Experimental Neurology最新文献_第4页

Daily intranasal resveratrol-conjugated gold nanoparticles administration promotes neuroprotection and improves neurological outcome in the R6/2 mouse model of Huntington's disease 每日鼻内白藜芦醇结合金纳米颗粒可促进亨廷顿病R6/2小鼠模型的神经保护并改善神经预后

IF 4.2 2区医学 Q1 NEUROSCIENCES

Experimental Neurology

Pub Date : 2026-04-01 Epub Date: 2026-01-07 DOI: 10.1016/j.expneurol.2026.115639

Emanuela Paldino , Emiliano Montalesi , Marco Fiocchetti , Flavia Dioguardi , Iole Venditti , Elena Olivieri , Maria Marino , Francesca R. Fusco

Pan-apoptosis and involvement of the inflammatory process are the hallmarks of Huntington's disease (HD). Inflammation currently represents one of the potential therapeutic targets for slowing and fighting the pathological phenotype of HD. The immunomodulatory properties of natural compounds, such as resveratrol, have been demonstrated in various disease models and human clinical trials. In the present study, we evaluated the neuroprotective and anti-inflammatory effects of the daily intranasal administration of resveratrol-conjugated gold nanoparticles in awake R6/2 mice, the genetic animal model of HD. Transgenic mice were treated daily with resveratrol-conjugated gold nanoparticles (0.1 mg/kg/day) starting from 5 weeks of age corresponding to the prodromal stage of the disease. After sacrifice, histological and immunofluorescence studies were performed. We found that resveratrol treated R6/2 mice survived longer and displayed a significant partial recovery of motor performance compared with R6/2 mice that received the nanoparticles with vehicle. Primary outcome measures such as striatal atrophy, neuronal intranuclear inclusions, and modulation of microglial reaction revealed a neuroprotective effect of resveratrol conjugated gold nanoparticles. Resveratrol provided a significant increase of neuroglobin, a neuroprotective globin, along with activated CREB and BDNF in the mice medium spiny neurons, accompanied by a down modulation of neuroinflammation, which, combined, might explain the beneficial effects observed in this model. Our findings showed that nanoparticles loaded with a specific compound which acts on the mutated protein intranuclear inclusions and inflammatory components may represent a valid therapeutic strategy in slowing down the symptoms of HD neurodegeneration.

泛细胞凋亡和炎症过程的参与是亨廷顿舞蹈病（HD）的标志。炎症目前是减缓和对抗HD病理表型的潜在治疗靶点之一。天然化合物（如白藜芦醇）的免疫调节特性已在各种疾病模型和人体临床试验中得到证实。在本研究中，我们在清醒的HD遗传动物模型R6/2小鼠中评估了每日鼻内给药白藜芦醇结合金纳米颗粒的神经保护和抗炎作用。从与疾病前驱期相对应的5周龄开始，每天用白藜芦醇偶联金纳米颗粒（0.1 mg/kg/天）治疗转基因小鼠。牺牲后，进行组织学和免疫荧光研究。我们发现白藜芦醇处理的R6/2小鼠存活时间更长，运动能力明显部分恢复。纹状体萎缩、神经元核内包涵体和小胶质细胞反应的调节等主要结局指标显示白藜芦醇共轭金纳米颗粒具有神经保护作用。白藜芦醇显著增加了小鼠中棘神经元中的神经球蛋白（一种神经保护性球蛋白），同时激活了CREB和BDNF，并伴有神经炎症的下调，这可能解释了该模型中观察到的有益效果。我们的研究结果表明，携带特定化合物的纳米颗粒可作用于突变蛋白核内包涵体和炎症成分，可能是减缓HD神经退行性疾病症状的有效治疗策略。

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引用次数: 0

Authors Response to Hubbard et al., Letter to Editor, YEXNR_115375 - (EXNR-25-183) on the manuscript “Comparison of blood-brain barrier permeability changes in gyrencephalic (ferret and nonhuman primate) and lissencephalic (rat) models following blast overpressure exposures” 作者对Hubbard等人的回复，致编辑的信，YEXNR_115375 - (EXNR-25-183)关于“爆炸超压暴露后脑回（雪貂和非人灵长类动物）和无脑（大鼠）模型血脑屏障通透性变化的比较”的稿件。

IF 4.2 2区医学 Q1 NEUROSCIENCES

Experimental Neurology

Pub Date : 2026-04-01 Epub Date: 2025-12-23 DOI: 10.1016/j.expneurol.2025.115603

Venkatasivasai Sujith Sajja , Joseph Long , Venkata Rama Rao Kakulavarapu , Shataakshi Dahal

引用次数: 0

Apelin-13 attenuates microglia-mediated neuroinflammation following intracerebral hemorrhage via targeting JAK2/STAT3 signaling pathway Apelin-13通过靶向JAK2/STAT3信号通路减轻脑出血后小胶质细胞介导的神经炎症

IF 4.2 2区医学 Q1 NEUROSCIENCES

Experimental Neurology

Pub Date : 2026-04-01 Epub Date: 2025-12-31 DOI: 10.1016/j.expneurol.2025.115633

Pingping Guo , Jingjing Li , Xiangyu Zhang , Qingli Wang , Yang Liu , Huizhen Zhou , Yun Chen , V. Wee Yong , Mengzhou Xue

Background

Neuroinflammation is a critical contributor to secondary brain injury and subsequent neurological decline after intracerebral hemorrhage (ICH). Apelin-13, the most bioactive isoform of the endogenous G protein-coupled receptor (GPCR) ligand, exhibits protective roles in multiple neurological disorders. Nevertheless, its therapeutic effects and underlying mechanisms in neuroinflammation following ICH remain elusive.

Methods

In vivo, ICH was induced in mice with collagenase type VII, followed by intracerebroventricular injection of Apelin-13. In vitro, BV2 microglia were pretreated with Apelin-13 overnight, followed by lipopolysaccharide (LPS) stimulation. To investigate the mechanistic role of Apelin-13, we employed specific shRNA for APJ knockdown and the selective JAK2/STAT3 inhibitor WP1066 for pathway blockage. Western blotting and immunofluorescence assays were applied to assess JAK2/STAT3 signaling activation and pro-inflammatory mediator expression.

Results

Apelin-13 significantly decreased hematoma volume and mitigated neurological impairments in ICH mice. Correspondingly, both in vivo and in vitro studies confirmed its efficacy in attenuating microglia-mediated neuroinflammation. Mechanistically, Apelin-13 significantly suppressed JAK2/STAT3 signaling pathway in LPS-stimulated BV2 microglia. This suppression was reversed by APJ knockdown, verifying the necessity of the Apelin-13/APJ interaction. Furthermore, combining WP1066 with Apelin-13 significantly enhanced its anti-inflammatory effects, as evidenced by a more pronounced reduction in p-JAK2/p-STAT3 levels and pro-inflammatory cytokine secretion. Finally, the inhibition of the microglial JAK2/STAT3 pathway by Apelin-13 was also confirmed in the perihematomal brain tissues of ICH mice.

Conclusions

Apelin-13 attenuated brain injury after ICH by suppressing microglia-mediated neuroinflammation through APJ receptor-dependent inhibition of the JAK2/STAT3 pathway.

背景神经炎症是脑出血（ICH）后继发性脑损伤和随后的神经功能衰退的重要因素。Apelin-13是内源性G蛋白偶联受体（GPCR）配体中最具生物活性的异构体，在多种神经系统疾病中具有保护作用。然而，其治疗脑出血后神经炎症的效果和潜在机制仍不清楚。方法采用7型胶原酶诱导小鼠脑出血，然后脑室内注射Apelin-13。体外，用Apelin-13预处理BV2小胶质细胞过夜，然后进行脂多糖（LPS）刺激。为了研究Apelin-13的机制作用，我们使用了特异性shRNA来下调APJ，并使用了选择性JAK2/STAT3抑制剂WP1066来阻断通路。Western blotting和免疫荧光法检测JAK2/STAT3信号的激活和促炎介质的表达。结果apelin -13能显著减少脑出血小鼠血肿体积，减轻神经损伤。相应地，体内和体外研究都证实了其减轻小胶质细胞介导的神经炎症的功效。机制上，Apelin-13在lps刺激的BV2小胶质细胞中显著抑制JAK2/STAT3信号通路。这种抑制被APJ敲除逆转，验证了Apelin-13/APJ相互作用的必要性。此外，WP1066与Apelin-13联合使用可显著增强其抗炎作用，p-JAK2/p-STAT3水平和促炎细胞因子分泌均显著降低。最后，在脑出血小鼠血肿周围脑组织中也证实了Apelin-13对小胶质细胞JAK2/STAT3通路的抑制作用。结论sapelin -13通过APJ受体依赖性抑制JAK2/STAT3通路，抑制小胶质细胞介导的神经炎症，减轻脑出血后脑损伤。

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引用次数: 0

Traumatic brain injury exacerbates mitochondrial dysfunction in APP/PS1 knock-in mice through time-dependent pathways 外伤性脑损伤通过时间依赖性途径加重APP/PS1敲入小鼠的线粒体功能障碍。

IF 4.2 2区医学 Q1 NEUROSCIENCES

Experimental Neurology

Pub Date : 2026-04-01 Epub Date: 2025-12-30 DOI: 10.1016/j.expneurol.2025.115629

Elika Z. Moallem , Hemendra J. Vekaria , Teresa Macheda , Margaret R. Hawkins , Kelly N. Roberts , Samir P. Patel , Patrick G. Sullivan , Adam D. Bachstetter

Cerebral hypometabolism occurs in both traumatic brain injury (TBI) and Alzheimer's disease (AD), but whether these conditions act through distinct or overlapping mechanisms is unclear. TBI disrupts cerebral metabolism via blood–brain barrier damage, altered glucose transporter expression, calcium buffering abnormalities, and oxidative damage to metabolic enzymes. AD-related hypometabolism is linked to amyloid-β (Aβ) effects on mitochondria, including impaired respiration, oxidative stress, and altered mitophagy, fusion, and fission. We tested whether TBI-induced mitochondrial dysfunction exacerbates Aβ-mediated impairment using a closed-head injury (CHI) model in APP/PS1 knock-in (KI) mice. Injuries were delivered at 4–5 months of age, before plaque formation and mitochondrial deficits in KI mice. Bioenergetics were measured at 1, 4, and 8 months post-injury in hippocampus and cortex using Seahorse assays on isolated mitochondria. At 1 month, genotype-by-injury interactions revealed greater dysfunction in KI mice than either condition alone, with males more vulnerable than females. At 4–8 months, amyloid-mediated effects predominated, while TBI-specific changes were no longer apparent, suggesting recovery or convergence onto shared mechanisms. These results indicate that TBI can temporarily worsen mitochondrial dysfunction in the context of early amyloidosis, with sex influencing vulnerability. Findings provide insight into the temporal relationship between TBI and amyloid-induced mitochondrial deficits and support the importance of sex as a biological variable in neurodegenerative disease progression.

脑代谢降低发生在创伤性脑损伤（TBI）和阿尔茨海默病（AD）中，但这些情况是否通过不同或重叠的机制起作用尚不清楚。创伤性脑损伤通过血脑屏障损伤、葡萄糖转运蛋白表达改变、钙缓冲异常和代谢酶氧化损伤扰乱脑代谢。ad相关的低代谢与淀粉样蛋白-β (Aβ)对线粒体的影响有关，包括呼吸受损、氧化应激和线粒体自噬、融合和裂变的改变。我们使用APP/PS1敲入（KI）小鼠闭合性脑损伤（CHI）模型，测试tbi诱导的线粒体功能障碍是否会加剧a β介导的损伤。损伤发生在4-5 月龄，在KI小鼠斑块形成和线粒体缺陷之前。在损伤后1、4和8 个月，用海马分离线粒体测定海马和皮质的生物能量。在1 个月时，基因型损伤相互作用显示KI小鼠的功能障碍比单独的任何一种情况都大，雄性比雌性更容易受到伤害。在4-8 个月时，淀粉样蛋白介导的作用占主导地位，而tbi特异性变化不再明显，表明恢复或趋同于共享机制。这些结果表明，在早期淀粉样变性的情况下，脑外伤可以暂时加重线粒体功能障碍，性别影响易感性。研究结果为TBI和淀粉样蛋白诱导的线粒体缺陷之间的时间关系提供了见解，并支持性别作为神经退行性疾病进展的生物学变量的重要性。

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引用次数: 0

Electroacupuncture ameliorates tau-driven cognitive decline by modulating NF-κB/NLRP3 inflammasome signaling in P301S mice 电针通过调节P301S小鼠NF-κB/NLRP3炎性体信号传导改善tau驱动的认知衰退。

IF 4.2 2区医学 Q1 NEUROSCIENCES

Experimental Neurology

Pub Date : 2026-04-01 Epub Date: 2025-12-31 DOI: 10.1016/j.expneurol.2025.115637

Ruixue Zheng , Xueyun Liu , Zhenge Liao , Runjie Wan , Gengbin Qiu , Min Li , Chunzhi Tang , Runjin Zhou , Juxian Song

Alzheimer's disease (AD) progression is driven by a vicious cycle wherein pathological Tau hyperphosphorylation promotes microglial activation and NF-κB/NLRP3 inflammasome signaling, leading to excessive secretion of proinflammatory cytokines that reciprocally exacerbate Tau pathology. While pharmacological NLRP3 inhibitors hold therapeutic potential for AD, critical barriers—including poor blood-brain barrier penetration, suboptimal target selectivity, and safety concerns—persist. This study investigated whether electroacupuncture (EA), a non-pharmacological neuromodulatory approach, could disrupt this Tau-inflammasome cycle. Using P301S Tau transgenic mice, two EA regimens were tested at the GV20 (Baihui) acupoint: 6-month-old mice receiving a 1-month EA intervention, and 6-month-old mice undergoing a prolonged 3-month EA intervention. Cognitive function was evaluated via Y-maze, novel object recognition (NOR), and Morris water maze (MWM) tests, while corticospinal function was assessed using tail-suspension limb-clasping scoring. Hippocampal Tau pathology and inflammatory signaling were analyzed by Western blot and immunohistochemistry, targeting total Tau, phosphorylated Tau, NF-κB, NLRP3, caspase-1, IL-1β, IL-18, TNF-α, and microglial morphology. Short-term (1-month) EA treatment significantly improved spatial working memory and recognition memory. Mechanistically, EA reduced p-Tau levels, suppressed NF-κB activation (decreased p-P65/P65 ratio), downregulated NLRP3 inflammasome components (NLRP3, cleaved caspase-1) and proinflammatory cytokines (IL-1β, IL-18 and TNF-α), and mitigated microglial hyperactivation. Importantly, long-term (3-month) EA treatment persistently suppressed p-Tau accumulation and neuroinflammation, thereby consolidating cognitive benefits even in P301S mice with severe corticospinal dysfunction. These findings establish EA as a multi-targeted immunomodulatory strategy that attenuates Tau-driven neuroinflammation through the TNF-α/NF-κB/NLRP3 signaling axis, highlighting its potential as a safe, non-pharmacological adjunct or alternative therapy for AD and related tauopathies.

阿尔茨海默病（AD）的进展是由一个恶性循环驱动的，其中病理性Tau过度磷酸化促进小胶质细胞活化和NF-κB/NLRP3炎性小体信号传导，导致促炎细胞因子的过度分泌，从而相互加剧Tau病理。虽然药物NLRP3抑制剂具有治疗AD的潜力，但关键障碍-包括血脑屏障穿透性差，次优靶标选择性和安全性问题-仍然存在。这项研究调查了电针（EA），一种非药物神经调节方法，是否可以破坏这种tau -炎性体周期。采用P301S Tau转基因小鼠，在GV20（百会）穴测试两种EA方案：6月龄小鼠接受1个月的EA干预，6月龄小鼠接受3个月的延长EA干预。通过y形迷宫、新物体识别（NOR）和Morris水迷宫（MWM）测试评估认知功能，采用悬尾扣肢评分评估皮质脊髓功能。以总Tau蛋白、磷酸化Tau蛋白、NF-κB、NLRP3、caspase-1、IL-1β、IL-18、TNF-α和小胶质细胞形态为指标，采用Western blot和免疫组化方法分析海马Tau蛋白病理和炎症信号传导。短期（1个月）EA治疗显著改善了空间工作记忆和识别记忆。从机制上讲，EA降低了p-Tau水平，抑制了NF-κB的活化（降低了p-P65/P65比值），下调了NLRP3炎性小体成分（NLRP3、cleaved caspase-1）和促炎细胞因子（IL-1β、IL-18和TNF-α），减轻了小胶质细胞的过度活化。重要的是，长期（3个月）EA治疗持续抑制p-Tau积聚和神经炎症，从而巩固认知益处，甚至在严重皮质脊髓功能障碍的P301S小鼠中也是如此。这些发现表明EA是一种多靶点的免疫调节策略，通过TNF-α/NF-κB/NLRP3信号轴减弱tau驱动的神经炎症，突出了其作为AD和相关tau病变的安全，非药物辅助或替代疗法的潜力。

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引用次数: 0

Demethyleneberberine attenuates combined cognitive and metabolic dysfunctions in an insulin-resistance-induced Alzheimer's disease rat model: Synthesis, in-silico and in-vivo insights 去亚甲基小檗碱减轻胰岛素抵抗诱导的阿尔茨海默病大鼠模型中的认知和代谢功能障碍：合成、计算机和体内观察

IF 4.2 2区医学 Q1 NEUROSCIENCES

Experimental Neurology

Pub Date : 2026-04-01 Epub Date: 2025-12-31 DOI: 10.1016/j.expneurol.2025.115634

Amritpal Kaur , Shareen Singh , Manjinder Singh , Pragati Silakari , Ashi Mannan , Sukriti Vishwas , Puneet Kumar , Vetriselvan Subramaniyan , Thakur Gurjeet Singh

In this study, we evaluated the therapeutic potential of DMB, a berberine derivative known for its enhanced bioavailability and reduced toxicity. DMB was synthesized and administered orally at doses of 5 and 10 mg/kg in an in vivo rat model of insulin resistance-induced Alzheimer's disease (AD). This model was established using a combination of a high-fat diet (HFD), streptozotocin (35 mg/kg; intraperitoneally), and amyloid-β₂₅_–₃₅. In-silico docking studies revealed that DMB exhibits a high binding affinity for key proteins implicated in both AD and diabetes, including insulin receptors, leptin receptors, protein tyrosine phosphatase 1B (PTP1B), HMG-CoA reductase, acetylcholinesterase (AChE), and butyrylcholinesterase (BChE). Molecular dynamics simulations confirmed the stable binding and inhibitory potential of Demethyleneberberine (DMB) against Insulin Receptor Tyrosine Kinase and AChE. Pharmacological network analysis indicated that DMB modulates multiple pathways involved in metabolic and cognitive decline, suggesting its promise as a therapeutic candidate for insulin resistance-induced AD. Neurobehavioral assessments demonstrated that DMB significantly (p < 0.001) improved cognitive function, ameliorated metabolic disruptions (elevated blood glucose and insulin levels), and normalized pro-inflammatory markers (Tumor Necrosis Factor-alpha (TNF-α), Interleukin 1-beta (IL-1β)) and oxidative stress parameters (Thiobarbituric Acid Reactive Substances (TBARS), glutathione (GSH), superoxide dismutase (SOD), and catalase (CAT). Additionally, DMB reduced levels of AD-related biomarkers, including BACE-1 (β-secretase 1), amyloid-β, and acetylcholinesterase, indicating its capacity to mitigate oxidative stress and amyloidogenesis. This multidisciplinary approach, integrating in vivo and in-silico methodologies, provides a comprehensive understanding of DMB's neuroprotective effects and underscores its potential as a therapeutic agent for both AD and diabetes.

在这项研究中，我们评估了DMB的治疗潜力，DMB是一种以提高生物利用度和降低毒性而闻名的小檗碱衍生物。合成DMB并在胰岛素抵抗性阿尔茨海默病（AD）大鼠模型中以5和10 mg/kg的剂量口服。采用高脂肪饲粮（HFD）、链脲佐菌素（35 mg/kg；腹腔注射）和淀粉样蛋白-β25-35联合建立模型。硅对接研究显示，DMB对AD和糖尿病相关的关键蛋白具有高结合亲和力，包括胰岛素受体、瘦素受体、蛋白酪氨酸磷酸酶1B （PTP1B）、HMG-CoA还原酶、乙酰胆碱酯酶（AChE）和丁基胆碱酯酶（BChE）。分子动力学模拟证实了去亚甲基小檗碱（DMB）对胰岛素受体酪氨酸激酶和AChE的稳定结合和抑制潜力。药理网络分析表明，DMB可调节代谢和认知能力下降的多种途径，提示其有望成为胰岛素抵抗性AD的治疗候选药物。神经行为评估显示DMB显著(p

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引用次数: 0

Prolonged antibiotic treatment accelerates neurological recovery and reduces long-term neuroinflammatory gene expression after experimental TBI in mice 长期抗生素治疗可加速小鼠实验性脑外伤后神经系统恢复并降低长期神经炎症基因表达。

IF 4.2 2区医学 Q1 NEUROSCIENCES

Experimental Neurology

Pub Date : 2026-04-01 Epub Date: 2026-01-13 DOI: 10.1016/j.expneurol.2026.115645

Katharina Ritter , Katharina Petri , Julian Denninger , Yi Zhang , Yong Wang , Michael K.E. Schäfer

Background

Neuroprotective effects of antibiotic medications are reported in the context of experimental traumatic brain injury (TBI), but the choice of substances and treatment intervals are inconsistent.

Methods

In this study, we tested whether continuous posttraumatic administration of a combined broad-spectrum antibiotic regimen of vancomycin, amoxicillin, and clavulanic acid affects neurological recovery, structural brain damage and neuroinflammation following experimental TBI by controlled cortical impact in 80 adult male C57BL/6 mice.

Results

Antibiotic treatment led to accelerated recovery from posttraumatic neuromotor impairment and exploratory behavioural disorders. Reduced astrocytic activation and neuronal loss in the ipsilesional thalamic region in the early (5 days post injury, dpi) and attenuated neuroinflammatory gene expression in the late (30 dpi) period were observed alongside a severe disruption of the intestinal microbial spectrum after five days of antibiotic treatment, while the structural brain damage remained unaffected.

Conclusion

We demonstrated accelerated neurological recovery and long-lasting effects of antibiotic treatment on the neuroinflammatory response after experimental TBI. Increased plasma levels of lipopolysaccharide-binding protein and short-chain fatty acids were evaluated, yet not identified as potential modulators. As the observed effects can not entirely be linked to the intestinal dysbiosis, direct modulation of secondary brain damage by the antibiotic substances should be considered as an alternate mechanism.

背景：在实验性创伤性脑损伤（TBI）的背景下，已有抗生素药物的神经保护作用的报道，但药物的选择和治疗间隔并不一致。方法：在这项研究中，我们测试了80只成年雄性C57BL/6小鼠创伤后持续使用万古霉素、阿莫西林和克拉维酸联合广谱抗生素方案是否会影响实验性TBI后的神经恢复、结构性脑损伤和神经炎症。结果：抗生素治疗可加速创伤后神经运动障碍和探索性行为障碍的恢复。在早期（损伤后5 天）观察到同伤丘脑区域星形细胞激活减少和神经元丢失，在晚期（30 dpi）观察到神经炎症基因表达减弱，同时在5天抗生素治疗后肠道微生物谱严重破坏，而结构性脑损伤未受影响。结论：我们证明了抗生素治疗对实验性TBI后神经炎症反应的加速恢复和持久效果。血浆中脂多糖结合蛋白和短链脂肪酸水平的升高被评估，但未被确定为潜在的调节剂。由于观察到的影响不能完全与肠道生态失调有关，抗生素物质直接调节继发性脑损伤应被视为一种替代机制。

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引用次数: 0

Investigating the therapeutic potential of nasal administration of mitochondria on blood-brain barrier integrity and vasogenic brain Edema in a rat ischemic stroke model 探讨鼻腔给药线粒体对大鼠缺血性脑卒中模型血脑屏障完整性和血管源性脑水肿的治疗潜力。

IF 4.2 2区医学 Q1 NEUROSCIENCES

Experimental Neurology

Pub Date : 2026-04-01 Epub Date: 2025-12-23 DOI: 10.1016/j.expneurol.2025.115609

Nooshin Sadeghian , Hamdollah Panahpour , Mohammad Reza Alipour , Fereshteh Farajdokht , Javad Shadman

Mitochondrial dysfunction is an early and critical factor in the development of ischemic stroke. This study investigated the therapeutic potential of intranasally delivered mitochondria to reduce vasogenic cerebral edema and protect blood-brain barrier (BBB) integrity in a rat model of ischemic stroke. Male rats underwent 60 min of middle cerebral artery occlusion to induce stroke and then received daily intranasal mitochondrial treatment (750 μg/50 μl) for two days. Cerebral edema was measured by the wet/dry method, and BBB permeability was assessed using Evans blue dye extravasation. Mitochondrial function was evaluated by assessing mitochondrial swelling, mitochondrial membrane potential (MMP), succinate dehydrogenase (SDH) activity, and reactive oxygen species (ROS) production. Protein levels of matrix metalloproteinase-9 (MMP-9), intercellular adhesion molecule-1 (ICAM-1), and markers of apoptosis were examined by immunofluorescence. The treatment significantly reduced infarct size, improved sensorimotor function, decreased cerebral edema, and preserved BBB integrity. These benefits correlated with improved mitochondrial function—demonstrated by reduced swelling and ROS, and restoration of MMP and SDH activity. Additionally, mitochondrial therapy lowered apoptosis and decreased expression of MMP-9 and ICAM-1. These findings suggest that intranasal mitochondrial administration mitigates cerebral edema and BBB disruption after ischemic stroke. This protective effect is likely achieved by enhancing mitochondrial function and lowering levels of inflammation-related proteins, suggesting a promising neuroprotective strategy targeting mitochondrial dysfunction in stroke.

线粒体功能障碍是缺血性脑卒中发生的早期和关键因素。本研究探讨了鼻内给药线粒体在缺血性脑卒中大鼠模型中减少血管源性脑水肿和保护血脑屏障（BBB）完整性的治疗潜力。雄性大鼠先阻断大脑中动脉60 min诱导脑卒中，然后每天给予鼻内线粒体治疗（750 μl /50 μl），连续2天。干湿法测定脑水肿，Evans蓝染料外渗法测定血脑屏障通透性。通过评估线粒体肿胀、线粒体膜电位（MMP）、琥珀酸脱氢酶（SDH）活性和活性氧（ROS）产生来评估线粒体功能。免疫荧光法检测基质金属蛋白酶-9 （MMP-9）、细胞间粘附分子-1 （ICAM-1）和凋亡标志物的蛋白水平。治疗显著减少梗死面积，改善感觉运动功能，减少脑水肿，并保持血脑屏障完整性。这些益处与线粒体功能的改善有关——肿胀和ROS的减少以及MMP和SDH活性的恢复证明了这一点。此外，线粒体治疗可降低细胞凋亡，降低MMP-9和ICAM-1的表达。这些发现表明，鼻内给药线粒体可减轻缺血性卒中后脑水肿和血脑屏障破坏。这种保护作用可能是通过增强线粒体功能和降低炎症相关蛋白水平来实现的，这表明一种针对中风线粒体功能障碍的有希望的神经保护策略。

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引用次数: 0

Role of A-delta low threshold mechanoreceptors and tropomyosin receptor kinase B plasticity in at-level aversive pain after spinal cord injury a - δ低阈机械受体和原肌球蛋白受体激酶B可塑性在脊髓损伤后水平厌恶性疼痛中的作用

IF 4.2 2区医学 Q1 NEUROSCIENCES

Experimental Neurology

Pub Date : 2026-04-01 Epub Date: 2025-12-31 DOI: 10.1016/j.expneurol.2025.115628

Shangrila Parvin, Kyeongran Jang, Sandra M. Garraway

The mechanisms of neuropathic pain after spinal cord injury (SCI) are not fully understood, although spinal and peripheral processes are involved. Maladaptive tropomyosin receptor kinase-B (TrkB) signaling has been implicated in pain hypersensitivity after SCI. A-delta-low threshold mechanoreceptors (Aδ-LTMRs) innervate the hairy skin and normally signal directional touch and are identified by their preferential TrkB expression. This study investigated whether Aδ-LTMRs play a role in at-level pain after thoracic contusion SCI. Using a modified light-dark chamber conditioned place aversion (CPA) paradigm, we assessed chamber preferences and transitions between chambers in response to mechanical stimulation, and optogenetic stimulation of Aδ-LTMRs in the trunk skin of adult TrkB^Cre mice of both sexes. Respiratory rates (RRs) were monitored at baseline and during truncal stimulation. The expression of brain-derived neurotrophic factor (BDNF), TrkB and pERK1/2 in the lesioned spinal cord and skin, and histological changes in Aδ-LTMRs in trunk skin were assessed. In addition, electrophysiological studies examined changes in Aδ-LTMRs membrane and firing properties, and response to bath-applied 7, 8-dihydroxyflavone (7,8-DHF), a TrkB agonist. The results showed that whereas brush stimulation evoked an aversive response at 4 weeks post-SCI that was accompanied by increased RRs, targeted stimulation of Aδ-LTMRs produced an aversive response 7 weeks post-SCI. SCI increased BDNF, TrkB and pERK1/2 expression in the skin, and augmented 7,8-DHF-induced inward current in Aδ-LTMRs. Together, these results suggest that plasticity of Aδ-LTMR, including an increase in TrkB signaling in the periphery, contribute to at-level affective pain following chronic SCI in adult mice.

脊髓损伤（SCI）后神经性疼痛的机制尚不完全清楚，尽管涉及脊髓和外周过程。原肌球蛋白受体激酶- b （TrkB）信号的不适应与脊髓损伤后的疼痛超敏反应有关。a- δ-低阈值机械感受器（a- δ- ltmrs）支配毛茸茸的皮肤，通常指示定向触摸，并通过其优先表达TrkB来识别。本研究探讨了a - δ- ltmr是否在胸挫伤脊髓损伤后的水平疼痛中起作用。利用改进的光-暗室条件下的场所厌恶（CPA）范式，我们评估了成年TrkBCre小鼠躯干皮肤a δ- ltmrs在机械刺激和光遗传刺激下的室偏好和室间转换。在基线和躯干刺激期间监测呼吸频率（rr）。观察脑源性神经营养因子（BDNF）、TrkB和pERK1/2在损伤脊髓和皮肤中的表达及躯干皮肤Aδ-LTMRs的组织学变化。此外，电生理研究还检测了a - δ- ltmrs膜和放电特性的变化，以及对TrkB激动剂7,8-二羟黄酮（7,8- dhf）的反应。结果表明，刷刺激在脊髓损伤后4周引起厌恶反应，并伴有rr升高，而a δ- ltmr靶向刺激在脊髓损伤后7周产生厌恶反应。SCI增加了皮肤中BDNF、TrkB和pERK1/2的表达，增强了Aδ-LTMRs中7,8- dhf诱导的内向电流。总之，这些结果表明，a - δ- ltmr的可塑性，包括外周TrkB信号的增加，有助于成年小鼠慢性脊髓损伤后的情感性疼痛。

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引用次数: 0

Abnormal upregulation of SPP1 promotes fibrotic scar after peripheral nerve repair (FS-PNR) by driving M2 macrophage polarization SPP1异常上调通过驱动M2巨噬细胞极化促进周围神经修复后纤维化瘢痕（FS-PNR）

IF 4.2 2区医学 Q1 NEUROSCIENCES

Experimental Neurology

Pub Date : 2026-04-01 Epub Date: 2025-12-23 DOI: 10.1016/j.expneurol.2025.115612

Jingyuan Fan , Zhe Li , Nan Zhang , Shuolin Wang , Canbin Zheng , Qingtang Zhu , Honggang Wang , Jian Qi , Liwei Yan

Fibrotic scar after peripheral nerve repair (FS-PNR) hinder axon regeneration and functional recovery. However, the mechanism underlying FS-PNR formation remains elusive. SPP1, a glycoprotein known to promote fibrosis in multiple organ systems, was abnormally upregulated in human peripheral nerve fibrotic scar tissues, though its cellular functions in FS-PNR were undefined. Using single- nucleus RNA sequencing, we confirmed SPP1 upregulation in FS-PNR patients and identified repair Schwann cells (rSCs) as its primary cellular source, with macrophages as key targets. To investigate this axis, we established an animal model replicating clinical FS-PNR pathology, validated by histopathological and functional assessments. Notably, SPP1 elevation correlated with increased M2 macrophage infiltration within fibrotic scars. Genetic ablation of SPP1 in mice significantly reduced scar formation and improved functional outcomes. Transcriptomic analysis revealed that SPP1 depletion promoted macrophage M1 polarization. Further in vitro studies demonstrated that SPP1 drives fibrogenesis by inducing macrophage M2 polarization. Together, our findings implicate SPP1 as a novel mediator of FS-PNR pathology via rSCs-macrophage crosstalk.

周围神经修复后的纤维化瘢痕（FS-PNR）阻碍轴突再生和功能恢复。然而，FS-PNR形成的机制尚不清楚。SPP1是一种已知可促进多器官系统纤维化的糖蛋白，在人周围神经纤维化瘢痕组织中异常上调，但其在FS-PNR中的细胞功能尚不明确。通过单核RNA测序，我们证实了SPP1在FS-PNR患者中上调，并确定修复雪旺细胞（rSCs）是其主要细胞来源，巨噬细胞是其关键靶点。为了研究这个轴，我们建立了一个复制临床FS-PNR病理的动物模型，并通过组织病理学和功能评估进行了验证。值得注意的是，SPP1升高与纤维化瘢痕内M2巨噬细胞浸润增加相关。基因消融小鼠SPP1可显著减少瘢痕形成并改善功能预后。转录组学分析显示SPP1缺失促进巨噬细胞M1极化。进一步的体外研究表明SPP1通过诱导巨噬细胞M2极化来驱动纤维形成。总之，我们的研究结果表明SPP1通过rscs -巨噬细胞串扰作为FS-PNR病理的新介质。

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引用次数: 0