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Gut microbiota-derived 3-indoleacetic acid confers a protection against sepsis-associated encephalopathy through microglial aryl hydrocarbon receptors. 肠道微生物群衍生的 3-吲哚乙酸通过小胶质细胞芳基烃受体对败血症相关脑病起到保护作用
IF 4.6 2区 医学 Q1 NEUROSCIENCES Pub Date : 2024-11-14 DOI: 10.1016/j.expneurol.2024.115055
Zhi-Bin Huang, Guo-Pan Zhang, Chen-Xin Lu, Cansheng Gong, Xiaotan Gao, Yanqi Lin, Ping Su, Wenyan Xu, Yongbao Lin, Na Lin, Xuyang Wu, Xiaohui Chen, Ting Zheng, Xiaochun Zheng

Background: The gut microbiota significantly contributes to the pathogenesis of central nervous system disorders. Among the bioactive molecules produced by the gut microbiota, 3-indoleacetic acid (IAA) has been shown to attenuate oxidative stress and inflammatory responses. This experiment aimed to determine the impacts of IAA on sepsis-associated encephalopathy (SAE) and the underlying mechanisms.

Methods: A total of 34 septic patients and 24 healthy controls were included in the analysis of the clinical correlation between fecal IAA and septic encephalopathy. Fecal microbiota transplantation was used to verify the role of the gut microbiota and its metabolites in SAE. Male C57BL/6 mice aged six to eight weeks, pre-treated with IAA via oral gavage, were subjected to the cecal ligation and puncture (CLP) procedures. This treatment was administered either in combination with an aryl hydrocarbon receptor (AhR) antagonist, CH223191, or a CSF1R inhibitor, PLX3397, to eliminate microglia. Both immunofluorescence staining and enzyme-linked immunosorbent assays were used to evaluate microglia activation and inflammatory cytokine secretion. Behavioral assessments were conducted to quantify neurological deficits.

Results: A decreased fecal level of IAA was observed in the patients with sepsis-associated delirium (SAD), a manifestation of SAE. A reduced IAA level was significantly associated with worsen clinical outcomes. Fecal microbiota transplantation from the SAD patients induced an SAE-like phenotype in mice, but supplementing exogenous IAA improved the SAE-like phenotype, mediated by microglia. IAA effectively binded with the aryl hydrocarbon receptor (AhR). Furthermore, IAA increased the nuclear activity of AhR in the lipopolysaccharide (LPS)-treated microglial cells, leading to reduced secretion of inflammatory cytokines. The AhR inhibitor CH223191 counteracted the protective effect of IAA against SAE in mice.

Conclusions: Gut microbiota-derived IAA confers a protection against SAE by activating AhR in microglia, improving neuronal and cognitive impairments. Thus, IAA holds the promise as a potential therapeutic agent for managing SAE.

背景:肠道微生物群对中枢神经系统疾病的发病机制有重要影响。在肠道微生物群产生的生物活性分子中,3-吲哚乙酸(IAA)已被证明可减轻氧化应激和炎症反应。本实验旨在确定IAA对败血症相关脑病(SAE)的影响及其内在机制:方法:共有 34 名脓毒症患者和 24 名健康对照者参与了粪便 IAA 与脓毒症脑病之间临床相关性的分析。粪便微生物群移植用于验证肠道微生物群及其代谢产物在脓毒症脑病中的作用。年龄在六到八周的雄性 C57BL/6 小鼠经口服 IAA 预处理后,接受盲肠结扎和穿刺(CLP)手术。该疗法与芳基烃受体(AhR)拮抗剂 CH223191 或 CSF1R 抑制剂 PLX3397 联合使用,以消除小胶质细胞。免疫荧光染色法和酶联免疫吸附试验被用来评估小胶质细胞的活化和炎性细胞因子的分泌。行为评估用于量化神经功能缺陷:结果:脓毒症相关谵妄(SAD)患者粪便中的IAA水平降低,这是SAE的一种表现形式。IAA水平的降低与临床预后的恶化密切相关。移植SAD患者的粪便微生物群可诱导小鼠出现SAE样表型,但补充外源IAA可改善由小胶质细胞介导的SAE样表型。IAA能有效地与芳基烃受体(AhR)结合。此外,IAA还能提高经脂多糖(LPS)处理的小胶质细胞中AhR的核活性,从而减少炎性细胞因子的分泌。AhR抑制剂CH223191抵消了IAA对小鼠SAE的保护作用:结论:肠道微生物群衍生的 IAA 可通过激活小胶质细胞中的 AhR 来保护小鼠免受 SAE 的伤害,从而改善神经元和认知障碍。因此,IAA有望成为控制SAE的潜在治疗药物。
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引用次数: 0
Acute intermittent hypoxia elicits sympathetic neuroplasticity independent of peripheral chemoreflex activation and spinal cord tissue hypoxia in a rodent model of high-thoracic spinal cord injury. 在高胸椎脊髓损伤的啮齿动物模型中,急性间歇性缺氧引起的交感神经可塑性与外周化学反射激活和脊髓组织缺氧无关。
IF 4.6 2区 医学 Q1 NEUROSCIENCES Pub Date : 2024-11-14 DOI: 10.1016/j.expneurol.2024.115054
Mehdi Ahmadian, Erin Erskine, Liisa Wainman, Oliver H Wearing, Jennifer S Duffy, Liam C Stewart, Ryan L Hoiland, Alissa Taki, Raphael R Perim, Gordon S Mitchell, Jonathan P Little, Patrick J Mueller, Glen E Foster, Christopher R West

The loss of medullary control of spinal circuits controlling the heart and blood vessels is a unifying mechanism linking both hemodynamic instability and the risk for cardiovascular diseases (CVD) following spinal cord injury (SCI). As such, new avenues to regulate sympathetic activity are essential to mitigate CVD in this population. Acute intermittent hypoxia (AIH) induces a type of neuroplasticity known as long-term facilitation (LTF), a persistent increase in nerve activity post-AIH in spinal motor circuits. Whether LTF occurs within the sympathetic circuit following SCI is largely unknown. We aimed to test whether AIH elicits sympathetic LTF (i.e., sLTF) and attenuates hypoactivity in sub-lesional splanchnic sympathetic circuits in a male rat model of SCI. In 3 experimental series, we tested whether 1) high-thoracic contusion SCI induces hypoactivity in splanchnic sympathetic nerve activity, 2) AIH elicits sLTF following SCI, and 3) sLTF requires carotid chemoreflex activation or spinal cord tissue hypoxia. Our results indicate that a single-session of AIH therapy (10 × 1 min of FiO2 = 0.1, interspersed with 2 min of FiO2 = 1.0) delivered at 2 weeks following SCI attenuates SCI-induced sympathetic hypoactivity by eliciting sLTF 90 min post-treatment that is independent of peripheral chemoreflex activation and/or spinal cord hypoxia. These findings advance our mechanistic understanding of AIH in the field and yield new insights into factors underpinning AIH-induced sLTF following SCI in a rat model. Our findings also set the stage for the chronic application of AIH to alleviate secondary complications resulting from sympathetic hypoactivity following SCI.

控制心脏和血管的脊髓回路失去延髓控制是脊髓损伤(SCI)后血液动力学不稳定和心血管疾病(CVD)风险之间的统一机制。因此,调节交感神经活动的新途径对于减轻这类人群的心血管疾病至关重要。急性间歇性缺氧(AIH)会诱发一种被称为长期促进(LTF)的神经可塑性,即脊髓运动回路在AIH后神经活动的持续增加。SCI 后交感神经回路中是否会出现 LTF 现象在很大程度上尚属未知。我们的目的是测试在雄性 SCI 大鼠模型中,AIH 是否会引起交感神经 LTF(即 sLTF)并减轻韧带下脾交感神经回路的低活性。在三个实验系列中,我们测试了:1)高位胸腔挫伤 SCI 是否会诱发脾交感神经活动减退;2)AIH 是否会在 SCI 后诱发 sLTF;3)sLTF 是否需要颈动脉化学反射或脊髓组织缺氧。我们的研究结果表明,在脊髓损伤后2周进行单次AIH治疗(10 × 1分钟FiO2 = 0.1,中间穿插2分钟FiO2 = 1.0),可在治疗后90分钟诱发sLTF,从而减轻脊髓损伤引起的交感神经活动减退,而这种活动减退与外周化学反射激活和/或脊髓缺氧无关。这些发现推进了我们对 AIH 的机理认识,并对大鼠模型 SCI 后 AIH 诱导 sLTF 的基础因素产生了新的见解。我们的研究结果还为长期应用 AIH 缓解 SCI 后交感神经功能减退引起的继发性并发症奠定了基础。
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引用次数: 0
A novel phosphodiesterase 5 inhibitor, RF26, improves memory impairment and ameliorates tau aggregation and neuroinflammation in the P301S tauopathy mouse model of Alzheimer's disease 新型磷酸二酯酶5抑制剂RF26能改善阿尔茨海默病P301S tauopathy小鼠模型的记忆损伤,并改善tau聚集和神经炎症。
IF 4.6 2区 医学 Q1 NEUROSCIENCES Pub Date : 2024-11-14 DOI: 10.1016/j.expneurol.2024.115058
Sara El-desouky , Mohammad Abdel-Halim , Reem K. Fathalla , Ashraf H. Abadi , Gary A. Piazza , Mohamed Salama , Sabry Ahmed El-khodery , Mohamed A. Youssef , Sara Elfarrash
Phosphodiesterase-5 (PDE5) inhibitors are primarily used in the treatment of erectile dysfunction and pulmonary hypertension, but have also been reported to have a potential therapeutic effect for the treatment of Alzheimer's disease (AD). This is likely to be through stimulation of nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) signaling by elevating cGMP, a secondary messenger involved in processes of neuroplasticity. In the present study, we evaluated the efficacy of a novel PDE5 inhibitor, RF26, using P301S tauopathy mice model. A body of experimental evidence suggests that the development of tau inclusions leads to the neurodegeneration observed in tauopathies, including AD, Frontotemporal dementia (FTD), Supranuclear palsy and others. RF26 successfully targeted NO/cGMP signaling pathway and showed a significant improvement of spatial memory task performance of P301S mice using Morris Water Maze and T-maze. Furthermore, RF26 -treated mice showed a significant reduction of phosphorylated tau load, gliosis and downregulated pro-inflammatory cytokines. The presented data support the efficacy of RF26 as a potent PDE5 inhibitor and calls for further investigation as a potential therapeutic drug for Alzheimer's and other tauopathy related neurological disorders.
磷酸二酯酶-5(PDE5)抑制剂主要用于治疗勃起功能障碍和肺动脉高压,但也有报道称其具有治疗阿尔茨海默病(AD)的潜在疗效。这可能是通过刺激一氧化氮(NO)/单磷酸环鸟苷(cGMP)信号传导,提高参与神经可塑性过程的次级信使--cGMP。在本研究中,我们利用 P301S tauopathy 小鼠模型评估了新型 PDE5 抑制剂 RF26 的疗效。大量实验证据表明,tau包涵体的发展导致了在tau病(包括AD、额颞叶痴呆(FTD)、核上性麻痹等)中观察到的神经退行性变。RF26 成功地靶向了 NO/cGMP 信号通路,并在莫里斯水迷宫和 T 型迷宫中显著改善了 P301S 小鼠的空间记忆能力。此外,经 RF26 处理的小鼠磷酸化 tau 负荷、神经胶质增生和促炎细胞因子下调均明显减少。所提供的数据证明了 RF26 作为一种强效 PDE5 抑制剂的功效,并呼吁将其作为治疗阿尔茨海默氏症和其他与牛磺酸病相关的神经系统疾病的潜在药物进行进一步研究。
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引用次数: 0
Activation of PAR1 contributes to ferroptosis of Schwann cells and inhibits regeneration of myelin sheath after sciatic nerve crush injury in rats via Hippo-YAP/ACSL4 pathway. PAR1 的激活有助于许旺细胞的铁凋亡,并通过 Hippo-YAP/ACSL4 通路抑制大鼠坐骨神经挤压伤后髓鞘的再生。
IF 4.6 2区 医学 Q1 NEUROSCIENCES Pub Date : 2024-11-12 DOI: 10.1016/j.expneurol.2024.115053
Wu Zhimin, Sun Jun, Liao Zhi, Sun Tao, Huang Lixin, Jia Qiao, Cong Ling, Chuan Chen, Zhang Baoyu, Wang Hui

Objective: Peripheral nerve injury (PNI) is characterized by high incidence and sequela rate. Recently, there was increasing evidence that has shown ferroptosis may impede functional recovery. Our objective is to explore the novel mechanism that regulates ferroptosis after PNI.

Methods: LC-MS/MS proteomics was used to explore the possible differential signals, while PCR array was performed to investigate the differential factors. Besides, we also tried to activate or inhibit the key factors and then observe the level of ferroptosis. Regeneration of myelin sheath was finally examined in vivo via transmission electron microscopy.

Results: Proteomics analysis suggested coagulation signal was activated after sciatic nerve crush injury, in which high expression of F2 (encoding thrombin) and F2r (encoding PAR1) were observed. Both thrombin and PAR1-targeted activator TRAP6 can induce ferroptosis in RSC96 cells, which can be rescued by Vorapaxar (PAR1 targeted inhibitor) in vitro. Further PCR array revealed that activation of PAR1 induced ferroptosis in RSC96 cells by increasing expression of YAP and ACSL4. Immunofluorescence of sciatic nerve confirmed that the expression of YAP and ACSL4 were simultaneously reduced after PAR1 inhibition, which may contribute to myelin regeneration after injury in SD rats.

Conclusion: Inhibition of PAR1 can relieve ferroptosis after sciatic nerve crush injury in SD rats through Hippo-YAP/ACSL4 pathway, thereby regulating myelin regeneration after injury. In summary, PAR1/Hippo-YAP/ACSL4 pathway may be a promising therapeutic target for promoting functional recovery post-sciatic crush injury.

目的:周围神经损伤(PNI)的特点是发病率高、后遗症多。最近,越来越多的证据表明,铁蛋白沉积可能会阻碍功能恢复。我们的目的是探索调控 PNI 后铁蛋白沉积的新机制:方法:采用 LC-MS/MS 蛋白组学方法探索可能的差异信号,同时进行 PCR 阵列研究差异因素。此外,我们还尝试激活或抑制关键因子,然后观察铁突变的水平。最后通过透射电子显微镜观察了体内髓鞘的再生情况:蛋白质组学分析表明,坐骨神经挤压伤后凝血信号被激活,其中 F2(编码凝血酶)和 F2r(编码 PAR1)被高表达。凝血酶和 PAR1 靶向激活剂 TRAP6 都能诱导 RSC96 细胞发生铁变态反应,而 Vorapaxar(PAR1 靶向抑制剂)能在体外挽救这种反应。进一步的 PCR 阵列显示,PAR1 的激活可通过增加 YAP 和 ACSL4 的表达来诱导 RSC96 细胞的铁变态反应。坐骨神经免疫荧光证实,PAR1抑制后,YAP和ACSL4的表达同时减少,这可能有助于SD大鼠损伤后的髓鞘再生:结论:抑制PAR1可通过Hippo-YAP/ACSL4通路缓解SD大鼠坐骨神经挤压伤后的铁蛋白沉积,从而调节损伤后的髓鞘再生。总之,PAR1/Hippo-YAP/ACSL4通路可能是促进坐骨神经挤压伤后功能恢复的一个有前景的治疗靶点。
{"title":"Activation of PAR1 contributes to ferroptosis of Schwann cells and inhibits regeneration of myelin sheath after sciatic nerve crush injury in rats via Hippo-YAP/ACSL4 pathway.","authors":"Wu Zhimin, Sun Jun, Liao Zhi, Sun Tao, Huang Lixin, Jia Qiao, Cong Ling, Chuan Chen, Zhang Baoyu, Wang Hui","doi":"10.1016/j.expneurol.2024.115053","DOIUrl":"10.1016/j.expneurol.2024.115053","url":null,"abstract":"<p><strong>Objective: </strong>Peripheral nerve injury (PNI) is characterized by high incidence and sequela rate. Recently, there was increasing evidence that has shown ferroptosis may impede functional recovery. Our objective is to explore the novel mechanism that regulates ferroptosis after PNI.</p><p><strong>Methods: </strong>LC-MS/MS proteomics was used to explore the possible differential signals, while PCR array was performed to investigate the differential factors. Besides, we also tried to activate or inhibit the key factors and then observe the level of ferroptosis. Regeneration of myelin sheath was finally examined in vivo via transmission electron microscopy.</p><p><strong>Results: </strong>Proteomics analysis suggested coagulation signal was activated after sciatic nerve crush injury, in which high expression of F2 (encoding thrombin) and F2r (encoding PAR1) were observed. Both thrombin and PAR1-targeted activator TRAP6 can induce ferroptosis in RSC96 cells, which can be rescued by Vorapaxar (PAR1 targeted inhibitor) in vitro. Further PCR array revealed that activation of PAR1 induced ferroptosis in RSC96 cells by increasing expression of YAP and ACSL4. Immunofluorescence of sciatic nerve confirmed that the expression of YAP and ACSL4 were simultaneously reduced after PAR1 inhibition, which may contribute to myelin regeneration after injury in SD rats.</p><p><strong>Conclusion: </strong>Inhibition of PAR1 can relieve ferroptosis after sciatic nerve crush injury in SD rats through Hippo-YAP/ACSL4 pathway, thereby regulating myelin regeneration after injury. In summary, PAR1/Hippo-YAP/ACSL4 pathway may be a promising therapeutic target for promoting functional recovery post-sciatic crush injury.</p>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":" ","pages":"115053"},"PeriodicalIF":4.6,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142617553","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Conceptualization and standardization of a non-invasive closed head injury model using directed shockwave to mice 利用定向冲击波对小鼠进行无创闭合性头部损伤模型的概念化和标准化。
IF 4.6 2区 医学 Q1 NEUROSCIENCES Pub Date : 2024-11-12 DOI: 10.1016/j.expneurol.2024.115051
Mohd Aleem, Princy Verma, Kailash Manda
Traumatic brain injury (TBI) is a leading cause of death and disability worldwide, with closed head injury (CHI) being one of the most common forms of TBI. Preclinical modeling of TBI is challenging due to confounding factors like craniectomy and poorly controlled injury severity. This study proposes a non-invasive CHI model using directed shockwaves. The mice heads were exposed to the shockwave and accommodated together following the implantation of RFID tags for automated neurocognitive assessment. Following a 13-days paradigm, mice underwent a digital gait analysis and subsequent classical behavioral test paradigms for affective, cognitive, and locomotor functions. Qualitative and quantitative histopathological assessment was carried out for shockwave pulses-dependent changes in terms of lesion volume, neuronal death, dendritic complexity, and spine density. Studies showed shockwave pulses-dependent differences in survivability, righting reflex, neural damage, and death. Shockwave-exposed mice showed significantly impaired learning and cognitive flexibility. Interestingly, exposed mice showed locomotor hyperactivity and risk-taking behavior (lack of anxiety) along with depression-like phenotypes. Our result suggests that the shockwave-based CHI models result in the clinically relevant phenotype and are precisely controlled for reproducibility.
创伤性脑损伤(TBI)是导致全球死亡和残疾的主要原因,其中闭合性颅脑损伤(CHI)是最常见的创伤性脑损伤形式之一。由于颅骨切除术和损伤严重程度控制不佳等干扰因素,创伤性脑损伤的临床前建模具有挑战性。本研究提出了一种使用定向冲击波的无创创伤性脑损伤模型。小鼠头部暴露在冲击波中,并在植入 RFID 标签后被安置在一起,以进行自动神经认知评估。在为期 13 天的范例研究后,小鼠接受了数字步态分析以及随后的情感、认知和运动功能经典行为测试范例。对冲击波脉冲导致的病变体积、神经元死亡、树突复杂性和脊柱密度变化进行了定性和定量组织病理学评估。研究显示,存活率、右旋反射、神经损伤和死亡与冲击波脉冲有关。受冲击波影响的小鼠的学习能力和认知灵活性明显受损。有趣的是,暴露的小鼠表现出运动机能亢进和冒险行为(缺乏焦虑)以及类似抑郁症的表型。我们的研究结果表明,基于冲击波的脊髓损伤模型能产生临床相关的表型,并能精确控制其可重复性。
{"title":"Conceptualization and standardization of a non-invasive closed head injury model using directed shockwave to mice","authors":"Mohd Aleem,&nbsp;Princy Verma,&nbsp;Kailash Manda","doi":"10.1016/j.expneurol.2024.115051","DOIUrl":"10.1016/j.expneurol.2024.115051","url":null,"abstract":"<div><div>Traumatic brain injury (TBI) is a leading cause of death and disability worldwide, with closed head injury (CHI) being one of the most common forms of TBI. Preclinical modeling of TBI is challenging due to confounding factors like craniectomy and poorly controlled injury severity. This study proposes a non-invasive CHI model using directed shockwaves. The mice heads were exposed to the shockwave and accommodated together following the implantation of RFID tags for automated neurocognitive assessment. Following a 13-days paradigm, mice underwent a digital gait analysis and subsequent classical behavioral test paradigms for affective, cognitive, and locomotor functions. Qualitative and quantitative histopathological assessment was carried out for shockwave pulses-dependent changes in terms of lesion volume, neuronal death, dendritic complexity, and spine density. Studies showed shockwave pulses-dependent differences in survivability, righting reflex, neural damage, and death. Shockwave-exposed mice showed significantly impaired learning and cognitive flexibility. Interestingly, exposed mice showed locomotor hyperactivity and risk-taking behavior (lack of anxiety) along with depression-like phenotypes. Our result suggests that the shockwave-based CHI models result in the clinically relevant phenotype and are precisely controlled for reproducibility.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"384 ","pages":"Article 115051"},"PeriodicalIF":4.6,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142617555","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Modeling of TDP-43 proteinopathy by chronic oxidative stress identifies rapamycin as beneficial in ALS patient-derived 2D and 3D iPSC models 慢性氧化应激导致的 TDP-43 蛋白病变模型确定雷帕霉素对 ALS 患者衍生的二维和三维 iPSC 模型有益。
IF 4.6 2区 医学 Q1 NEUROSCIENCES Pub Date : 2024-11-12 DOI: 10.1016/j.expneurol.2024.115057
Valeria Casiraghi , Marta Nice Sorce , Serena Santangelo , Sabrina Invernizzi , Patrizia Bossolasco , Chiara Lattuada , Cristina Battaglia , Marco Venturin , Vincenzo Silani , Claudia Colombrita , Antonia Ratti
Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disorder characterized neuropathologically by TDP-43 proteinopathy with loss of TDP-43 nuclear splicing activity and formation of cytoplasmic TDP-43 aggregates. The lack of suitable experimental models of TDP-43 proteinopathy has hampered the discovery of effective therapies. We already showed that chronic and mild oxidative insult by sodium arsenite (ARS) triggered TDP-43 cytoplasmic aggregation and stress granules (SGs) formation in ALS patient-derived fibroblasts and motor neurons differentiated from induced pluripotent stem cells (iPSC-MNs). However, whether this insult induces a reduction of TDP-43 splicing activity in the nucleus, thus recapitulating both gain and loss of function pathomechanisms, still remains to be determined.
In this study we first showed that chronic ARS in human neuroblastoma cells triggered TDP-43 cytoplasmic mislocalization, SGs formation and defective splicing of TDP-43 target genes UNC13A and POLDIP3 as functional readouts of TDP-43 proteinopathy. Additionally, a dysregulation of autophagy and senescence markers was observed in this condition. In a preliminary drug screening approach with autophagy-promoting drugs, namely rapamycin, lithium carbonate and metformin, only rapamycin prevented ARS-induced loss of TDP-43 splicing activity. We then demonstrated that, in addition to TDP-43 cytoplasmic aggregation, chronic ARS triggered TDP-43 loss of splicing activity also in ALS patient-derived primary fibroblasts and iPSC-MNs and that rapamycin was beneficial to reduce these TDP-43 pathological features. By switching to a neuro-glial 3D in vitro model, we observed that treatment of ALS iPSC-brain organoids with chronic ARS also induced a defective TDP-43 splicing activity which was prevented by rapamycin.
Collectively, we established different human cell models of TDP-43 proteinopathy which recapitulate TDP-43 gain and loss of function, prevented by rapamycin administration. Human neuroblastoma cells and patient-derived fibroblasts and 2D- and 3D-iPSC models exposed to chronic oxidative stress represent therefore suitable in vitro platforms for future drug screening approaches in ALS.
肌萎缩侧索硬化症(ALS)是一种致命的神经退行性疾病,其神经病理学特征是 TDP-43 蛋白病变,TDP-43 核剪接活性丧失并形成细胞质 TDP-43 聚集体。TDP-43 蛋白病缺乏合适的实验模型,这阻碍了有效疗法的发现。我们已经证明,亚砷酸钠(ARS)的慢性轻度氧化损伤会引发 ALS 患者来源的成纤维细胞和诱导多能干细胞(iPSC-MNs)分化的运动神经元中的 TDP-43 胞质聚集和应激颗粒(SGs)形成。然而,这种损伤是否会诱导细胞核中TDP-43剪接活性的降低,从而重现功能获得和丧失的病理机制,仍有待确定。在这项研究中,我们首次发现在人类神经母细胞瘤细胞中慢性 ARS 会引发 TDP-43 细胞质错定位、SGs 形成以及 TDP-43 靶基因 UNC13A 和 POLDIP3 的剪接缺陷,这些都是 TDP-43 蛋白病变的功能读数。此外,在这种情况下还观察到自噬和衰老标记的失调。在使用雷帕霉素、碳酸锂和二甲双胍等自噬促进药物的初步药物筛选方法中,只有雷帕霉素能阻止 ARS 诱导的 TDP-43 剪接活性丧失。我们随后证明,除了 TDP-43 细胞质聚集外,慢性 ARS 还会在 ALS 患者来源的原代成纤维细胞和 iPSC-MNs 中引发 TDP-43 剪接活性丧失,而雷帕霉素有利于减少这些 TDP-43 病理特征。通过转换到神经胶质细胞三维体外模型,我们观察到用慢性ARS处理ALS iPSC-脑器官组织也会诱发TDP-43剪接活性缺陷,而雷帕霉素可以阻止这种缺陷。总之,我们建立了不同的TDP-43蛋白病人类细胞模型,这些模型再现了TDP-43的功能增益和丧失,并通过雷帕霉素的应用加以预防。因此,暴露于慢性氧化应激的人类神经母细胞瘤细胞和患者衍生成纤维细胞以及二维和三维 iPSC 模型是未来 ALS 药物筛选方法的合适体外平台。
{"title":"Modeling of TDP-43 proteinopathy by chronic oxidative stress identifies rapamycin as beneficial in ALS patient-derived 2D and 3D iPSC models","authors":"Valeria Casiraghi ,&nbsp;Marta Nice Sorce ,&nbsp;Serena Santangelo ,&nbsp;Sabrina Invernizzi ,&nbsp;Patrizia Bossolasco ,&nbsp;Chiara Lattuada ,&nbsp;Cristina Battaglia ,&nbsp;Marco Venturin ,&nbsp;Vincenzo Silani ,&nbsp;Claudia Colombrita ,&nbsp;Antonia Ratti","doi":"10.1016/j.expneurol.2024.115057","DOIUrl":"10.1016/j.expneurol.2024.115057","url":null,"abstract":"<div><div>Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disorder characterized neuropathologically by TDP-43 proteinopathy with loss of TDP-43 nuclear splicing activity and formation of cytoplasmic TDP-43 aggregates. The lack of suitable experimental models of TDP-43 proteinopathy has hampered the discovery of effective therapies. We already showed that chronic and mild oxidative insult by sodium arsenite (ARS) triggered TDP-43 cytoplasmic aggregation and stress granules (SGs) formation in ALS patient-derived fibroblasts and motor neurons differentiated from induced pluripotent stem cells (iPSC-MNs). However, whether this insult induces a reduction of TDP-43 splicing activity in the nucleus, thus recapitulating both gain and loss of function pathomechanisms, still remains to be determined.</div><div>In this study we first showed that chronic ARS in human neuroblastoma cells triggered TDP-43 cytoplasmic mislocalization, SGs formation and defective splicing of TDP-43 target genes <em>UNC13A</em> and <em>POLDIP3</em> as functional readouts of TDP-43 proteinopathy. Additionally, a dysregulation of autophagy and senescence markers was observed in this condition. In a preliminary drug screening approach with autophagy-promoting drugs, namely rapamycin, lithium carbonate and metformin, only rapamycin prevented ARS-induced loss of TDP-43 splicing activity. We then demonstrated that, in addition to TDP-43 cytoplasmic aggregation, chronic ARS triggered TDP-43 loss of splicing activity also in ALS patient-derived primary fibroblasts and iPSC-MNs and that rapamycin was beneficial to reduce these TDP-43 pathological features. By switching to a neuro-glial 3D <em>in vitro</em> model, we observed that treatment of ALS iPSC-brain organoids with chronic ARS also induced a defective TDP-43 splicing activity which was prevented by rapamycin.</div><div>Collectively, we established different human cell models of TDP-43 proteinopathy which recapitulate TDP-43 gain and loss of function, prevented by rapamycin administration. Human neuroblastoma cells and patient-derived fibroblasts and 2D- and 3D-iPSC models exposed to chronic oxidative stress represent therefore suitable <em>in vitro</em> platforms for future drug screening approaches in ALS.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"383 ","pages":"Article 115057"},"PeriodicalIF":4.6,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142617559","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Sevoflurane aggravates cognitive impairment in OSAS mice through tau phosphorylation and mitochondrial dysfunction. 七氟烷通过tau磷酸化和线粒体功能障碍加重OSAS小鼠的认知功能障碍。
IF 4.6 2区 医学 Q1 NEUROSCIENCES Pub Date : 2024-11-12 DOI: 10.1016/j.expneurol.2024.115056
Feixiang Li, Dujuan Li, Bingqing Gong, Zichen Song, Yang Yu, Yonghao Yu, Yongyan Yang

With an aging population, the incidence of obstructive sleep apnea syndrome (OSAS) is rising, resulting in a growing number of patients undergoing surgery who are also affected by OSAS. The combined impact of anesthetic drugs and OSAS-related neurological damage has drawn significant attention. Here, wild-type (WT) and Tau-knockout (Tau-KO) mice were subjected to intermittent hypoxia and sevoflurane exposure to induce OSAS and sevoflurane-induced neurotoxicity. Protein expression of tau phosphorylation (Tau-Ser202/Thr205 and Tau-Ser422) was measured by Western blotting. Immunofluorescence was used to visualize tau phosphorylation (Tau-Ser202/Thr205) in the hippocampal CA1 region. Mitochondrial function was evaluated by measuring reactive oxygen species (ROS), mitochondrial membrane potential (MMP), and ATP levels. Cognitive functions were assessed using the Morris water maze and Y-maze tests. We found that compared to the WT OSAS group, sevoflurane significantly increased tau phosphorylation and mitochondrial dysfunction in WT OSAS mice, leading to cognitive impairment. Interestingly, idebenone treatment mitigated sevoflurane-induced mitochondrial dysfunction and cognitive impairment in WT OSAS mice, but it did not affect tau phosphorylation. Compared to the Tau-KO control group, Tau-KO OSAS mice exhibited mitochondrial dysfunction and cognitive impairment, but sevoflurane did not exacerbate mitochondrial dysfunction or cognitive impairment in these mice. These findings suggest that sevoflurane exacerbates cognitive impairments in OSAS mice through tau phosphorylation-induced mitochondrial dysfunction, but also uncovered differing mechanisms between cognitive impairments induced by OSAS and those exacerbated by sevoflurane.

随着人口老龄化,阻塞性睡眠呼吸暂停综合症(OSAS)的发病率不断上升,导致越来越多的手术患者也受到 OSAS 的影响。麻醉药物和 OSAS 相关神经损伤的综合影响引起了人们的极大关注。在这里,野生型(WT)和Tau基因敲除(Tau-KO)小鼠受到间歇性缺氧和七氟烷暴露,以诱导OSAS和七氟烷诱导的神经毒性。用 Western 印迹法测定 tau 磷酸化(Tau-Ser202/Thr205 和 Tau-Ser422)的蛋白表达。免疫荧光用于观察海马 CA1 区的 tau 磷酸化(Tau-Ser202/Thr205)。线粒体功能通过测量活性氧(ROS)、线粒体膜电位(MMP)和 ATP 水平进行评估。认知功能通过莫里斯水迷宫和Y迷宫测试进行评估。我们发现,与 WT OSAS 组相比,七氟醚显著增加了 WT OSAS 小鼠的 tau 磷酸化和线粒体功能障碍,从而导致认知障碍。有趣的是,依地苯酮治疗减轻了七氟烷诱导的线粒体功能障碍和WT OSAS小鼠的认知障碍,但并不影响tau磷酸化。与 Tau-KO 对照组相比,Tau-KO OSAS 小鼠表现出线粒体功能障碍和认知功能损害,但七氟烷并未加剧这些小鼠的线粒体功能障碍或认知功能损害。这些研究结果表明,七氟醚通过tau磷酸化诱导的线粒体功能障碍加剧了OSAS小鼠的认知障碍,但同时也发现了OSAS诱导的认知障碍与七氟醚加剧的认知障碍之间的不同机制。
{"title":"Sevoflurane aggravates cognitive impairment in OSAS mice through tau phosphorylation and mitochondrial dysfunction.","authors":"Feixiang Li, Dujuan Li, Bingqing Gong, Zichen Song, Yang Yu, Yonghao Yu, Yongyan Yang","doi":"10.1016/j.expneurol.2024.115056","DOIUrl":"10.1016/j.expneurol.2024.115056","url":null,"abstract":"<p><p>With an aging population, the incidence of obstructive sleep apnea syndrome (OSAS) is rising, resulting in a growing number of patients undergoing surgery who are also affected by OSAS. The combined impact of anesthetic drugs and OSAS-related neurological damage has drawn significant attention. Here, wild-type (WT) and Tau-knockout (Tau-KO) mice were subjected to intermittent hypoxia and sevoflurane exposure to induce OSAS and sevoflurane-induced neurotoxicity. Protein expression of tau phosphorylation (Tau-Ser202/Thr205 and Tau-Ser422) was measured by Western blotting. Immunofluorescence was used to visualize tau phosphorylation (Tau-Ser202/Thr205) in the hippocampal CA1 region. Mitochondrial function was evaluated by measuring reactive oxygen species (ROS), mitochondrial membrane potential (MMP), and ATP levels. Cognitive functions were assessed using the Morris water maze and Y-maze tests. We found that compared to the WT OSAS group, sevoflurane significantly increased tau phosphorylation and mitochondrial dysfunction in WT OSAS mice, leading to cognitive impairment. Interestingly, idebenone treatment mitigated sevoflurane-induced mitochondrial dysfunction and cognitive impairment in WT OSAS mice, but it did not affect tau phosphorylation. Compared to the Tau-KO control group, Tau-KO OSAS mice exhibited mitochondrial dysfunction and cognitive impairment, but sevoflurane did not exacerbate mitochondrial dysfunction or cognitive impairment in these mice. These findings suggest that sevoflurane exacerbates cognitive impairments in OSAS mice through tau phosphorylation-induced mitochondrial dysfunction, but also uncovered differing mechanisms between cognitive impairments induced by OSAS and those exacerbated by sevoflurane.</p>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":" ","pages":"115056"},"PeriodicalIF":4.6,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142617566","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Unlocking new Frontiers: The cellular and molecular impact of extracorporeal shock wave therapy (ESWT) on central nervous system (CNS) disorders and peripheral nerve injuries (PNI) 开启新前沿:体外冲击波疗法 (ESWT) 对中枢神经系统 (CNS) 疾病和周围神经损伤 (PNI) 的细胞和分子影响。
IF 4.6 2区 医学 Q1 NEUROSCIENCES Pub Date : 2024-11-10 DOI: 10.1016/j.expneurol.2024.115052
Baodan Cao , Xiaobin Tang , Chuangjian Liu , Guangyu Xu , Mingcheng Lei , Fan Wu , Wei Chen , Hongbin Ni , Feng Zhang
Neurological disorders encompassing both central nervous system (CNS) diseases and peripheral nerve injuries (PNI), represent significant challenges in modern clinical practice. Conditions such as stroke, spinal cord injuries, and carpal tunnel syndrome can cause debilitating impairments, leading to reduced quality of life and placing a heavy burden on healthcare systems. Current treatment strategies, including pharmacological interventions and surgical procedures, often yield limited results, and many patients experience suboptimal outcomes or treatment-associated risks. In light of these limitations, there is a growing interest in exploring non-invasive therapeutic alternatives. Among these, extracorporeal shock wave therapy (ESWT) has eme rged as a promising modality, demonstrating efficacy in musculoskeletal conditions and gaining attention for its potential role in neurological disorders. This manuscript aims to provide a comprehensive overview of the cellular and molecular mechanisms underlying ESWT, focusing on its therapeutic applications in CNS diseases and PNI, thereby shedding light on its potential to revolutionize the treatment landscape for neurological conditions.
神经系统疾病包括中枢神经系统(CNS)疾病和周围神经损伤(PNI),是现代临床实践中的重大挑战。中风、脊髓损伤和腕管综合征等疾病会造成衰弱性损伤,导致生活质量下降,并给医疗系统带来沉重负担。目前的治疗策略,包括药物干预和外科手术,往往效果有限,许多患者的治疗效果不理想或存在治疗相关风险。鉴于这些局限性,人们对探索非侵入性替代治疗方法的兴趣与日俱增。其中,体外冲击波疗法(ESWT)已成为一种前景广阔的治疗方式,在肌肉骨骼疾病中显示出疗效,并因其在神经系统疾病中的潜在作用而备受关注。本手稿旨在全面概述 ESWT 的细胞和分子机制,重点介绍其在中枢神经系统疾病和 PNI 中的治疗应用,从而揭示其彻底改变神经系统疾病治疗格局的潜力。
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引用次数: 0
Enhancing data standards to advance translation in spinal cord injury. 加强数据标准,促进脊髓损伤的转化。
IF 4.6 2区 医学 Q1 NEUROSCIENCES Pub Date : 2024-11-08 DOI: 10.1016/j.expneurol.2024.115048
Vanessa K Noonan, Suzanne Humphreys, Fin Biering-Sorensen, Susan Charlifue, Yuying Chen, James D Guest, Linda A T Jones, Jennifer French, Eva Widerstrom-Noga, Vance P Lemmon, Allen W Heinemann, Jan M Schwab, Aaron A Phillips, Marzieh Mussavi Rizi, John L K Kramer, Catherine R Jutzeler, Abel Torres-Espin

Data standards are available for spinal cord injury (SCI). The International SCI Data Sets were created in 2002 and there are currently 27 freely available. In 2015 the National Institute of Neurological Disorders and Stroke developed clinical common data elements to promote clinical data sharing in SCI. The objective of this paper is to provide an overview of SCI data standards, describe learnings from the traumatic brain injury (TBI) field using data to enhance research and care, and discuss future opportunities in SCI. Given the complexity of SCI, frameworks such as a systems medicine approach and Big Data perspective have been advanced. Implementation of these frameworks require multi-modal data and a shift towards open science and principles such as requiring data to be FAIR (Findable, Accessible, Interoperable and Reusable). Advanced analytics such as artificial intelligence require data to be interoperable so data can be exchanged among different technology systems and software applications. The TBI field has multiple ongoing initiatives to promote sharing and data reuse for both pre-clinical and clinical studies, which is an opportunity for the SCI field given these injuries can often occur concomitantly. The adoption of interoperable standards, data sharing, open science, and the use of advanced analytics in SCI is needed to facilitate translation in research and care. It is critical that people with lived experience are engaged to ensure data are relevant and enhances quality of life.

脊髓损伤(SCI)有数据标准。国际 SCI 数据集于 2002 年创建,目前有 27 个数据集可免费使用。2015 年,美国国家神经疾病和中风研究所开发了临床通用数据元素,以促进 SCI 临床数据共享。本文旨在概述 SCI 数据标准,介绍创伤性脑损伤(TBI)领域利用数据加强研究和护理的经验,并讨论 SCI 的未来机遇。鉴于 SCI 的复杂性,系统医学方法和大数据视角等框架已被提出。实施这些框架需要多模态数据,并转向开放科学和原则,如要求数据具有 FAIR(可查找、可访问、可互操作和可重用)。人工智能等高级分析要求数据具有互操作性,以便在不同的技术系统和软件应用程序之间交换数据。创伤性脑损伤领域正在实施多项计划,以促进临床前和临床研究中的数据共享和重复使用,这对 SCI 领域来说是一个机遇,因为这些损伤往往可能同时发生。需要在 SCI 领域采用互操作标准、数据共享、开放科学和先进分析技术,以促进研究和护理的转化。关键是要让有生活经验的人参与进来,以确保数据的相关性并提高生活质量。
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引用次数: 0
Modulation of GABAergic system as a therapeutic option in stroke. 调节 GABA 能系统作为治疗中风的一种选择。
IF 4.6 2区 医学 Q1 NEUROSCIENCES Pub Date : 2024-11-08 DOI: 10.1016/j.expneurol.2024.115050
Milka Perovic, Damjan Pavlovic, Zoe Palmer, Mariana S B Udo, Cristiane T Citadin, Krista M Rodgers, Celeste Yin-Chien Wu, Quanguang Zhang, Hung Wen Lin, Vesna Tesic

Stroke is one of the leading causes of death and permanent adult disability worldwide. Despite the improvements in reducing the rate and mortality, the societal burden and costs of treatment associated with stroke management are increasing. Most of the therapeutic approaches directly targeting ischemic injury have failed to reduce short- and long-term morbidity and mortality and more effective therapeutic strategies are still needed to promote post-stroke functional recovery. Decades of stroke research have been focused on hyperexcitability and glutamate-induced excitotoxicity in the acute phase of ischemia and their relation to motor deficits. Recent advances in understanding the pathophysiology of stroke have been made with several lines of evidence suggesting that changes in the neurotransmission of the major inhibitory system via γ-Aminobutyric acid (GABA) play a particularly important role in functional recovery and deserve further attention. The present review provides an overview of how GABAergic neurotransmission changes correlate with stroke recovery and outlines GABAergic system modulators with special emphasis on neurosteroids that have been shown to affect stroke pathogenesis or plasticity or to protect against cognitive decline. Supporting evidence from both animal and human clinical studies is presented and the potential for GABA signaling-targeted therapies for stroke is discussed to translate this concept to human neural repair therapies. Age and sex are considered crucial parameters related to the pathophysiology of stroke and important factors in the development of therapeutic pharmacological strategies. Future work is needed to deepen our knowledge of the neurochemical changes after stroke, extend the conceptual framework, and allow for the development of more effective interventions that include the modulation of the inhibitory system.

中风是导致全球成人死亡和永久性残疾的主要原因之一。尽管在降低发病率和死亡率方面取得了进展,但与中风治疗相关的社会负担和治疗费用却在不断增加。大多数直接针对缺血性损伤的治疗方法都未能降低短期和长期的发病率和死亡率,因此仍需要更有效的治疗策略来促进卒中后的功能恢复。几十年来,脑卒中研究的重点一直是缺血急性期的过度兴奋和谷氨酸诱导的兴奋毒性及其与运动障碍的关系。最近,人们对脑卒中病理生理学的认识取得了进展,一些证据表明,通过γ-氨基丁酸(GABA)的主要抑制系统神经传递的变化在功能恢复中发挥着特别重要的作用,值得进一步关注。本综述概述了 GABA 能神经递质变化如何与中风恢复相关联,并概述了 GABA 能系统调节剂,特别强调了已被证明能影响中风发病机制或可塑性或防止认知功能下降的神经类固醇。报告还介绍了来自动物和人类临床研究的支持性证据,并讨论了针对中风的 GABA 信号疗法的潜力,以便将这一概念转化为人类神经修复疗法。年龄和性别被认为是与中风病理生理学相关的关键参数,也是开发治疗药物策略的重要因素。我们需要在未来的工作中加深对中风后神经化学变化的了解,扩展概念框架,并开发包括调节抑制系统在内的更有效的干预措施。
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引用次数: 0
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Experimental Neurology
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