Science were searched up to July 2025, following the PRISMA 2020 guidelines. Of 1855 records, 44 studies involving post-TBI animals and exercise training as intervention were included. Exercise protocols varied, including voluntary wheel running, treadmill running, and swimming, with durations ranging from 7 to 94 days, and 4–7 sessions per week. The quality of included studies was appraised on the CAMARADES checklist.

Results

Exercise training reduced hippocampal reactive oxygen species (ROS), microglial reactivity, pro-inflammatory cytokines, and caspase-3 activity, while increasing total antioxidant capacity (TAC) and anti-apoptotic markers in post-TBI rodents. It elevated PGC-1α, electron transport system activity, BDNF, TrkB, and Synapsin-1 expression, and promoted neurogenesis post-TBI. Functionally, exercise improved cognitive function, spatial learning, and memory, and reduced anxiety and depression-like behaviors in post-TBI rodents.

Conclusion

Exercise training reduced oxidative stress, neuroinflammation, apoptosis, and enhanced mitochondrial function, neurotrophic signaling, neurogenesis, and cognitive function in post-TBI rodents. (PROSPERO: CRD420251072276).

目的：创伤性脑损伤（TBI）诱导氧化应激、神经炎症、程序性细胞死亡、线粒体功能障碍、神经营养信号和神经发生受损，导致海马功能障碍。运动训练是一种很有前途的非药物干预，具有潜在的神经保护作用。本系统综述旨在评价运动训练对脑损伤后神经生物学机制和认知功能的影响。方法：按照PRISMA 2020指南，检索截至2025年7月的PubMed、Embase和Web of Science。在1855项记录中，有44项研究涉及脑外伤后动物和运动训练作为干预。锻炼方案多种多样，包括自主轮跑、跑步机跑和游泳，持续时间从7到94 天不等，每周4-7次。纳入研究的质量用CAMARADES检查表进行评价。结果：运动训练降低了脑外伤后啮齿动物海马活性氧（ROS）、小胶质细胞反应性、促炎细胞因子和caspase-3活性，同时增加了总抗氧化能力（TAC）和抗凋亡标志物。上调PGC-1α、电子传递系统活性、BDNF、TrkB和Synapsin-1表达，促进脑外伤后神经发生。在功能上，运动改善了脑外伤后啮齿动物的认知功能、空间学习和记忆，并减少了焦虑和抑郁样行为。结论：运动训练可降低脑外伤后啮齿动物的氧化应激、神经炎症、细胞凋亡，增强线粒体功能、神经营养信号、神经发生和认知功能。(普洛斯彼罗:CRD420251072276)。

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引用次数: 0

Exploring the roles of AKR1C1, AKR1C2, and AKR1C3 in the nervous system: Mechanisms and perspectives AKR1C1、AKR1C2和AKR1C3在神经系统中的作用：机制和观点。

IF 4.2 2区医学 Q1 NEUROSCIENCES

Experimental Neurology

Pub Date : 2025-12-04 DOI: 10.1016/j.expneurol.2025.115580

Xinyi Chen , Lu Gan , Yunfei Huang , Shu hua Wei , Wenhao Wang , Ying Huang

Aldo-keto reductase 1C (AKR1C) enzymes, including AKR1C1, AKR1C2, and AKR1C3, play crucial roles in the metabolism of steroid hormones and prostaglandins through their catalytic activities. Although their functions have been extensively studied in endocrine tissues and hormone-dependent malignancies, their significance in the nervous system remains underexplored. Emerging evidence suggests that AKR1C enzymes regulate neurosteroid homeostasis, modulate GABAergic neurotransmission, support synaptic plasticity, and participate in cellular defense against oxidative stress. These multifaceted activities implicate AKR1C1–C3 in diverse neural processes, including neuroprotection, emotional regulation, and neurodevelopment. Furthermore, the potential involvement of AKR1C1, AKR1C2, and AKR1C3 in neurodegenerative diseases such as Alzheimer's, Parkinson's, and Huntington's disease suggests their possible therapeutic relevance. This review consolidates current findings on the molecular characteristics, brain region-specific expression, and neurophysiological functions of AKR1C enzymes, and discusses their emerging roles in central nervous system disorders. By presenting these insights, this review offers a valuable framework for researchers to explore new directions in the development of neuroprotective and neuroregenerative strategies.

醛酮还原酶1C （AKR1C）酶，包括AKR1C1、AKR1C2和AKR1C3，通过其催化活性在类固醇激素和前列腺素的代谢中发挥重要作用。尽管它们在内分泌组织和激素依赖性恶性肿瘤中的功能已被广泛研究，但它们在神经系统中的意义仍未得到充分探讨。新出现的证据表明，AKR1C酶调节神经类固醇稳态，调节gaba能神经传递，支持突触可塑性，并参与细胞防御氧化应激。这些多方面的活动使AKR1C1-C3参与多种神经过程，包括神经保护、情绪调节和神经发育。此外，AKR1C1、AKR1C2和AKR1C3在阿尔茨海默病、帕金森病和亨廷顿病等神经退行性疾病中的潜在作用表明它们可能具有治疗意义。本文综述了目前在AKR1C酶的分子特征、脑区域特异性表达和神经生理功能方面的研究成果，并讨论了它们在中枢神经系统疾病中的新作用。通过提出这些见解，本综述为研究人员探索神经保护和神经再生策略发展的新方向提供了一个有价值的框架。

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引用次数: 0

Inhibition of the TRPM4 channel by 9-PH attenuates hippocampal endothelial injury induced by sleep deprivation and the subsequent neuroinflammation and neurological dysfunction 9-PH抑制TRPM4通道可减轻睡眠剥夺引起的海马内皮损伤以及随后的神经炎症和神经功能障碍。

IF 4.2 2区医学 Q1 NEUROSCIENCES

Experimental Neurology

Pub Date : 2025-12-03 DOI: 10.1016/j.expneurol.2025.115584

Hao Yang , Sirou Huang , Yiwen Ma , Yichen Lu , Yuan Chai

Sleep deprivation (SD) is a significant public health concern and a recognized risk factor for cognitive impairment. While both vascular dysfunction and neuroinflammation are implicated, the mechanistic link between them remains elusive. Here, we identify a pathogenic positive feedback loop centered on endothelial transient receptor potential melastatin 4 (TRPM4) as a core driver of SD-induced pathology. We demonstrate that SD triggers an early and specific upregulation of TRPM4 in hippocampal endothelial cells, which in turn induces blood-brain barrier (BBB) disruption, characterized by tight junction loss and perivascular edema. This endothelial injury promotes the release of high-mobility group box 1 (HMGB1), which activates microglial TLR4–NF-κB signaling and neuroinflammation. Crucially, we provide direct evidence that microglia-derived inflammatory mediators feed back to upregulate endothelial TRPM4 expression in an NF-κB-dependent manner, thereby establishing a self-sustaining TRPM4–HMGB1–NF-κB loop. Pharmacological inhibition of TRPM4 with 9-phenanthrol (9-PH) following SD onset effectively disrupted this cycle, preserving BBB integrity, suppressing microglial activation and neuronal apoptosis, and rescuing hippocampal-dependent cognitive function. These protective effects were associated with concurrent downregulation of the HMGB1–TLR4–NF-κB axis. Our findings establish endothelial TRPM4 as a master initiator and amplifier of SD-induced neurovascular unit injury, revealing the TRPM4–HMGB1–NF-κB loop as a promising therapeutic target for mitigating the cognitive consequences of sleep loss.

睡眠剥夺（SD）是一个重要的公共卫生问题，也是公认的认知障碍风险因素。虽然血管功能障碍和神经炎症都有牵连，但它们之间的机制联系仍然难以捉摸。在这里，我们发现了一个以内皮瞬时受体潜能美拉他汀4 （TRPM4）为中心的致病性正反馈回路，作为sd诱导病理的核心驱动因素。我们证明，SD触发海马内皮细胞中TRPM4的早期特异性上调，进而诱导血脑屏障（BBB）破坏，其特征是紧密连接丢失和血管周围水肿。这种内皮损伤促进高迁移性组盒1 （HMGB1）的释放，激活小胶质细胞TLR4-NF-κB信号和神经炎症。至关重要的是，我们提供了直接证据，证明小胶质细胞衍生的炎症介质以NF-κB依赖的方式反馈上调内皮细胞TRPM4的表达，从而建立了一个自我维持的TRPM4- hmgb1 -NF-κB回路。SD发病后用9-phenanthrol （9-PH）药物抑制TRPM4有效地破坏了这一循环，保持血脑屏障完整性，抑制小胶质细胞激活和神经元凋亡，并挽救海马依赖的认知功能。这些保护作用与HMGB1-TLR4-NF-κB轴同时下调有关。我们的研究结果证实内皮细胞TRPM4是sd诱导的神经血管单位损伤的主要启动者和放大器，揭示了TRPM4- hmgb1 - nf -κB环是减轻睡眠缺失认知后果的有希望的治疗靶点。

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引用次数: 0

Calcaratarin D exerts neuroprotective effects in Alzheimer's disease mouse model by inhibiting CERT-mediated NF-κB pathway Calcaratarin D通过抑制cert介导的NF-κB通路在老年痴呆症小鼠模型中发挥神经保护作用。

IF 4.2 2区医学 Q1 NEUROSCIENCES

Experimental Neurology

Pub Date : 2025-12-02 DOI: 10.1016/j.expneurol.2025.115585

Jin-zhi Pan , Meng-yao Yu , Ming-zhu Tian , Run Liu , Wei Zhao , Qian Luo

Alzheimer's disease (AD) is a neurodegenerative disease characterized by β-amyloid plaque accumulation, neuroinflammation, and dysregulation of sphingolipid metabolism, mainly manifested as irreversible cognitive decline and memory loss. A key pathological hallmark of AD is neuroinflammation, largely fueled by the persistent stimulation of microglia and subsequent pro-inflammatory cytokine production, which worsens disease development. Calcaratarin D (CalD), a ladanane-type diterpenoid sourced from Hedychium flavum rhizomes, has been reported to exhibit significant anti-inflammatory effects. However, its potential therapeutic benefits in AD remain unknown. Therefore, this research focused on exploring the neuroprotective effects of CalD in AD and elucidating its potential mechanisms. We established a mouse model of AD by targeting delivery of Aβ₁₋₄₂ oligomers to the hippocampus. Behavioral tests showed that CalD significantly improved the memory loss and spatial learning ability of AD mice. Western blotting and immunofluorescence staining further confirmed that CalD effectively reduced Aβ deposition and inhibited the excessive activation of microglia. Network pharmacology analysis found that the mechanism of action of CalD mainly involved inflammatory signaling pathways and sphingolipid metabolism. Subsequently, in vivo and in vitro experiments confirmed that CalD could inhibit the excessive activation of the TLR4/NF-κB/NLRP3 signaling pathway and restore the ceramide homeostasis in AD mice. On this basis, molecular docking and small interfering RNA experiments further clarified that CalD played an anti-inflammatory by targeting CERT. In summary, these findings indicate that CalD exerts neuroprotective effects by modulating neuroinflammation and ceramide metabolic dysregulation, suggesting that CalD has therapeutic potential in AD.

阿尔茨海默病（Alzheimer's disease， AD）是一种以β-淀粉样斑块积聚、神经炎症和鞘脂代谢失调为特征的神经退行性疾病，主要表现为不可逆的认知能力下降和记忆丧失。阿尔茨海默病的一个关键病理标志是神经炎症，主要是由小胶质细胞的持续刺激和随后的促炎细胞因子的产生引起的，这加剧了疾病的发展。钙素D （Calcaratarin D, CalD）是一种从黄姜黄根茎中提取的ladanane型二萜类化合物，具有显著的抗炎作用。然而，它对阿尔茨海默病的潜在治疗效果尚不清楚。因此，本研究重点探讨CalD在AD中的神经保护作用，并阐明其潜在机制。我们通过将a β₁₄₂低聚物靶向递送到海马建立了AD小鼠模型。行为学测试显示，CalD显著改善了AD小鼠的记忆丧失和空间学习能力。Western blotting和免疫荧光染色进一步证实CalD能有效减少Aβ沉积，抑制小胶质细胞过度活化。网络药理学分析发现CalD的作用机制主要涉及炎症信号通路和鞘脂代谢。随后，体内和体外实验证实，CalD可以抑制AD小鼠TLR4/NF-κB/NLRP3信号通路的过度激活，恢复神经酰胺稳态。在此基础上，分子对接和小干扰RNA实验进一步阐明了CalD通过靶向CERT对鞘脂代谢发挥抗炎和调节作用。综上所述，这些发现表明CalD通过调节神经炎症和神经酰胺代谢失调发挥神经保护作用，提示CalD在AD中具有治疗潜力。

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引用次数: 0