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Nicotinic acid attenuates amyloid β1-42-induced mitochondrial dysfunction and inhibits the mitochondrial pathway of apoptosis in differentiated SH-SY5Y cells 烟酸可减轻淀粉样β1-42诱导的线粒体功能障碍,并抑制分化的SH-SY5Y细胞线粒体凋亡途径。
IF 4.2 3区 医学 Q2 Neuroscience Pub Date : 2024-05-22 DOI: 10.1016/j.neuint.2024.105772
Anna Litwiniuk , Małgorzata Kalisz , Anita Domańska , Magdalena Chmielowska , Lidia Martyńska , Agnieszka Baranowska-Bik , Wojciech Bik

Alzheimer's disease (AD) is a chronic neurodegenerative disease characterized by progressive memory loss and behavioral disorders. The excessive accumulation of amyloid β (Aβ) and the formation of neurofibrillary tangles (NFTs) damage synaptic connections and the death of neurons. However, the underlying mechanisms of pathogenesis of AD remain unclear. Growing evidence indicates that impaired mitochondrial function may play a crucial role in the development of AD. In the current study, we investigated whether nicotinic acid (NA) could protect against amyloid β1-42-induced cytotoxicity in differentiated SH-SY5Y cells. Our results revealed the neuroprotective effects of NA on the differentiated SH-SY5Y cells treated with Aβ1-42. In detail, the 1-h pre-incubation with NA increased cell viability and lowered LDH levels. NA pre-incubation abolished Aβ1-42 treatment-associated alterations of mRNA levels of synaptic genes and enhanced the relative β3 Tubulin fluorescence intensity. NA eliminated the Aβ1-42-induced mitochondrial dysfunction by increasing the potential of mitochondrial membranes and maintaining a balance between the fusion and fission of mitochondria. Moreover, Aβ1-42 decreased mRNA levels of anti-apoptotic bcl2 and increased mRNA levels of pro-apoptotic: bim, bak, cytochrome c, and caspase 9. At the same time, the NA pre-treatment reduced Aβ1-42-dependent apoptotic death of differentiated SH-SY5Y cells.

The above data suggest that NA presents a protective activity against Aβ1-42-induced cytotoxicity in differentiated SH-SY5Y cells by inhibiting the mitochondrial pathway of apoptosis and restoring the proper function of mitochondria.

阿尔茨海默病(AD)是一种慢性神经退行性疾病,以进行性记忆丧失和行为障碍为特征。淀粉样β(Aβ)的过度积累和神经纤维缠结(NFT)的形成会破坏突触连接,导致神经元死亡。然而,注意力缺失症的发病机制仍不清楚。越来越多的证据表明,线粒体功能受损可能在AD的发病过程中起着至关重要的作用。在本研究中,我们探讨了烟酸(NA)能否保护分化的SH-SY5Y细胞免受淀粉样β1-42诱导的细胞毒性。我们的研究结果表明,NA对经Aβ1-42处理的分化SH-SY5Y细胞具有神经保护作用。具体而言,与 NA 预孵育一小时可提高细胞活力并降低 LDH 水平。NA预孵育可消除Aβ1-42处理相关的突触基因mRNA水平的改变,并增强β3 Tubulin荧光的相对强度。NA通过提高线粒体膜的电位和维持线粒体融合与分裂之间的平衡,消除了Aβ1-42诱导的线粒体功能障碍。此外,Aβ1-42 还降低了抗凋亡的 bcl2 的 mRNA 水平,提高了促凋亡的 bim、bak、细胞色素 c 和 caspase 9 的 mRNA 水平。同时,NA 预处理可减少 Aβ1-42 依赖性分化的 SH-SY5Y 细胞凋亡。上述数据表明,NA通过抑制线粒体凋亡途径和恢复线粒体的正常功能,对Aβ1-42诱导的分化SH-SY5Y细胞的细胞毒性具有保护作用。
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引用次数: 0
Focus on brain-lung crosstalk: Preventing or treating the pathological vicious circle between the brain and the lung 关注脑肺串扰:预防或治疗脑肺之间的病理恶性循环。
IF 4.2 3区 医学 Q2 Neuroscience Pub Date : 2024-05-18 DOI: 10.1016/j.neuint.2024.105768
Xiaoqiu Li , Jie Deng , Yu Long , Yin Ma , Yuanyuan Wu , Yue Hu , Xiaofang He , Shuang Yu , Dan Li , Nan Li , Fei He

Recently, there has been increasing attention to bidirectional information exchange between the brain and lungs. Typical physiological data is communicated by channels like the circulation and sympathetic nervous system. However, communication between the brain and lungs can also occur in pathological conditions. Studies have shown that severe traumatic brain injury (TBI), cerebral hemorrhage, subarachnoid hemorrhage (SAH), and other brain diseases can lead to lung damage. Conversely, severe lung diseases such as acute respiratory distress syndrome (ARDS), pneumonia, and respiratory failure can exacerbate neuroinflammatory responses, aggravate brain damage, deteriorate neurological function, and result in poor prognosis. A brain or lung injury can have adverse effects on another organ through various pathways, including inflammation, immunity, oxidative stress, neurosecretory factors, microbiome and oxygen. Researchers have increasingly concentrated on possible links between the brain and lungs. However, there has been little attention given to how the interaction between the brain and lungs affects the development of brain or lung disorders, which can lead to clinical states that are susceptible to alterations and can directly affect treatment results. This review described the relationships between the brain and lung in both physiological and pathological conditions, detailing the various pathways of communication such as neurological, inflammatory, immunological, endocrine, and microbiological pathways. Meanwhile, this review provides a comprehensive summary of both pharmacological and non-pharmacological interventions for diseases related to the brain and lungs. It aims to support clinical endeavors in preventing and treating such ailments and serve as a reference for the development of relevant medications.

最近,人们越来越关注大脑和肺部之间的双向信息交流。典型的生理数据通过血液循环和交感神经系统等渠道进行交流。然而,在病理情况下,大脑和肺之间也会发生交流。研究表明,严重的脑外伤(TBI)、脑出血、蛛网膜下腔出血(SAH)和其他脑部疾病会导致肺部损伤。相反,急性呼吸窘迫综合征(ARDS)、肺炎和呼吸衰竭等严重肺部疾病会加剧神经炎症反应,加重脑损伤,恶化神经功能,导致预后不良。脑损伤或肺损伤可通过炎症、免疫、氧化应激、神经分泌因子、微生物组和氧等各种途径对另一个器官产生不良影响。研究人员越来越关注大脑和肺之间可能存在的联系。然而,人们很少关注脑与肺之间的相互作用如何影响脑部或肺部疾病的发展,这可能导致临床状态容易发生改变,并直接影响治疗效果。本综述描述了生理和病理状态下脑与肺之间的关系,详细介绍了神经、炎症、免疫、内分泌和微生物等各种交流途径。同时,本综述全面总结了针对脑肺相关疾病的药物和非药物干预措施。其目的是为预防和治疗此类疾病的临床工作提供支持,并为相关药物的开发提供参考。
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引用次数: 0
Intracerebroventricular infusion of secretoneurin inhibits neuronal NLRP3-Apoptosis pathway and preserves learning and memory after cerebral ischemia 脑室内灌注 Secretoneurin 可抑制神经元 NLRP3-Apoptosis 通路并保护脑缺血后的学习和记忆。
IF 4.2 3区 医学 Q2 Neuroscience Pub Date : 2024-05-16 DOI: 10.1016/j.neuint.2024.105770
Caihong Gu , Xiuwen Kang , Xiaobing Chen , Yan Sun , Xiaomin Li

Transient global cerebral ischemia (GCI) results in delayed neuronal death, primarily apoptosis, in the hippocampal CA1 subregion, which leads to severe cognitive deficits. While therapeutic hypothermia is an approved treatment for patients following cardiac arrest, it is associated with various adverse effects. Secretoneurin (SN) is an evolutionarily conserved neuropeptide generated in the brain, adrenal medulla and other endocrine tissues. In this study, SN was infused into the rat brain by intracerebroventricular injection 1 day after GCI, and we demonstrated that SN could significantly preserve spatial learning and memory in the Barnes maze tasks examined on days 14–17 after GCI. To further investigate underlying pathways involved, we demonstrated that, on day 5 after GCI, SN could significantly inhibit GCI-induced expression levels of Apoptosis Inducing Factor (AIF) and cleaved-PARP1, as well as neuronal apoptosis and synaptic loss in the hippocampal CA1 region. Additionally, SN could attenuate GCI-induced activation of both caspase-1 and caspase-3, and the levels of pro-inflammatory cytokines IL-1β and IL-18 in the CA1 region. Mechanically, we observed that treatment with SN effectively inhibited NLRP3 protein elevation and the bindings of NLRP3-ASC and ASC-caspase-1 in hippocampal neurons after GCI. In summary, our data indicate that SN could effectively attenuate NLRP3 inflammasome formation, as well as the activation of caspase-1 and -3, the production of pro-inflammatory cytokines, and ultimately the neuronal apoptotic loss induced by GCI. Potential neuronal pyroptosis, or caspase-1-dependent cell death, could also be involved in ischemic neuronal death, which needs further investigation.

短暂性全脑缺血(GCI)会导致海马 CA1 亚区神经元延迟死亡,主要是细胞凋亡,从而导致严重的认知障碍。虽然治疗性低温是一种获准用于心脏骤停患者的治疗方法,但它与各种不良反应有关。分泌神经肽(SN)是一种进化保守的神经肽,产生于大脑、肾上腺髓质和其他内分泌组织。在本研究中,我们在大鼠GCI后1天通过脑室内注射将SN注入大鼠大脑,结果表明SN能显著保护大鼠在GCI后第14至17天进行的巴恩斯迷宫任务中的空间学习和记忆。为了进一步研究其中的潜在途径,我们证实,在 GCI 后的第 5 天,SN 可以显著抑制 GCI 诱导的凋亡诱导因子(AIF)和裂解-PARP1 的表达水平,以及海马 CA1 区的神经元凋亡和突触丢失。此外,SN还能减轻GCI诱导的caspase-1和caspase-3的激活,以及CA1区促炎细胞因子IL-1β和IL-18的水平。在机制上,我们观察到 SN 能有效抑制 GCI 后海马神经元中 NLRP3 蛋白的升高以及 NLRP3-ASC 和 ASC-caspase-1 的结合。总之,我们的数据表明,SN 能有效抑制 NLRP3 炎性体的形成,以及 Caspase-1 和 -3 的激活、促炎性细胞因子的产生,并最终抑制 GCI 诱导的神经元凋亡。潜在的神经元热凋亡或依赖于 caspase-1 的细胞死亡也可能参与缺血性神经元死亡,这还需要进一步研究。
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引用次数: 0
Cannabidiol prevents LPS-induced inflammation by inhibiting the NLRP3 inflammasome and iNOS activity in BV2 microglia cells via CB2 receptors and PPARγ 大麻二酚通过 CB2 受体和 PPARγ 抑制 BV2 小胶质细胞中的 NLRP3 炎性体和 iNOS 活性,从而预防 LPS 诱导的炎症。
IF 4.2 3区 医学 Q2 Neuroscience Pub Date : 2024-05-16 DOI: 10.1016/j.neuint.2024.105769
Fernanda da Silva Rodrigues , William Robert Newton , Isadora D’Ávila Tassinari , Felipe Henrique da Cunha Xavier , Adél Marx , Luciano Stürmer de Fraga , Karen Wright , Renata Padilha Guedes , Victorio Bambini-Jr

Neuroinflammation stands as a critical player in the pathogenesis of diverse neurological disorders, with microglial cells playing a central role in orchestrating the inflammatory landscape within the central nervous system. Cannabidiol (CBD) has gained attention for its potential to elicit anti-inflammatory responses in microglia, offering promising perspectives for conditions associated with neuroinflammation. Here we investigated whether the NLRP3 inflammasome and inducible nitric oxide synthase (iNOS) are involved in the protective effects of CBD, and if their modulation is dependent on cannabinoid receptor 2 (CB2) and PPARγ signalling pathways. We found that treatment with CBD attenuated pro-inflammatory markers in lipopolysaccharide (LPS)-challenged BV2 microglia in a CB2- and PPARγ-dependent manner. At a molecular level, CBD inhibited the LPS-induced pro-inflammatory responses by suppressing iNOS and NLRP3/Caspase-1-dependent signalling cascades, resulting in reduced nitric oxide (NO), interleukin-1β (IL-1β), and tumour necrosis factor-alpha (TNF-α) concentrations. Notably, the protective effects of CBD on NLRP3 expression, Caspase-1 activity, and IL-1β concentration were partially hindered by the antagonism of both CB2 receptors and PPARγ, while iNOS expression and NO secretion were dependent exclusively on PPARγ activation, with no CB2 involvement. Interestingly, CBD exhibited a protective effect against TNF-α increase, regardless of CB2 or PPARγ activation. Altogether, these findings indicate that CB2 receptors and PPARγ mediate the anti-inflammatory effects of CBD on the NLRP3 inflammasome complex, iNOS activity and, ultimately, on microglial phenotype. Our results highlight the specific components responsible for the potential therapeutic applications of CBD on neuroinflammatory conditions.

神经炎症是多种神经系统疾病发病机制中的关键因素,而小胶质细胞在协调中枢神经系统内的炎症过程中发挥着核心作用。大麻二酚(CBD)因其在小胶质细胞中激发抗炎反应的潜力而备受关注,为治疗与神经炎症相关的疾病提供了前景广阔的前景。在这里,我们研究了 NLRP3 炎性体和诱导型一氧化氮合酶(iNOS)是否参与了 CBD 的保护作用,以及它们的调节是否依赖于大麻素受体 2(CB2)和 PPARγ 信号通路。我们发现,用 CBD 治疗可减轻脂多糖(LPS)挑战的 BV2 小胶质细胞中的促炎标记物,而 CB2 和 PPARγ 对其有依赖性。在分子水平上,CBD 通过抑制 iNOS 和 NLRP3/Caspase-1 依赖性信号级联抑制了 LPS 诱导的促炎反应,从而降低了一氧化氮(NO)、白细胞介素-1β(IL-1β)和肿瘤坏死因子-α(TNF-α)的浓度。值得注意的是,CBD 对 NLRP3 表达、Caspase-1 活性和 IL-1β 浓度的保护作用部分受到 CB2 受体和 PPARγ 的拮抗作用的阻碍,而 iNOS 的表达和 NO 的分泌则完全依赖于 PPARγ 的激活,没有 CB2 的参与。有趣的是,CBD 对 TNF-α 的增加有保护作用,而与 CB2 或 PPARγ 的激活无关。总之,这些研究结果表明,CB2 受体和 PPARγ 介导了 CBD 对 NLRP3 炎性体复合物、iNOS 活性的抗炎作用,并最终介导了对小胶质细胞表型的抗炎作用。我们的研究结果强调了 CBD 对神经炎症潜在治疗作用的特定成分。
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引用次数: 0
Amino acid transporters in neurological disorders and neuroprotective effects of cysteine derivatives 神经系统疾病中的氨基酸转运体和半胱氨酸衍生物的神经保护作用。
IF 4.2 3区 医学 Q2 Neuroscience Pub Date : 2024-05-16 DOI: 10.1016/j.neuint.2024.105771
Santosh Kumar Adla, Heinileena Virtanen, Thanavit Thongsodsaeng, Kristiina M. Huttunen

For most diseases and disorders occurring in the brain, the full causes behind them are yet unknown, but many show signs of dysfunction of amino acid transporters or abnormalities in amino acid metabolism. The blood-brain barrier (BBB) plays a key role in supporting the function of the central nervous system (CNS). Because of its unique structure, the BBB can maintain the optimal environment for CNS by controlling the passage of hydrophilic molecules from blood to the brain. Nutrients, such as amino acids, can cross the BBB via specific transporters. Many amino acids are essential for CNS function, and dysfunction of these amino acid transporters can lead to abnormalities in amino acid levels. This has been linked to causes behind certain genetic brain diseases, such as schizophrenia, autism spectrum disorder, and Huntington's disease (HD). One example of crucial amino acids is L-Cys, the rate-limiting factor in the biosynthesis of an important antioxidant, glutathione (GSH). Deficiency of L-Cys and GSH has been linked to oxidative stress and has been shown as a plausible cause behind certain CNS diseases, like schizophrenia and HD. This review presents the current status of potential L-Cys therapies and gives future directions that can be taken to improve amino acid transportation related to distinct CNS diseases.

对于大多数发生在大脑中的疾病和失调,其背后的全部原因尚不清楚,但许多疾病和失调都显示出氨基酸转运体功能障碍或氨基酸代谢异常的迹象。血脑屏障(BBB)在支持中枢神经系统(CNS)功能方面发挥着关键作用。由于其独特的结构,血脑屏障可以通过控制亲水性分子从血液进入大脑来维持中枢神经系统的最佳环境。氨基酸等营养物质可通过特定的转运体穿过 BBB。许多氨基酸是中枢神经系统功能所必需的,这些氨基酸转运体的功能障碍会导致氨基酸水平异常。这与某些遗传性脑部疾病的病因有关,如精神分裂症、自闭症谱系障碍和亨廷顿氏病(HD)。关键氨基酸的一个例子是 L-Cys,它是重要抗氧化剂谷胱甘肽(GSH)生物合成过程中的限速因子。L-Cys 和 GSH 的缺乏与氧化应激有关,已被证明是某些中枢神经系统疾病(如精神分裂症和 HD)的可能原因。本综述介绍了潜在的 L-Cys 疗法的现状,并给出了改善与不同中枢神经系统疾病相关的氨基酸运输的未来方向。
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引用次数: 0
Lateral habenula 5-HT1B receptors are involved in regulation of anxiety-like behaviors in parkinsonian rats 外侧脑5-HT1B受体参与调节帕金森病大鼠的焦虑样行为
IF 4.2 3区 医学 Q2 Neuroscience Pub Date : 2024-05-13 DOI: 10.1016/j.neuint.2024.105766
Guoyi Tang , Yuan Guo , Ruotong Li , Yixuan Wang , Jie Yang , Shasha Gao , Jian Liu

Although the output of the lateral habenula (LHb) controls the activity of midbrain dopaminergic and serotonergic systems, which are implicated in the pathophysiology of anxiety, it is not clear the role of LHb 5-HT1B receptors in regulation of anxiety-like behaviors, particularly in Parkinson's disease-related anxiety. In this study, unilateral 6-hydroxydopamine lesions of the substantia nigra pars compacta in rats induced anxiety-like behaviors, led to decreased normalized δ power and increased normalized θ power in the LHb, and decreased dopamine (DA) level in the prelimbic cortex (PrL) compared with sham rats. Down-regulation of LHb 5-HT1B receptors by RNA interference produced anxiety-like effects, decreased normalized δ power and increased normalized θ power in the LHb in both sham and lesioned rats. Further, intra-LHb injection of 5-HT1B receptor agonist CP93129 induced anxiolytic-like responses, increased normalized δ power and decreased normalized θ power in the LHb, and increased DA and serotonin (5-HT) release in the PrL; conversely, 5-HT1B receptor antagonist SB216641 produced anxiety-like effects, decreased normalized δ power and increased normalized θ power in the LHb, and decreased DA and 5-HT release in the PrL in sham and lesioned rats. Additionally, effects of CP93129 and SB216641 on the behaviors, normalized δ and θ power in the LHb, and DA and 5-HT release in the PrL were decreased in lesioned rats, which were consistent with down-regulation of LHb 5-HT1B receptors after DA depletion. Collectively, these findings suggest that 5-HT1B receptors in the LHb are involved in the regulation of anxiety-like behaviors.

虽然外侧哈文脑(LHb)的输出控制着中脑多巴胺能和血清素能系统的活动,而这些系统与焦虑的病理生理学有关联,但目前还不清楚LHb 5-HT1B受体在调节焦虑样行为中的作用,尤其是在帕金森病相关焦虑中的作用。在这项研究中,与假大鼠相比,单侧黑质(substantia nigra pars compacta)的6-羟基多巴胺病变会诱发焦虑样行为,导致LHb正常化δ功率下降和正常化θ功率上升,以及边缘前皮层(PrL)的多巴胺(DA)水平下降。通过RNA干扰下调LHb 5-HT1B受体会产生焦虑样效应,降低假大鼠和病变大鼠LHb的正常化δ功率,增加正常化θ功率。此外,在LHb内注射5-HT1B受体激动剂CP93129可诱导抗焦虑样反应,增加LHb的归一化δ功率,降低归一化θ功率,增加PrL的DA和5-羟色胺(5-HT)释放;相反,5-HT1B 受体拮抗剂 SB216641 会对假大鼠和病变大鼠产生焦虑样效应,降低 LHb 的正常化 δ 功率,增加正常化 θ 功率,减少 PrL 的 DA 和 5-HT 释放。此外,CP93129 和 SB216641 对病变大鼠的行为、LHb 中的正常化δ和θ功率以及 PrL 中的 DA 和 5-HT 释放的影响均有所下降,这与 DA 耗尽后 LHb 5-HT1B 受体的下调是一致的。这些研究结果表明,LHb中的5-HT1B受体参与了焦虑样行为的调节。
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引用次数: 0
Astrocytic GDNF ameliorates anesthesia and surgery-induced cognitive impairment by promoting hippocampal synaptic plasticity in aged mice 星形胶质细胞生长因子(GDNF)通过促进老年小鼠海马突触可塑性改善麻醉和手术诱发的认知障碍
IF 4.2 3区 医学 Q2 Neuroscience Pub Date : 2024-05-13 DOI: 10.1016/j.neuint.2024.105765
Xiaowan Lin , Peng Ren , Ziyi Xue , Xiao Liu , Ying Cao , Tianzuo Li , Huihui Miao

Background

Perioperative neurocognitive disorders (PND) are common complications after surgery in older patients. However, the specific mechanism of this condition remains unclear. Glial cell line-derived neurotrophic factor (GDNF) is an important neurotrophin that abundantly expressed throughout the brain. It can enhance synaptic plasticity and alleviate learning and memory impairments. Thus, the purpose of this study was to investigate the role of GDNF in PND and the mechanisms involved.

Methods

The PND animal model was established by performing left tibial fracture surgery on 18-month-old C57BL/6 mice under sevoflurane anesthesia. Recombinant adeno-associated virus (rAAV)-GDNF or empty vectors were injected bilaterally into the hippocampal CA1 region of aged mice 3 weeks before anesthesia/surgery. The open field and fear conditioning test were used to assess the behavior changes. Golgi staining and electrophysiology were utilized to evaluate the morphological and functional alterations of neuronal synaptic plasticity. Western blot analysis was carried out to measure the proteins expression levels and immunofluorescence staining was performed to probe the cellular localization of GDNF.

Results

Mice with surgery and anesthesia showed a significant decrease in hippocampus-dependent learning and memory, accompanied by a decline in hippocampal synaptic plasticity. Anesthesia/surgery induced a reduction of GDNF, which was colocalized with astrocytes. Overexpression of GDNF in astrocytes could ameliorate the decline in cognitive function by improving hippocampal synaptic plasticity, meanwhile astrocytic GDNF rescued the anesthesia/surgery-induced decrease in GFRα1 and NCAM.

Conclusion

The study concludes that astrocytic GDNF may improve anesthesia/surgery-induced cognitive impairment by promoting hippocampal synaptic plasticity in aged mice via the GFRα1/NCAM pathway.

背景:围手术期神经认知障碍(PND)是老年患者手术后常见的并发症。然而,这种疾病的具体机制仍不清楚。胶质细胞系源性神经营养因子(GDNF)是一种重要的神经营养素,在大脑中大量表达。它能增强突触可塑性,缓解学习和记忆障碍。因此,本研究旨在探讨 GDNF 在 PND 中的作用及其机制:方法:在七氟烷麻醉下对 18 个月大的 C57BL/6 小鼠进行左胫骨骨折手术,建立 PND 动物模型。在麻醉/手术前3周,将重组腺相关病毒(rAAV)-GDNF或空载体双侧注入老龄小鼠的海马CA1区。采用开阔场和恐惧条件反射测试评估小鼠的行为变化。利用高尔基体染色和电生理学评估神经元突触可塑性的形态和功能改变。采用 Western 印迹分析法测量蛋白质的表达水平,免疫荧光染色法探测细胞定位:结果:手术和麻醉小鼠的海马学习记忆能力显著下降,海马突触可塑性也随之下降。麻醉/手术导致 GDNF 减少,GDNF 与星形胶质细胞共定位。在星形胶质细胞中过表达GDNF可通过改善海马突触可塑性来改善认知功能的下降,同时星形胶质细胞GDNF可挽救麻醉/手术诱导的GFRα1和NCAM的下降:研究结论:星形胶质NF可通过GFRα1/NCAM途径促进老年小鼠海马突触可塑性,从而改善麻醉/手术诱导的认知功能损伤。
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引用次数: 0
Evaluation of the protective effect of capric acid on behavioral and biochemical alterations in valproic acid-induced model of autism 评估己酸对丙戊酸诱导的自闭症模型中行为和生化改变的保护作用。
IF 4.2 3区 医学 Q2 Neuroscience Pub Date : 2024-05-13 DOI: 10.1016/j.neuint.2024.105767
Nikhila Shekhar, Ajit Kumar Thakur

Aim and objective

The purpose of the study is to determine the neuroprotective effect of capric acid on sodium valproate-induced model of autism.

Methods

In this study, the effect of CA was observed in animals with single dose of valproic acid (600 mg/kg, i. p.) where the disease condition was confirmed by developmental impairment in pups. Behavioral tests that assess anxiety, depression, stereotypical and repetitive behavior, social interaction, learning and memory, and other confounding variables were performed. Subsequently, oxidative stress parameters, pro-inflammatory cytokine levels and mitochondrial complex activities in the selected brain regions were analyzed.

Results

Valproic acid successfully produced autism-like symptoms from post-natal day 7 and also demonstrated impairment in social behavior, learning and memory, and anxiety and depression. Valproic acid was found to produce oxidative stress and neuro-inflammation in the hippocampus, prefrontal cortex, and cerebellum. Treatment with capric acid produced a positive effect on the alterations with maximum effects evident at 400 mg/kg, p. o. through amelioration of behavioral as well as biochemical changes.

Conclusion

The current study concluded that capric acid could act as a likely candidate for the treatment and management of autism via significant modulation of neurobehavioral parameters, oxidative stress, mitochondrial dysfunction and inflammatory markers.

目的和目标本研究旨在确定己酸对丙戊酸钠诱导的自闭症模型的神经保护作用:本研究观察了己酸对单剂丙戊酸钠(600 毫克/千克,静脉注射)诱导的自闭症动物的影响。进行的行为测试包括焦虑、抑郁、刻板和重复行为、社会交往、学习和记忆以及其他混杂变量。随后,对选定脑区的氧化应激参数、促炎细胞因子水平和线粒体复合物活性进行了分析:结果:丙戊酸从出生后第 7 天起就能成功地产生类似自闭症的症状,并表现出社交行为、学习和记忆、焦虑和抑郁等方面的障碍。研究发现,丙戊酸会在海马、前额叶皮层和小脑中产生氧化应激和神经炎症。使用癸酸治疗对这些变化产生了积极影响,通过改善行为和生化变化,400 毫克/千克(口服)时效果最明显:目前的研究认为,癸酸可以通过显著调节神经行为参数、氧化应激、线粒体功能障碍和炎症标志物来治疗和控制自闭症。
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引用次数: 0
Exosomes from hypoxic ADSCs ameliorate neuronal damage post spinal cord injury through circ-Wdfy3 delivery and inhibition of ferroptosis 缺氧性 ADSCs 外泌体通过 circ-Wdfy3 递送和抑制铁变态反应改善脊髓损伤后的神经元损伤。
IF 4.2 3区 医学 Q2 Neuroscience Pub Date : 2024-05-10 DOI: 10.1016/j.neuint.2024.105759
Minghao Shao , Sen Ye , Yanzhen Chen , Changzhang Yu , Wei Zhu

Background

Exosomes generated from adipose-derived mesenchymal stem cells (Exos), and in particular hypoxia-pretreated ADSCs (HExos), possess therapeutic properties that promote spinal cord repair following spinal cord injury (SCI). Nevertheless, the regulatory mechanisms through which HExos exert their effects remain unclear.

Methods

Here, next-generation sequencing (NGS) was utilized to examine abnormal circRNA expression comparing HExos to Exos. Bioinformatics analysis and RNA pulldown assays together with luciferase reporter assays were applied to determine interactions among miRNAs, mRNAs and circRNAs. ELISA and immunofluorescence staining were used to examine inflammatory cytokine levels, apoptosis and ROS deposition in LPS-treated HT-22 cells, respectively. The therapeutic effects of Exos and HExos on a mouse model of SCI were analyzed by immunohistochemistry and immunofluorescence staining.

Results

Our findings confirmed that HExos have more significant therapeutic influences on decreasing ROS and inflammatory cytokine levels post-SCI than Exos. NGS revealed that circ-Wdfy3 expression levels were significantly higher in HExos than Exos. Downregulation of circ-Wdfy3 led to a decrease in HExo-induced therapeutic effects on spinal cord repair post-SCI, indicating that circ-Wdfy3 has a critical role in the regulation of HExo-mediated protection against SCI. Our bioinformatics, RNA pulldown and luciferase reporter data demonstrated that GPX4 and miR-423-3p were downstream targets of circ-Wdfy3. GPX4 downregulation or miR-423-3p overexpression reversed the protective effects of circ-Wdfy3 on LPS-treated HT-22 cells. Furthermore, overexpression of circ-Wdfy3 led to an in increase in the Exo-induced therapeutic effects on spinal cord repair post-SCI through the inhibition of ferroptosis.

Conclusions

circ-WDfy3-overexpressing Exos promote spinal cord repair post-SCI through mediation of ferroptosis via the miR-138-5p/GPX4 pathway.

背景:由脂肪间充质干细胞(Exos),特别是缺氧预处理的ADSCs(HExos)产生的外泌体具有促进脊髓损伤(SCI)后脊髓修复的治疗特性。方法:本文利用下一代测序技术(NGS)研究了 HExos 和 Exos 的异常 circRNA 表达。生物信息学分析和 RNA pulldown 分析以及荧光素酶报告实验被用来确定 miRNA、mRNA 和 circRNA 之间的相互作用。ELISA和免疫荧光染色分别用于检测LPS处理的HT-22细胞中的炎性细胞因子水平、细胞凋亡和ROS沉积。免疫组织化学和免疫荧光染色分析了 Exos 和 HExos 对 SCI 小鼠模型的治疗效果:结果:我们的研究结果证实,与 Exos 相比,HExos 在降低 SCI 后 ROS 和炎性细胞因子水平方面具有更显著的治疗效果。NGS 发现,HExos 中 circ-Wdfy3 的表达水平明显高于 Exos。下调 circ-Wdfy3 会导致 HExo 诱导的对 SCI 后脊髓修复的治疗效果下降,这表明 circ-Wdfy3 在 HExo 介导的 SCI 保护调控中起着关键作用。我们的生物信息学、RNA pulldown和荧光素酶报告数据表明,GPX4和miR-423-3p是circ-Wdfy3的下游靶标。GPX4 下调或 miR-423-3p 过表达会逆转 circ-Wdfy3 对 LPS 处理的 HT-22 细胞的保护作用。结论:circ-WDfy3过表达Exos通过miR-138-5p/GPX4通路介导铁突变,促进SCI后脊髓修复。
{"title":"Exosomes from hypoxic ADSCs ameliorate neuronal damage post spinal cord injury through circ-Wdfy3 delivery and inhibition of ferroptosis","authors":"Minghao Shao ,&nbsp;Sen Ye ,&nbsp;Yanzhen Chen ,&nbsp;Changzhang Yu ,&nbsp;Wei Zhu","doi":"10.1016/j.neuint.2024.105759","DOIUrl":"10.1016/j.neuint.2024.105759","url":null,"abstract":"<div><h3>Background</h3><p>Exosomes generated from adipose-derived mesenchymal stem cells (Exos), and in particular hypoxia-pretreated ADSCs (HExos), possess therapeutic properties that promote spinal cord repair following spinal cord injury (SCI). Nevertheless, the regulatory mechanisms through which HExos exert their effects remain unclear.</p></div><div><h3>Methods</h3><p>Here, next-generation sequencing (NGS) was utilized to examine abnormal circRNA expression comparing HExos to Exos. Bioinformatics analysis and RNA pulldown assays together with luciferase reporter assays were applied to determine interactions among miRNAs, mRNAs and circRNAs. ELISA and immunofluorescence staining were used to examine inflammatory cytokine levels, apoptosis and ROS deposition in LPS-treated HT-22 cells, respectively. The therapeutic effects of Exos and HExos on a mouse model of SCI were analyzed by immunohistochemistry and immunofluorescence staining.</p></div><div><h3>Results</h3><p>Our findings confirmed that HExos have more significant therapeutic influences on decreasing ROS and inflammatory cytokine levels post-SCI than Exos. NGS revealed that circ-Wdfy3 expression levels were significantly higher in HExos than Exos. Downregulation of circ-Wdfy3 led to a decrease in HExo-induced therapeutic effects on spinal cord repair post-SCI, indicating that circ-Wdfy3 has a critical role in the regulation of HExo-mediated protection against SCI. Our bioinformatics, RNA pulldown and luciferase reporter data demonstrated that GPX4 and miR-423-3p were downstream targets of circ-Wdfy3. GPX4 downregulation or miR-423-3p overexpression reversed the protective effects of circ-Wdfy3 on LPS-treated HT-22 cells. Furthermore, overexpression of circ-Wdfy3 led to an in increase in the Exo-induced therapeutic effects on spinal cord repair post-SCI through the inhibition of ferroptosis.</p></div><div><h3>Conclusions</h3><p>circ-WDfy3-overexpressing Exos promote spinal cord repair post-SCI through mediation of ferroptosis via the miR-138-5p/GPX4 pathway.</p></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":null,"pages":null},"PeriodicalIF":4.2,"publicationDate":"2024-05-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140911543","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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
Oxidative stress mediated decrement of spinal endomorphin-2 contributes to lumbar disc herniation sciatica in rats 氧化应激介导的脊髓内啡肽-2减少导致大鼠腰椎间盘突出症坐骨神经痛。
IF 4.2 3区 医学 Q2 Neuroscience Pub Date : 2024-05-08 DOI: 10.1016/j.neuint.2024.105764
Le Niu , Chun-Jiang Zuo , Yong-Ling Zhang , Cui-Xia Ma , Xiang-Wen Zhou , Shi-Ru Sun , Xue-Xue Tang , Guo-Quan Huang , Si-Cheng Zhai

Increasing evidence supported that oxidative stress induced by herniated lumbar disc played important role in the formation of lumbar disc herniation sciatica (LDHS), however, the neural mechanisms underlying LDHS need further clarification. Endomorphin-2 (EM2) is the endogenous ligand for mu-opioid receptor (MOR), and there is increasing evidence implicating the involvement of spinal EM2 in neuropathic pain. In this study, using an nucleus pulposus implantation induced LDHS rat model that displayed obvious mechanical allodynia, it was found that the expression of EM2 in dorsal root ganglion (DRG) and spinal cord was significantly decreased. It was further found that oxidative stress in DRG and spinal cord was significantly increased in LDHS rats, and the reduction of EM2 in DRG and spinal cord was determined by oxidative stress dominated increment of dipeptidylpeptidase IV activity. A systemic treatment with antioxidant could prevent the forming of mechanical allodynia in LDHS rats. In addition, MOR expression in DRG and spinal cord remained unchanged in LDHS rats. Intrathecal injection of MOR antagonist promoted pain behavior in LDHS rats, and the analgesic effect of intrathecal injection of EM2 was stronger than that of endomorphin-1 and morphine. Taken together, our findings suggest that oxidative stress mediated decrement of EM2 in DRG and spinal cord causes the loss of endogenous analgesic effects and enhances the pain sensation of LDHS.

越来越多的证据表明,腰椎间盘突出症诱导的氧化应激在腰椎间盘突出坐骨神经痛(LDHS)的形成中起着重要作用,然而,LDHS的神经机制还需要进一步阐明。内啡肽-2(EM2)是μ-阿片受体(MOR)的内源性配体,越来越多的证据表明脊髓EM2参与了神经病理性疼痛。本研究使用髓核植入诱导的 LDHS 大鼠模型,该模型表现出明显的机械异感,研究发现 EM2 在背根神经节(DRG)和脊髓中的表达明显减少。研究进一步发现,LDHS 大鼠背根神经节和脊髓中的氧化应激明显增加,而 DRG 和脊髓中 EM2 的减少是由氧化应激主导的二肽基肽酶 IV 活性增加决定的。使用抗氧化剂进行全身治疗可以防止 LDHS 大鼠机械痛觉的形成。此外,LDHS大鼠DRG和脊髓中的MOR表达保持不变。鞘内注射MOR拮抗剂可促进LDHS大鼠的疼痛行为,鞘内注射EM2的镇痛效果强于内吗啡-1和吗啡。综上所述,我们的研究结果表明,氧化应激介导的DRG和脊髓中EM2的减少会导致内源性镇痛作用的丧失,并增强LDHS的痛觉。
{"title":"Oxidative stress mediated decrement of spinal endomorphin-2 contributes to lumbar disc herniation sciatica in rats","authors":"Le Niu ,&nbsp;Chun-Jiang Zuo ,&nbsp;Yong-Ling Zhang ,&nbsp;Cui-Xia Ma ,&nbsp;Xiang-Wen Zhou ,&nbsp;Shi-Ru Sun ,&nbsp;Xue-Xue Tang ,&nbsp;Guo-Quan Huang ,&nbsp;Si-Cheng Zhai","doi":"10.1016/j.neuint.2024.105764","DOIUrl":"10.1016/j.neuint.2024.105764","url":null,"abstract":"<div><p>Increasing evidence supported that oxidative stress induced by herniated lumbar disc played important role in the formation of lumbar disc herniation sciatica (LDHS), however, the neural mechanisms underlying LDHS need further clarification. Endomorphin-2 (EM2) is the endogenous ligand for mu-opioid receptor (MOR), and there is increasing evidence implicating the involvement of spinal EM2 in neuropathic pain. In this study, using an nucleus pulposus implantation induced LDHS rat model that displayed obvious mechanical allodynia, it was found that the expression of EM2 in dorsal root ganglion (DRG) and spinal cord was significantly decreased. It was further found that oxidative stress in DRG and spinal cord was significantly increased in LDHS rats, and the reduction of EM2 in DRG and spinal cord was determined by oxidative stress dominated increment of dipeptidylpeptidase IV activity. A systemic treatment with antioxidant could prevent the forming of mechanical allodynia in LDHS rats. In addition, MOR expression in DRG and spinal cord remained unchanged in LDHS rats. Intrathecal injection of MOR antagonist promoted pain behavior in LDHS rats, and the analgesic effect of intrathecal injection of EM2 was stronger than that of endomorphin-1 and morphine. Taken together, our findings suggest that oxidative stress mediated decrement of EM2 in DRG and spinal cord causes the loss of endogenous analgesic effects and enhances the pain sensation of LDHS.</p></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":null,"pages":null},"PeriodicalIF":4.2,"publicationDate":"2024-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140903616","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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
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Neurochemistry international
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