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Differential evaluation of neuromuscular injuries to understand re-innervation at the neuromuscular junction 神经肌肉损伤的鉴别评估,了解神经肌肉接头处的再神经支配。
IF 4.6 2区 医学 Q1 NEUROSCIENCES Pub Date : 2024-10-10 DOI: 10.1016/j.expneurol.2024.114996
Daniel B. Hoffman , Christiana J. Raymond-Pope , Emma E. Pritchard , Angela S. Bruzina , Thomas J. Lillquist , Benjamin T. Corona , Jarrod A. Call , Sarah M. Greising
Peripheral nerve-crush injury is a well-established model of neuromuscular junction (NMJ) denervation and subsequent re-innervation. Functionally, the skeletal muscle follows a similar pattern as neural recovery, with immediate loss of force production that steadily improves in parallel with rates of re-innervation. On the other hand, traumatic injury to the muscle itself, specifically volumetric muscle loss (VML), results in an irrecoverable loss of muscle function. Recent work has indicated significant impairments to the NMJ following this injury that appear chronic in nature, alongside the lack of functional recovery. Thus, the goal of this study was to compare the effects of nerve and muscle injury on NMJ remodeling. Even numbers of adult male and female mice were used with three experimental groups: injury Naïve, nerve crush, and VML injury; and three terminal timepoints: 3-, 48-, and 112-days post-injury. Confirming the assumed recoverability of the two injury models, we found in vivo maximal torque was fully restored following nerve-crush injury but remained at a significant deficit following VML. Compared to injury Naïve and nerve-crush injury, we found VML results in aberrantly high trophic signaling (e.g., neuregulin-1) and numbers of supporting cells, including terminal Schwann cells and sub-synaptic nuclei. In some cases, sex differences were detected, including higher rates of innervation in females than males. Both nerve crush and VML injury display chronic changes to NMJ morphology, such as increased fragmentation and nerve sprouting, highlighting the potential of VML for modeling NMJ regeneration in adulthood, alongside the established nerve-injury models.
周围神经挤压伤是神经肌肉接头(NMJ)去神经支配和随后再神经支配的一个成熟模型。从功能上讲,骨骼肌的恢复模式与神经恢复类似,都是立即丧失力量,并随着神经再支配率的提高而稳步改善。另一方面,肌肉本身的创伤性损伤,特别是肌肉体积损失(VML),会导致肌肉功能不可恢复的丧失。最近的研究表明,这种损伤对 NMJ 造成了严重损害,而且这种损害似乎是慢性的,同时缺乏功能恢复。因此,本研究的目的是比较神经和肌肉损伤对 NMJ 重塑的影响。本研究使用了数量相等的成年雄性和雌性小鼠,分为三个实验组:损伤新生组、神经挤压组和 VML 损伤组;以及三个终点时间点:损伤后 3 天、48 天和 112 天。我们发现,在神经挤压损伤后,体内最大扭矩完全恢复,但在 VML 损伤后,体内最大扭矩仍明显不足,这证实了两种损伤模型的假定恢复能力。与正常损伤和神经挤压损伤相比,我们发现 VML 会导致营养信号(如神经胶质蛋白-1)和支持细胞(包括末端许旺细胞和突触下核)数量异常增多。在某些情况下,还发现了性别差异,包括女性神经支配率高于男性。神经挤压和 VML 损伤都显示出 NMJ 形态的慢性变化,如碎片增加和神经萌发,这凸显了 VML 与已建立的神经损伤模型一样,在模拟成年期 NMJ 再生方面的潜力。
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引用次数: 0
An infrastructure for qualified data sharing and team science in late-stage translational spinal cord injury research 脊髓损伤后期转化研究中合格数据共享和团队科学的基础设施。
IF 4.6 2区 医学 Q1 NEUROSCIENCES Pub Date : 2024-10-10 DOI: 10.1016/j.expneurol.2024.114995
J. Russell Huie , Abel Torres-Espin , Jeffrey Sacramento , Anastasia V. Keller , Wilsaan M. Joiner , Ryan North , David J. Reinkensmeyer , Ephron S. Rosenzweig , Jacob Koffler , Mark H. Tuszynski , Carolyn J. Sparrey , Jessica L. Nielson , Michael S. Beattie , Jacqueline C. Bresnahan , Jeffrey S. Grethe , Adam R. Ferguson
The complex and heterogeneous nature of spinal cord injury has limited translational bench-to-bedside results. The wide variety of data, including injury parameters, biochemical, histological, and behavioral outcome measures represent a ‘big data’ problem, calling for modern data science solutions. There are some instances in which SCI researchers collect sensitive data that needs to remain private, such as datasets designed to meet regulatory approval, sensitive intellectual property, and non-human primate studies. For these types of data, we have developed a Private Data Commons for SCI (PDC-SCI). Our objective is to give an overview of this novel data commons, describing how this type of commons works, how it can benefit the research community, and the cases in which it would be most useful. This private infrastructure is ideal for multi-lab transdisciplinary studies that require a well-organized, scalable data commons for rapid data sharing within a closed, distributed team. As a use-case for the PDC-SCI, we demonstrate the VA Gordon Mansfield SCI Consortium, in which multimodal data from behavior, biomechanics of injury, hospital records, imaging, and histology are integrated, shared, and analyzed to facilitate insights and knowledge discovery.
脊髓损伤的复杂性和异质性限制了从临床到临床的转化结果。包括损伤参数、生化、组织学和行为结果测量在内的各种数据是一个 "大数据 "问题,需要现代数据科学解决方案。在某些情况下,SCI 研究人员会收集一些需要保密的敏感数据,例如为满足监管审批而设计的数据集、敏感的知识产权和非人灵长类动物研究。针对这些类型的数据,我们开发了 SCI 私有数据公共空间(PDC-SCI)。我们的目标是概述这种新型数据共享机制,介绍这种共享机制的工作原理、如何使研究界受益以及在哪些情况下最有用。这种私人基础设施是多实验室跨学科研究的理想选择,因为这些研究需要一个组织良好、可扩展的数据共享空间,以便在一个封闭的分布式团队中快速共享数据。作为 PDC-SCI 的一个使用案例,我们展示了退伍军人事务部戈登-曼斯菲尔德 SCI 联合会,在该联合会中,来自行为、损伤生物力学、医院记录、成像和组织学的多模态数据得到了整合、共享和分析,以促进洞察力和知识发现。
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引用次数: 0
Neuroprotective agents ineffective in mitigating autonomic dysreflexia following experimental spinal cord injury 神经保护剂无法有效缓解实验性脊髓损伤后的自主神经反射障碍。
IF 4.6 2区 医学 Q1 NEUROSCIENCES Pub Date : 2024-10-10 DOI: 10.1016/j.expneurol.2024.114993
Tamila Kalimullina , Rahul Sachdeva , Kiran Pawar , Steven Cao , Arshdeep Marwaha , Jie Liu , Ward Plunet , Jordan Squair , Christopher R. West , Wolfram Tetzlaff , Andrei V. Krassioukov

Background and objectives

Loss of supraspinal cardiovascular control and secondary damage following spinal cord injury (SCI) lead to cardiovascular dysfunction, where autonomic dysreflexia (AD), triggered by stimuli below the injury, can cause uncontrolled blood pressure (BP) surges, posing severe health risks such as stroke and seizures. While anti-inflammatory neuroprotective agents have been studied for motor recovery, their impact on cardiovascular function remains under investigated. The objective was to assess the efficacy of four clinically approved neuroprotective agents in promoting cardiovascular recovery following SCI.

Methods

Male Wistar rats received contusion at the third thoracic spinal segment (T3). Fluoxetine, Glyburide, Valproic acid, and Indomethacin were first administered at 1 h or 6 h post-SCI, and every 12 h for two weeks thereafter. Four weeks following SCI, hemodynamics were measured at rest and during colorectal distension. Locomotor function was assessed prior to SCI and weekly for four weeks after SCI, using the Basso-Beattie-Bresnahan (BBB) locomotor scale. Quantitative comparisons of lesion area were performed.

Results

Contrary to the published literature, Indomethacin and Valproic acid resulted in high morbidity and mortality rates 60 % and 40 % respectively) within 2–3 days of administration. Fluoxetine, and Glyburide were well-tolerated. There were no differences in change in systolic BP with colorectal distension compared to control i.e., all experimental groups experienced severe episodes of AD [F(6, 67) = 0.94, p = 0.47]. There was no significant difference in BBB scores in any experimental group compared to control [F(18, 252) = 0.3, p = 0.99]. No between-group differences were observed in tissue sparing at the lesion epicentre [F(6, 422) = 6.98, p = 0.29].

Discussion

Despite promising beneficial effect reported in previous studies, none of the drugs demonstrated improvement in cardiovascular or motor function. Indomethacin and Valproic acid exhibited unexpected high mortality at doses deemed safe in the literature. This emphasizes the necessity for reproducibility studies in pre-clinical research and underscores the importance of publishing null findings to guide future investigations.
背景和目的:脊髓损伤(SCI)后脊髓上心血管控制的丧失和继发性损伤会导致心血管功能障碍,损伤下方的刺激会引发自主神经反射障碍(AD),导致血压(BP)飙升失控,带来严重的健康风险,如中风和癫痫发作。虽然抗炎神经保护剂已被用于研究运动恢复,但其对心血管功能的影响仍未得到充分研究。本研究旨在评估四种临床认可的神经保护剂在促进 SCI 后心血管恢复方面的功效:雄性 Wistar 大鼠第三胸椎节段(T3)受到挫伤。在脊髓损伤后 1 小时或 6 小时首次给药氟西汀、格列本脲、丙戊酸和吲哚美辛,之后每 12 小时给药一次,持续两周。脊髓损伤后四周,测量静息时和结肠扩张时的血液动力学。使用巴索-巴蒂-布雷斯纳汉(Basso-Beattie-Bresnahan,BBB)运动功能量表,在脊髓损伤前和脊髓损伤后四周内每周对运动功能进行评估。对病变区域进行了定量比较:与已发表的文献相反,吲哚美辛和丙戊酸在用药后 2-3 天内的发病率和死亡率较高,分别为 60% 和 40%。氟西汀和格列本脲的耐受性良好。与对照组相比,结肠直肠胀气时收缩压的变化没有差异,即所有实验组都出现了严重的急性肠梗阻发作[F(6, 67) = 0.94, p = 0.47]。与对照组相比,所有实验组的 BBB 评分均无明显差异 [F(18, 252) = 0.3, p = 0.99]。在病灶中心组织疏松方面,没有观察到组间差异[F(6,422)= 6.98,P = 0.29]:讨论:尽管之前的研究显示了良好的疗效,但没有一种药物能改善心血管或运动功能。在文献认为安全的剂量下,吲哚美辛和丙戊酸表现出意想不到的高死亡率。这强调了在临床前研究中进行可重复性研究的必要性,并突出了公布无效研究结果以指导未来研究的重要性。
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引用次数: 0
Pre-operative environmental enrichment does not yield a prophylactic effect against traumatic brain injury-induced neurobehavioral deficits 术前丰富环境并不能预防脑外伤引起的神经行为障碍。
IF 4.6 2区 医学 Q1 NEUROSCIENCES Pub Date : 2024-10-09 DOI: 10.1016/j.expneurol.2024.114990
Eleni H. Moschonas , Jade A. Steber , Haley E. Capeci , Hailey M. Donald , Vincent J. Vozzella , Rachel A. Bittner , Ellen M. Annas , Piper L. Rennerfeldt , Jeffrey P. Cheng , Corina O. Bondi , Anthony E. Kline
The robustness of environmental enrichment (EE) in ameliorating neurobehavioral and cognitive deficits after experimental traumatic brain injury (TBI) is unequivocal. What is equivocal is whether EE can function as a prophylactic to afford resiliency and neuroprotection against TBI. We hypothesized that pre-operative EE would yield a protective effect against TBI-induced motor, cognitive, and coping deficits, and that further improvements would be conferred when EE is provided before and after TBI. To test the hypotheses, adult male rats received either 4 weeks of EE or standard (STD) housing prior to undergoing a controlled cortical impact of moderate severity (2.8 mm deformation at 4 m/s) or sham injury while under anesthesia. After injury, the rats were randomly assigned to post-operative EE or STD housing. Motor ability, spatial learning, and memory retention were assessed by beam-walk and water maze tests, respectively. Active and passive behavioral coping strategies were evaluated with the shock probe defensive burying (SPDB) test. c-Fos and cortical lesion volume were also quantified. The post-TBI enrichment groups (EE + TBI + EE and STD + TBI + EE) did not differ (p > 0.05) and performed better than the post-TBI STD-housed groups (EE + TBI + STD and STD + TBI + STD) on motor and cognition (p < 0.05). The post-TBI STD groups did not differ, regardless of whether in EE or STD living conditions before injury (p > 0.05). Moreover, both post-TBI enrichment groups performed better in the SPDB test relative to the STD + TBI + STD group (p < 0.05). c-Fos + cells were upregulated in the ipsilateral CA1 in both pre-injury EE groups relative to the pre-injury STD groups (p < 0.05). No statistical differences were observed in cortical lesion volume among the groups. Overall, these data do not support the hypothesis as no neuroprotective effect was observed with 4 weeks of pre-operative EE and no additional benefit was achieved in the TBI group receiving both pre-and-post EE relative to the TBI group receiving only post-EE. However, the data do reinforce the consistency of post-TBI EE in producing robust neurobehavioral benefits, which further supports this paradigm as a relevant preclinical model of neurorehabilitation.
丰富环境(EE)在改善实验性创伤性脑损伤(TBI)后的神经行为和认知障碍方面的作用是毋庸置疑的。目前尚不明确的是,EE 能否作为一种预防措施,提供对创伤性脑损伤的恢复能力和神经保护。我们假设,术前 EE 将对 TBI 引起的运动、认知和应对缺陷产生保护作用,而在 TBI 前后提供 EE 将进一步改善这些缺陷。为了验证这些假设,成年雄性大鼠在接受中等严重程度的受控皮层撞击(2.8 毫米变形,4 米/秒)或麻醉状态下的假损伤之前,接受了为期 4 周的 EE 或标准(STD)饲养。受伤后,大鼠被随机分配到术后 EE 或 STD 饲养区。运动能力、空间学习能力和记忆保持能力分别通过横梁行走和水迷宫测试进行评估。此外,还对c-Fos和皮质损伤体积进行了量化。创伤后强化组(EE + TBI + EE 和 STD + TBI + EE)在运动和认知方面与创伤后 STD 居住组(EE + TBI + STD 和 STD + TBI + STD)相比没有差异(P > 0.05),表现更好(P 0.05)。此外,相对于 STD + TBI + STD 组,TBI 后强化组在 SPDB 测试中的表现均优于 STD + TBI + STD 组(相对于受伤前 STD 组,受伤前 EE 组的 p 均为 1(p 0.05))。
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引用次数: 0
Differential impact of optogenetic stimulation of direct and indirect pathways from dorsolateral and dorsomedial striatum on motor symptoms in Huntington's disease mice 光遗传刺激背外侧和背内侧纹状体的直接和间接通路对亨廷顿病小鼠运动症状的不同影响
IF 4.6 2区 医学 Q1 NEUROSCIENCES Pub Date : 2024-10-09 DOI: 10.1016/j.expneurol.2024.114991
Sara Conde-Berriozabal , Laia Sitjà-Roqueta , Esther García-García , Lia García-Gilabert , Anna Sancho-Balsells , Sara Fernández-García , Ened Rodriguez-Urgellés , Albert Giralt , Anna Castañé , Manuel J. Rodríguez , Jordi Alberch , Mercè Masana
The alterations in the basal ganglia circuitry are core pathological hallmark in Huntington's Disease (HD) and traditionally linked to its sever motor symptoms. Recently it was shown that optogenetic stimulation of cortical afferences to the striatum is able to reverse motor symptoms in HD mice. However, the specific contribution of the direct and indirect striatal output pathways from the dorsolateral (DLS) and dorsomedial striatum (DMS) to the motor phenotype is still not clear. Here, we aim to uncover the contributions of these striatal subcircuits to motor control in wild type (WT) and HD mice by using the symptomatic R6/1 mice. We systematically evaluated locomotion, exploratory behavior, and motor learning effects of the selective optogenetic stimulation of D1 or A2A expressing neurons (direct and indirect pathway, respectively), in DLS or DMS. Bilateral optogenetic stimulation of the direct pathway from DLS and the indirect pathway from DMS resulted in subtle locomotor enhancements, while unaltering exploratory behavior. Additionally, bilateral stimulation of the indirect pathway from the DLS improved performance in the accelerated rotarod task, suggesting a role in motor learning. In contrast, in HD mice, stimulation of these pathways did not modulate any of these behaviors. Overall, this study highlights that selective stimulation of direct and indirect pathways from DLS and DMS have subtle impact in locomotion, exploratory activity or motor learning. The lack of responses in HD mice also suggests that strategies involving cortico-striatal circuits rather than striatal output circuits might be a better strategy for managing motor symptoms in movement disorders.
基底神经节回路的改变是亨廷顿舞蹈症(Huntington's Disease,HD)的核心病理特征,传统上与其严重的运动症状有关。最近的研究表明,光遗传刺激大脑皮层与纹状体的联系能够逆转 HD 小鼠的运动症状。然而,来自背外侧(DLS)和背内侧纹状体(DMS)的直接和间接纹状体输出通路对运动表型的具体贡献仍不清楚。在这里,我们利用有症状的 R6/1 小鼠,旨在揭示这些纹状体亚电路对野生型(WT)和 HD 小鼠运动控制的贡献。我们在 DLS 或 DMS 中系统地评估了选择性光遗传刺激 D1 或 A2A 表达神经元(分别为直接和间接通路)对运动、探索行为和运动学习的影响。对DLS的直接通路和DMS的间接通路进行双侧光遗传刺激会导致微妙的运动增强,同时不会改变探索行为。此外,对来自 DLS 的间接通路的双侧刺激提高了小鼠在加速旋转任务中的表现,这表明小鼠在运动学习中发挥了作用。与此相反,在 HD 小鼠中,刺激这些通路不会调节任何这些行为。总之,这项研究强调,选择性刺激来自 DLS 和 DMS 的直接和间接通路对运动、探索活动或运动学习有微妙的影响。HD小鼠缺乏反应也表明,涉及皮质-纹状体回路而非纹状体输出回路的策略可能是控制运动障碍患者运动症状的更好策略。
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引用次数: 0
Neuroprotection of celastrol against postoperative cognitive dysfunction through dampening cGAS-STING signaling 塞拉斯托通过抑制 cGAS-STING 信号对术后认知功能障碍的神经保护作用
IF 4.6 2区 医学 Q1 NEUROSCIENCES Pub Date : 2024-10-05 DOI: 10.1016/j.expneurol.2024.114987
Xueshan Bu , Hui Guo , Wenwei Gao , Lei Zhang , Jiabao Hou , Bixi Li , Zhongyuan Xia , Wei Wang
Neuroinflammation is a central player in postoperative cognitive dysfunction (POCD), an intractable and highly confounding neurological complication with finite therapeutic options. Celastrol, a quinone methide triterpenoid, is a bioactive ingredient extracted from Tripterygium wilfordii with talented anti-inflammatory capacity. However, it is unclear whether celastrol can prevent anesthesia/surgery-evoked cognitive deficits in an inflammation-specific manner. The STING agonist 5,6-dimethylxanthenone-4-acetic acid (DMXAA) was used to determine whether celastrol possesses neuroprotection dependent on the STING pathway in vivo and in vitro. Isoflurane and laparotomy triggered cGAS-STING activation, caspase-3/GSDME-dependent pyroptosis, and enhanced Iba-1 immunoreactivity. Celastrol improved cognitive performance and decreased the levels of cGAS, 2′3′-cGAMP, STING, NF-κB phosphorylation, Iba-1, TNF-α, IL-6, and IFN-β. Downregulation of cleaved caspase-3 and N-GSDME was observed in the hippocampus of POCD mice and HT22 cells after celastrol administration, accompanied by limited secretion of pyroptosis-pertinent pro-inflammatory cytokines IL-1β and IL-18. DMXAA neutralized the favorable influences of celastrol on cognitive function, as confirmed by the activation of the STING/caspase-3/GSDME axis. These findings implicate celastrol as a therapeutic agent for POCD through anti-inflammation and anti-pyroptosis.
神经炎症是导致术后认知功能障碍(POCD)的主要原因,而认知功能障碍是一种难以治愈且极易混淆的神经系统并发症,治疗方法有限。Celastrol 是一种醌甲甙三萜类化合物,是从威灵仙中提取的一种生物活性成分,具有很强的抗炎能力。然而,目前还不清楚塞拉斯托是否能以炎症特异性的方式预防麻醉/手术诱发的认知障碍。研究人员使用 STING 激动剂 5,6-二甲基氧杂蒽酮-4-乙酸(DMXAA)来确定青霉酚是否在体内和体外具有依赖于 STING 通路的神经保护作用。异氟醚和开腹手术引发了cGAS-STING激活、caspase-3/GSDME依赖性热凋亡和Iba-1免疫活性增强。塞拉斯托能改善认知能力,降低cGAS、2'3'-cGAMP、STING、NFκB磷酸化、Iba-1、TNFα、IL-6和IFN-β的水平。服用塞拉斯特罗后,在 POCD 小鼠的海马和 HT22 细胞中观察到了裂解的 Caspase-3 和 N-GSDME 的下调,同时还观察到了与热昏迷相关的促炎细胞因子 IL-1β 和 IL-18 的有限分泌。通过激活 STING/caspase-3/GSDME轴,DMXAA中和了塞拉斯托对认知功能的有利影响。这些研究结果表明,赛拉司醇可通过抗炎和抗突变作用成为 POCD 的治疗药物。
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引用次数: 0
Activation of chaperone-mediated autophagy exerting neuroprotection effect on intracerebral hemorrhage-induced neuronal injury by targeting Lamp2a 通过靶向 Lamp2a 激活伴侣介导的自噬,对脑出血诱导的神经元损伤发挥神经保护作用
IF 4.6 2区 医学 Q1 NEUROSCIENCES Pub Date : 2024-10-04 DOI: 10.1016/j.expneurol.2024.114986
Yun Zheng , Lu Peng , Guannan Jiang , Jialei Zhou , Siyuan Yang , Lei Bai , Xiang Li Sr , Mingqing He
Intracerebral hemorrhage (ICH) is a common and devastating type of stroke, marked by significant morbidity and a grim prognosis. The inflammation cascade triggered by astrocytes plays a critical role in secondary brain injury (SBI) following ICH, leading to detrimental effects such as cell death. However, effective intervention strategies are currently lacking. This study aims to investigate the role of the astrocyte cascade reaction following ICH and identify potential intervention targets. Utilizing the GSE216607 and GSE206971 databases for analysis, we established a mouse autologous blood model. Firstly, our research revealed a significant activation of the autophagy pathway following intracerebral hemorrhage (ICH), with a notable upregulation of Lamp2a, a key factor in chaperone-mediated autophagy (CMA), primarily localized in astrocytes. Additionally, the downregulation of Lamp2a resulted in a significant augmentation of A1 reactive astrocytes, concomitant with a reduction in myelin coverage area, heightened neuronal injury, exacerbated motor and sensory deficits, and diminished neurological scores after ICH in mice. Conversely, CA77.1, an activator of CMA, could reverse ICH-induced augmentation of A1 reactive astrocytes, myelin damage, neuronal death, and neurobehavioral disorders. In conclusion, the activation of astrocyte CMA following ICH can exert neuroprotective effects. Lamp2a represents a promising therapeutic target for post-ICH treatment.
脑内出血(ICH)是一种常见的破坏性中风,发病率高,预后严重。星形胶质细胞引发的炎症级联反应在 ICH 后的继发性脑损伤(SBI)中起着关键作用,导致细胞死亡等有害影响。然而,目前尚缺乏有效的干预策略。本研究旨在探讨 ICH 后星形胶质细胞级联反应的作用,并确定潜在的干预目标。我们利用 GSE216607 和 GSE206971 数据库进行分析,建立了小鼠自体血模型。首先,我们的研究揭示了脑内出血(ICH)后自噬通路的显著激活,主要定位于星形胶质细胞的伴侣介导的自噬(CMA)关键因子 Lamp2a 明显上调。此外,Lamp2a 的下调导致 A1 反应性星形胶质细胞显著增加,同时导致小鼠 ICH 后髓鞘覆盖面积减少、神经元损伤加重、运动和感觉障碍加剧以及神经系统评分降低。相反,CMA 的激活剂 CA77.1 可以逆转 ICH 引起的 A1 反应性星形胶质细胞增加、髓鞘损伤、神经元死亡和神经行为障碍。总之,激活 ICH 后的星形胶质细胞 CMA 可发挥神经保护作用。Lamp2a 是治疗 ICH 后的一个很有前景的治疗靶点。
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引用次数: 0
Nabiximols (NBX) suppresses tremor in a rat Harmaline model of essential tremor Nabiximols (NBX) 可抑制大鼠 Harmaline 本质性震颤模型中的震颤。
IF 4.6 2区 医学 Q1 NEUROSCIENCES Pub Date : 2024-10-04 DOI: 10.1016/j.expneurol.2024.114988
Sally Loomis, Elena Samoylenko, David Virley, Andrew C. McCreary

Background

Essential tremor (ET) is one of the most prevalent movement disorders; despite this, there remains an unmet need for novel therapies. The treatment of rats with harmaline modulates the rhythmicity of inferior olivary neurons, resulting in generalized tremor with a frequency of 9–12 Hz in rats, comparable to that of human ET (4–12 Hz).

Purpose

Interestingly, cannabinoids reduce tremor, therefore we have assessed the cannabinoid nabiximols (NBX; marketed as Sativex) a complex botanical drug mixture, in the harmaline-rat model of ET.

Method

We tested the effects of acute (single dose) and subchronic (10 days) treatment of NBX (at 5.2, 10.4 and 20.8 mg kg−1 p.o.) administered prior to harmaline and acute NBX (20.8 mg kg−1) administered post-harmaline in male SD rats. Propranolol (20 mg kg−1 i.p.) was used as a positive control. Observed Scoring (OS) was carried out prior to placement in a tremor-monitoring apparatus for the calculation of Tremor Index (TI) and Motion Power Percentage (MPP).

Results

Acute and subchronic NBX significantly attenuated harmaline-induced tremor at 10.4 and 20.8 mg kg−1, respectively, for each parameter (OS, TI, and MPP) when administered pre-harmaline as did propranolol (20 mg kg−1). NBX did not attenuate harmaline-induced tremor when administered post-harmaline.

Conclusions

These data suggest efficacy of acute and subchronic NBX to reduce tremors, based on OS, TI and MPP readouts if administered prior to harmaline. These data are the first to indicate the preclinical effects of an oral botanical cannabinoid formulation, NBX, in an animal model of ET.
背景:本质性震颤(ET)是最常见的运动障碍之一;尽管如此,对新型疗法的需求仍未得到满足。目的:有趣的是,大麻素能减少震颤,因此我们评估了大麻素 nabiximols(NBX;市场名为 Sativex)--一种复合植物药混合物--在哈马林-大鼠 ET 模型中的作用:我们以雄性 SD 大鼠为研究对象,测试了在服用哈马林之前急性(单剂量)和亚慢性(10 天)服用 NBX(5.2、10.4 和 20.8 毫克/公斤-1 p.o.)以及在服用哈马林之后急性服用 NBX(20.8 毫克/公斤-1)的效果。普萘洛尔(20 毫克/千克-1 毫升)作为阳性对照。在将大鼠放入震颤监测仪器前进行观察评分(OS),以计算震颤指数(TI)和运动力百分比(MPP):急性和亚慢性 NBX 与普萘洛尔(20 毫克/千克-1)一样,分别以 10.4 毫克/千克-1 和 20.8 毫克/千克-1 的剂量显著减轻肝素诱发的震颤。在服用哈马林后服用 NBX 不会减轻哈马林引起的震颤:这些数据表明,根据OS、TI和MPP读数,急性和亚慢性NBX对减少震颤有疗效,如果在服用哈马林之前给药的话。这些数据首次表明了口服植物大麻素制剂 NBX 在 ET 动物模型中的临床前效果。
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引用次数: 0
CXCR2 mediated trafficking of neutrophils and neutrophil extracellular traps are required for myelin clearance after a peripheral nerve injury 中性粒细胞和中性粒细胞胞外捕获物在外周神经损伤后的髓鞘清除过程中需要由 CXCR2 介导的中性粒细胞和中性粒细胞胞外捕获物的迁移。
IF 4.6 2区 医学 Q1 NEUROSCIENCES Pub Date : 2024-10-03 DOI: 10.1016/j.expneurol.2024.114985
Brian M. Balog, Jon P. Niemi, Thomas Disabato, Faye Hashim, Richard E. Zigmond
Neutrophils are a vital part of the innate immune system. Many of their functions eliminate bacteria & viruses, like neutrophil extracellular traps (NETs), which trap bacteria, enhancing macrophage phagocytosis. It was surprising when it was demonstrated that neutrophils are a part of Wallerian degeneration, a process that is essential for nerve regeneration after a nerve injury. It is not known what signals attract neutrophils into the nerve and how they aid Wallerian degeneration. Neutrophils accumulate in the distal nerve within one day after an injury and are found in the nerve from one to three days. We demonstrate that CXCR2 mediates the trafficking of neutrophils into the distal nerve, and without CXCR2 Wallerian degeneration, as indicated by luxol fast blue staining, was reduced seven days after a sciatic nerve crush or transection injury. NETs were detected in the distal nerve after a sciatic nerve transection. NET formation has been shown to require protein arginine deiminase 4 (PAD4), which citrullinates histone 3. Inhibiting PAD4 reduced NET formation significantly in the distal nerve at two days and myelin clearance at seven days indicating that NETs aid myelin clearance. These results demonstrate another function for NETs other than clearing pathogens. Neutrophils have been detected after injuries to the central nervous system and diseases in humans and animal models. Our results demonstrate neutrophils aid myelin clearance, suggesting a role for their presence in central nervous system injuries and diseases.
中性粒细胞是先天性免疫系统的重要组成部分。它们的许多功能可以消灭细菌和病毒,比如中性粒细胞胞外捕获器(NET)可以捕获细菌,增强巨噬细胞的吞噬能力。令人惊讶的是,嗜中性粒细胞是瓦勒氏变性的一部分,而瓦勒氏变性是神经损伤后神经再生的必要过程。目前还不清楚是什么信号吸引中性粒细胞进入神经,以及它们如何帮助沃勒氏变性。中性粒细胞在神经损伤后一天内聚集到远端神经,并在一到三天内存在于神经中。我们证明,CXCR2介导了中性粒细胞向远端神经的迁移,如果没有CXCR2,坐骨神经挤压或横断损伤七天后,华勒氏变性(通过鲁索快蓝染色显示)会减少。坐骨神经横断后,在远端神经中检测到了NET。研究表明,NET的形成需要精氨酸脱氨酶4(PAD4),它能使组蛋白3瓜氨酸化。抑制 PAD4 可在两天后显著减少远端神经中 NET 的形成,并在七天后显著减少髓鞘的清除,这表明 NET 有助于髓鞘的清除。这些结果证明了NET除清除病原体外的另一种功能。在人类和动物模型中,中性粒细胞在中枢神经系统受伤和患病后被检测到。我们的研究结果表明,中性粒细胞有助于髓鞘清除,这表明中性粒细胞在中枢神经系统损伤和疾病中发挥作用。
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引用次数: 0
Neuro-inflammatory pathways in COVID-19-induced central nervous system injury: Implications for prevention and treatment strategies COVID-19 诱导的中枢神经系统损伤中的神经炎症途径:对预防和治疗策略的影响
IF 4.6 2区 医学 Q1 NEUROSCIENCES Pub Date : 2024-10-03 DOI: 10.1016/j.expneurol.2024.114984
Muhammad Liaquat Raza , Mustafa Hussain Imam , Warisha Zehra , Subia Jamil
This review explores the neuroinflammatory pathways underlying COVID-19-induced central nervous system (CNS) injury, with a focus on mechanisms of brain damage and strategies for prevention. A comprehensive literature review was conducted to summarize current knowledge on the pathways by which SARS-CoV-2 reaches the brain, the neuroinflammatory responses triggered by viral infection, neurological symptoms and long COVID. Results: We discuss the mechanisms of neuroinflammation in COVID-19, including blood-brain barrier disruption, cytokine storm, microglial activation, and peripheral immune cell infiltration. Additionally, we highlight potential strategies for preventing CNS injury, including pharmacological interventions, immunomodulatory therapies, and lifestyle modifications. Conclusively, Understanding the neuroinflammatory pathways in COVID-19-induced CNS injury is crucial for developing effective prevention and treatment strategies to protect brain health during and after viral infection.
这篇综述探讨了 COVID-19 引发中枢神经系统(CNS)损伤的神经炎症途径,重点是脑损伤的机制和预防策略。我们进行了全面的文献综述,总结了目前关于 SARS-CoV-2 到达大脑的途径、病毒感染引发的神经炎症反应、神经系统症状和长期 COVID 的知识。结果:我们讨论了 COVID-19 的神经炎症机制,包括血脑屏障破坏、细胞因子风暴、小胶质细胞活化和外周免疫细胞浸润。此外,我们还强调了预防中枢神经系统损伤的潜在策略,包括药物干预、免疫调节疗法和生活方式调整。总之,了解 COVID-19 诱导的中枢神经系统损伤的神经炎症途径对于制定有效的预防和治疗策略以保护病毒感染期间和之后的大脑健康至关重要。
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引用次数: 0
期刊
Experimental Neurology
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