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Exposure to lipid mixture induces intracellular lipid droplet formation and impairs mitochondrial functions in astrocytes 暴露于脂质混合物会诱导细胞内脂滴的形成,并损害星形胶质细胞线粒体的功能。
IF 4.2 3区 医学 Q2 Neuroscience Pub Date : 2024-06-14 DOI: 10.1016/j.neuint.2024.105792
Yi-Chen Li, Jing-Ting Fu, Shun-Fen Tzeng

Astrocytes, the predominant glial cells in the central nervous system (CNS), play diverse roles including metabolic support for neurons, provision of neurotrophic factors, facilitation of synaptic neurotransmitter uptake, regulation of ion balance, and involvement in synaptic formation. The accumulation of lipids has been noted in various neurological conditions, yet the response of astrocytes to lipid-rich environments remains unclear. In this study, primary astrocytes isolated from the neonatal rat cortex were exposed to a lipid mixture (LM) comprising cholesterol and various fatty acids to explore their reaction. Our results showed that astrocyte viability remained unchanged following 24 h of 5% or 10% LM treatment. However, exposure to LM for 96 h resulted in reduced cell viability. In addition, LM treatment led to the accumulation of lipid droplets (LDs) in astrocytes, with LD size increasing over prolonged exposure periods. Following 24 h of LM treatment and then 48 h in fresh medium, a significant reduction in intracellular LD size was observed in cultures treated with 5% LM, while no change occurred in cultures exposed to 10% LM. Yet, exposure to 10% LM for 24 h significantly increased the expression of the cholesterol efflux regulatory protein/ATP-binding cassette transporter (ABCA1) gene, responsible for intracellular cholesterol efflux, resulting in reduced cholesterol content within astrocytes. Moreover, LM exposure led to decreased mitochondrial membrane potential (MMP) and increased levels of mature apoptosis-inducing factor (AIF). The smaller LDs were observed to co-localize with microtubule-associated protein 1A/1 B light chain 3 B (LC3) and lysosomal-associated membrane protein-1 (LAMP-1) in LM-treated astrocytes, coinciding with lysosomal acidification. These results indicate that the continuous buildup of LDs in astrocytes residing in lipid-enriched environments may be attributed to disruptions caused by LM in mitochondrial and lysosomal functions. Such disruptions could potentially impede the supportive role of astrocytes in neuronal function.

星形胶质细胞是中枢神经系统(CNS)中最主要的胶质细胞,发挥着多种作用,包括为神经元提供代谢支持、提供神经营养因子、促进突触神经递质摄取、调节离子平衡以及参与突触形成。在各种神经系统疾病中都发现了脂质的积累,但星形胶质细胞对富脂质环境的反应仍不清楚。本研究将从新生大鼠皮层中分离出的原代星形胶质细胞暴露于由胆固醇和各种脂肪酸组成的脂质混合物(LM)中,以探究它们的反应。结果表明,5% 或 10% LM 处理 24 小时后,星形胶质细胞的活力保持不变。然而,暴露于 LM 96 小时后,细胞活力会降低。此外,LM 处理会导致脂滴(LDs)在星形胶质细胞中积累,随着暴露时间的延长,LDs 的大小也会增加。经过 24 小时的 LM 处理,然后在新鲜培养基中培养 48 小时后,在用 5% LM 处理的培养物中观察到细胞内 LD 大小显著减少,而暴露于 10% LM 的培养物中则没有变化。然而,暴露于 10%的 LM 24 小时后,负责细胞内胆固醇外流的胆固醇外流调节蛋白/ATP 结合盒转运体(ABCA1)基因的表达明显增加,导致星形胶质细胞内胆固醇含量减少。此外,暴露于 LM 会导致线粒体膜电位(MMP)降低和成熟的凋亡诱导因子(AIF)水平升高。在经 LM 处理的星形胶质细胞中,观察到较小的 LD 与微管相关蛋白 1A/1B 轻链 3B(LC3)和溶酶体相关膜蛋白-1(LAMP-1)共定位,这与溶酶体酸化相吻合。这些结果表明,居住在富脂环境中的星形胶质细胞中 LD 的持续积累可能是由于 LM 破坏了线粒体和溶酶体的功能。这种干扰可能会阻碍星形胶质细胞在神经元功能中发挥支持作用。
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引用次数: 0
Thiazolium salt mimics the non-coenzyme effects of vitamin B1 in rat synaptosomes 噻唑盐在大鼠突触体中模拟维生素 B1 的非辅酶效应
IF 4.2 3区 医学 Q2 Neuroscience Pub Date : 2024-06-14 DOI: 10.1016/j.neuint.2024.105791
Yu.M. Parkhomenko , A.I. Vovk , Z.S. Protasova , S. Yu Pylypchuk , S.A. Chorny , O.S. Pavlova , O.A. Mejenska , L.I. Chehovska , S.P. Stepanenko

Long-term studies have confirmed a causal relationship between the development of neurodegenerative processes and vitamin B1 (thiamine) deficiency. However, the biochemical mechanisms underlying the high neurotropic activity of thiamine are not fully understood. At the same time, there is increasing evidence that vitamin B1, in addition to its coenzyme functions, may have non-coenzyme activities that are particularly important for neurons. To elucidate which effects of vitamin B1 in neurons are due to its coenzyme function and which are due to its non-coenzyme activity, we conducted a comparative study of the effects of thiamine and its derivative, 3-decyloxycarbonylmethyl-5-(2-hydroxyethyl)-4-methyl-1,3-thiazolium chloride (DMHT), on selected processes in synaptosomes. The ability of DMHT to effectively compete with thiamine for binding to thiamine-binding sites on the plasma membrane of synaptosomes and to participate as a substrate in the thiamine pyrophosphokinase reaction was demonstrated. In experiments with rat brain synaptosomes, unidirectional effects of DMHT and thiamine on the activity of the pyruvate dehydrogenase complex (PDC) and on the incorporation of radiolabeled [2–14C]pyruvate into acetylcholine were demonstrated. The observed effects of thiamine and DMHT on the modulation of acetylcholine synthesis can be explained by suggesting that both compounds, which interact in cells with enzymes of thiamine metabolism, are phosphorylated and exert an inhibitory/activating effect (concentration-dependent) on PDC activity by affecting the regulatory enzymes of the complex. Such effects were not observed in the presence of structural analogues of thiamine and DMHT without a 2-hydroxyethyl substituent at position 5 of the thiazolium cycle. The effect of DMHT on the plasma membrane Ca-ATPase was similar to that of thiamine. At the same time, DMHT showed high cytostatic activity against neuroblastoma cells.

长期研究证实,神经退行性病变的发生与缺乏维生素 B1(硫胺素)之间存在因果关系。然而,人们对硫胺素具有高度神经刺激活性的生化机制尚不完全清楚。同时,越来越多的证据表明,维生素 B1 除了具有辅酶功能外,还可能具有对神经元特别重要的非辅酶活性。为了弄清维生素 B1 对神经元的影响哪些是由于其辅酶功能,哪些是由于其非辅酶活性,我们对硫胺素及其衍生物--3-癸氧羰基甲基-5-(2-羟乙基)-4-甲基-1,3-噻唑氯化物(DMHT)--对突触体中某些过程的影响进行了比较研究。实验证明,DMHT 能够有效地与硫胺素竞争,与突触体质膜上的硫胺素结合位点结合,并作为底物参与硫胺素焦磷激酶反应。在用大鼠脑突触体进行的实验中,证实了 DMHT 和硫胺素对丙酮酸脱氢酶复合物(PDC)的活性以及放射性标记的 [2-14C]丙酮酸掺入乙酰胆碱的单向作用。硫胺素和 DMHT 对乙酰胆碱合成调节作用的观察结果表明,这两种化合物在细胞中与硫胺素代谢酶相互作用,通过影响复合体的调节酶,使其磷酸化并对 PDC 活性产生抑制/激活作用(浓度依赖性)。在硫胺素和 DMHT 的结构类似物存在的情况下,如果噻唑鎓循环的第 5 位没有 2- 羟乙基取代基,则不会观察到这种效应。DMHT 对质膜 Ca-ATP 酶的影响与硫胺相似。同时,DMHT 对神经母细胞瘤细胞具有很高的细胞抑制活性。
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引用次数: 0
Curcumin as a potential therapeutic agent for treating neurodegenerative diseases 姜黄素是一种治疗神经退行性疾病的潜在药物。
IF 4.2 3区 医学 Q2 Neuroscience Pub Date : 2024-06-07 DOI: 10.1016/j.neuint.2024.105790
Valeria Perales-Salinas , Sushmitha S. Purushotham , Yossi Buskila

Neurodegenerative diseases are characterized by the progressive loss of neuronal structure and function, posing a tremendous burden on health systems worldwide. Although the underlying pathological mechanisms for various neurodegenerative diseases are still unclear, a common pathological hallmark is the abundance of neuroinflammatory processes, which affect both disease onset and progression. In this review, we explore the pathways and role of neuroinflammation in various neurodegenerative diseases and further assess the potential use of curcumin, a natural spice with antioxidant and anti-inflammatory properties that has been extensively used worldwide as a traditional medicine and potential therapeutic agent. Following the examination of preclinical and clinical studies that assessed curcumin as a potential therapeutic agent, we highlight the bioavailability of curcumin in the body and discuss both the challenges and benefits of using curcumin as a therapeutic compound for treating neurodegeneration. Although elucidating the involvement of curcumin in aging and neurodegeneration has great potential for developing future CNS-related therapeutic targets, further research is required to elucidate the mechanisms by which Curcumin affects brain physiology, especially BBB integrity, under both physiological and disease conditions.

神经退行性疾病的特征是神经元结构和功能的逐渐丧失,给全球卫生系统造成了巨大负担。尽管各种神经退行性疾病的潜在病理机制尚不清楚,但一个共同的病理特征是神经炎症过程的大量存在,这对疾病的发生和发展都有影响。姜黄素是一种具有抗氧化和抗炎特性的天然香料,在全世界被广泛用作传统药物和潜在的治疗药物。在对姜黄素作为一种潜在治疗剂的临床前和临床研究进行审查之后,我们强调了姜黄素在体内的生物利用度,并讨论了将姜黄素作为一种治疗化合物用于治疗神经变性的挑战和益处。虽然阐明姜黄素在衰老和神经退行性变中的作用对于开发未来中枢神经系统相关治疗靶点具有巨大潜力,但还需要进一步研究,以阐明姜黄素在生理和疾病条件下影响大脑生理,特别是影响 BBB 完整性的机制。
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引用次数: 0
Inhibiting the activation of enteric glial cells alleviates intestinal inflammation and comorbid anxiety- and depressive-like behaviors in the ulcerative colitis mice 抑制肠胶质细胞的活化可减轻溃疡性结肠炎小鼠的肠道炎症以及合并的焦虑和抑郁样行为。
IF 4.4 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-06-07 DOI: 10.1016/j.neuint.2024.105789
Yan Li , Yan Wang , Qian Sun , Meng-Ying Li , Jia-Zhou Xu , Yun-Qing Li , Hua Zhang

Ulcerative colitis (UC) is a common inflammatory bowel disease with a complex origin in clinical settings. It is frequently accompanied by negative emotional responses, including anxiety and depression. Enteric glial cells (EGCs) are important components of the gut-brain axis and are involved in the development of the enteric nervous system (ENS), intestinal neuroimmune, and regulation of intestinal motor functions. Since there is limited research encompassing the regulatory function of EGCs in anxiety- and depression-like behaviors induced by UC, this study aims to reveal their regulatory role in such behaviors and associated intestinal inflammation. This study applied morphological, molecular biological, and behavioral methods to observe the morphological and functional changes of EGCs in UC mice. The results indicated a significant activation of EGCs in the ENS of dextran sodium sulfate -induced UC mice. This activation was evidenced by morphological alterations, such as elongation or terminal swelling of processes. Besides EGCs activation, UC mice exhibited significantly elevated expression levels of pro-inflammatory cytokines in the peripheral blood, accompanied by anxiety- and depression-like behaviors. The inhibition of EGCs activity within the ENS can ameliorate the anxiety- and depression-like behaviors caused by UC. Our data suggest that UC and its resulting behaviors may be related to the activation of EGCs within the ENS. Moreover, the modulation of intestinal inflammation through inhibition of EGCs activation emerges as a promising clinical approach for alleviating UC-induced anxiety- and depression-like behaviors.

溃疡性结肠炎(UC)是一种常见的炎症性肠病,在临床上病因复杂。它经常伴有负面情绪反应,包括焦虑和抑郁。肠胶质细胞(EGCs)是肠道-大脑轴的重要组成部分,参与肠道神经系统(ENS)的发育、肠道神经免疫和肠道运动功能的调节。由于有关EGCs在UC诱导的焦虑和抑郁样行为中的调节功能的研究有限,本研究旨在揭示EGCs在此类行为和相关肠道炎症中的调节作用。本研究采用形态学、分子生物学和行为学方法观察了EGCs在UC小鼠体内的形态和功能变化。结果表明,右旋糖酐硫酸钠诱导的UC小鼠的ENS中的EGCs被明显激活。这种活化表现为形态学上的改变,如过程的伸长或末端肿胀。除EGCs活化外,UC小鼠外周血中促炎细胞因子的表达水平也明显升高,并伴有焦虑和抑郁样行为。抑制 ENS 中 EGCs 的活性可以改善 UC 引起的焦虑和抑郁行为。我们的数据表明,UC 及其导致的行为可能与 ENS 中 EGCs 的激活有关。此外,通过抑制EGCs的活化来调节肠道炎症是一种很有前景的临床方法,可用于缓解UC引起的焦虑和抑郁样行为。
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引用次数: 0
Pharmacological inhibition of cGAS ameliorates postoperative cognitive dysfunction by suppressing caspase-3/GSDME-dependent pyroptosis 抑制 cGAS 的药理作用可通过抑制 caspase-3/GSDME 依赖性裂解来改善术后认知功能障碍
IF 4.2 3区 医学 Q2 Neuroscience Pub Date : 2024-06-04 DOI: 10.1016/j.neuint.2024.105788
Xueshan Bu , Ping Gong , Lei Zhang , Wenqin Song , Jiabao Hou , Qingwen Li , Wei Wang , Zhongyuan Xia

Neuroinflammation is a major driver of postoperative cognitive dysfunction (POCD). The cyclic GMP-AMP synthase-stimulator of interferon gene (cGAS–STING) signaling is a prominent alarming device for aberrant double-stranded DNA (dsDNA) that has emerged as a key mediator of neuroinflammation in cognitive-related diseases. However, the role of the cGAS–STING pathway in the pathogenesis of POCD remains unclear. A POCD model was developed in male C57BL/6J mice by laparotomy under isoflurane (Iso) anesthesia. The cGAS inhibitor RU.521 and caspase-3 agonist Raptinal were delivered by intraperitoneal administration. BV2 cells were exposed to Iso and lipopolysaccharide (LPS) in the absence or presence of RU.521, and then cocultured with HT22 cells in the absence or presence of Raptinal. Cognitive function was assessed using the Morris water maze test and novel object recognition test. Immunofluorescence assays were used to observe the colocalization of dsDNA and cGAS. The downstream proteins and pro-inflammatory cytokines were detected using the Western blot and enzyme-linked immunosorbent assay (ELISA). Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining was used to assess the degree of cell death in the hippocampus following anesthesia/surgery treatment. Isoflurane/laparotomy and Iso + LPS significantly augmented the levels of cGAS in the hippocampus and BV2 cells, accompanied by mislocalized dsDNA accumulation in the cytoplasm. RU.521 alleviated cognitive impairment, diminished the levels of 2′3′-cGAMP, cGAS, STING, phosphorylated NF-κB p65 and NF-κB-pertinent pro-inflammatory cytokines (TNFα and IL-6), and repressed pyroptosis-associated elements containing cleaved caspase-3, N-GSDME, IL-1β and IL-18. These phenotypes could be rescued by Raptinal in vivo and in vitro. These findings suggest that pharmacological inhibition of cGAS mitigates neuroinflammatory burden of POCD by dampening caspase-3/GSDME-dependent pyroptosis, providing a potential therapeutic strategy for POCD.

神经炎症是术后认知功能障碍(POCD)的主要驱动因素。环GMP-AMP合成酶-干扰素基因刺激器(cGAS-STING)信号传导是异常双链DNA(dsDNA)的显著报警装置,已成为认知相关疾病中神经炎症的关键介质。然而,cGAS-STING通路在POCD发病机制中的作用仍不清楚。研究人员在异氟醚(Iso)麻醉下对雄性 C57BL/6J 小鼠进行开腹手术,建立了 POCD 模型。腹腔注射 cGAS 抑制剂 RU.521 和 caspase-3 激动剂 Raptinal。在无RU.521或有RU.521的情况下,将BV2细胞暴露于Iso和脂多糖(LPS),然后在无Raptinal或有Raptinal的情况下与HT22细胞共培养。认知功能通过莫里斯水迷宫测试和新物体识别测试进行评估。免疫荧光试验用于观察dsDNA和cGAS的共定位。使用 Western 印迹和酶联免疫吸附试验(ELISA)检测下游蛋白和促炎细胞因子。末端脱氧核苷酸转移酶dUTP缺口标记(TUNEL)染色用于评估麻醉/手术治疗后海马细胞的死亡程度。异氟醚/扁桃体切除术和异体+LPS显著增加了海马和BV2细胞中cGAS的水平,并伴随着胞质中dsDNA的错位聚集。RU.521 可减轻认知障碍,降低 2′3′-cGAMP、cGAS、STING、磷酸化 NF-κB p65 和 NF-κB 相关促炎细胞因子(TNFα 和 IL-6)的水平,并抑制含有裂解的 caspase-3、N-GSDME、IL-1β 和 IL-18 的嗜热相关元素。这些表型在体内和体外均可被雷普替尼尔所挽救。这些研究结果表明,药理抑制cGAS可以通过抑制依赖于caspase-3/GSDME的热凋亡减轻POCD的神经炎症负担,为POCD提供了一种潜在的治疗策略。
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引用次数: 0
Red nucleus mGluR1 and mGluR5 facilitate the development of neuropathic pain through stimulating the expressions of TNF-α and IL-1β 红核 mGluR1 和 mGluR5 通过刺激 TNF-α 和 IL-1β 的表达促进神经病理性疼痛的发展
IF 4.2 3区 医学 Q2 Neuroscience Pub Date : 2024-06-04 DOI: 10.1016/j.neuint.2024.105786
Xue Tian , Wen-Tao Wang , Miao-Miao Zhang , Qing-Qing Yang , Ya-Li Xu , Ji-Bo Wu , Xin-Xin Xie , Jun-Yang Wang , Jing-Yuan Wang

Our previous study has identified that glutamate in the red nucleus (RN) facilitates the development of neuropathic pain through metabotropic glutamate receptors (mGluR). Here, we further explored the actions and possible molecular mechanisms of red nucleus mGluR Ⅰ (mGluR1 and mGluR5) in the development of neuropathic pain induced by spared nerve injury (SNI). Our data indicated that both mGluR1 and mGluR5 were constitutively expressed in the RN of normal rats. Two weeks after SNI, the expressions of mGluR1 and mGluR5 were significantly boosted in the RN contralateral to the nerve injury. Administration of mGluR1 antagonist LY367385 or mGluR5 antagonist MTEP to the RN contralateral to the nerve injury at 2 weeks post-SNI significantly ameliorated SNI-induced neuropathic pain. However, unilateral administration of mGluRⅠ agonist DHPG to the RN of normal rats provoked a significant mechanical allodynia, this effect could be blocked by LY367385 or MTEP. Further studies indicated that the expressions of TNF-α and IL-1β in the RN were also elevated at 2 weeks post-SNI. Administration of mGluR1 antagonist LY367385 or mGluR5 antagonist MTEP to the RN at 2 weeks post-SNI significantly inhibited the elevations of TNF-α and IL-1β. However, administration of mGluR Ⅰ agonist DHPG to the RN of normal rats significantly enhanced the expressions of TNF-α and IL-1β, these effects were blocked by LY367385 or MTEP. These results suggest that activation of red nucleus mGluR1 and mGluR5 facilitate the development of neuropathic pain by stimulating the expressions of TNF-α and IL-1β. mGluR Ⅰ maybe potential targets for drug development and clinical treatment of neuropathic pain.

我们之前的研究发现,红核(RN)中的谷氨酸通过代谢型谷氨酸受体(mGluR)促进神经病理性疼痛的发生。在此,我们进一步探讨了红核 mGluR Ⅰ(mGluR1 和 mGluR5)在幸免神经损伤(SNI)诱导的神经病理性疼痛发生过程中的作用和可能的分子机制。我们的数据表明,mGluR1 和 mGluR5 在正常大鼠的 RN 中均呈组成型表达。SNI两周后,mGluR1和mGluR5在神经损伤对侧RN中的表达明显增加。在 SNI 两周后,向神经损伤对侧 RN 施用 mGluR1 拮抗剂 LY367385 或 mGluR5 拮抗剂 MTEP 可明显改善 SNI 引起的神经病理性疼痛。然而,对正常大鼠的 RN 单侧施用 mGluRⅠ 激动剂 DHPG 会引起明显的机械异感,LY367385 或 MTEP 可阻断这种效应。进一步的研究表明,SNI 后 2 周时,RN 中 TNF-α 和 IL-1β 的表达也升高。在 SNI 后 2 周给 RN 注射 mGluR1 拮抗剂 LY367385 或 mGluR5 拮抗剂 MTEP 可显著抑制 TNF-α 和 IL-1β 的升高。然而,给正常大鼠的 RN 施用 mGluR Ⅰ 激动剂 DHPG 会显著增强 TNF-α 和 IL-1β 的表达,LY367385 或 MTEP 可阻断这些效应。这些结果表明,激活红核 mGluR1 和 mGluR5 可刺激 TNF-α 和 IL-1β 的表达,从而促进神经病理性疼痛的发生。
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引用次数: 0
Novel psychoplastogen DM506 reduces cue-induced heroin-seeking and inhibits tonic GABA currents in the Prelimbic Cortex 新型精神生长因子DM506可减少线索诱导的海洛因觅食行为,并抑制前边缘皮层的强直性GABA电流。
IF 4.2 3区 医学 Q2 Neuroscience Pub Date : 2024-06-03 DOI: 10.1016/j.neuint.2024.105785
Kassandra Looschen , Shailesh Narayan Khatri , Malabika Maulik , Colin Salisbury , Alaina F. Carman , Katilyn Corriveau , Colton Smith , Dina Manetti , Maria Novella Romanelli , Hugo R. Arias , Cassandra D. Gipson , Swarup Mitra

Opioid use disorder is a major public health crisis that is manifested by persistent drug-seeking behavior and high relapse frequency. Most of the available treatments rely on targeting opioid receptors using small molecules that do not provide sustained symptom alleviation. Psychoplastogens are a novel class of non-opioid drugs that produce rapid and sustained effects on neuronal plasticity, intended to produce therapeutic benefits. Ibogalogs are synthetic derivatives of iboga alkaloids that lack hallucinogenic or adverse side effects. In the current study, we examine the therapeutic potential of DM506, a novel ibogalog lacking any cardiotoxic or hallucinogenic effects, in cue-induced seeking behavior following heroin self-administration. At a single systemic dose of 40 mg/kg, DM506 significantly decreased cue-induced seeking in both male and female rats at abstinence day 1 (AD1) following heroin self-administration. Upon re-testing for cue-induced seeking at AD14, we found that males receiving DM506 continued to show decreased cue-induced seeking, an effect not observed in females. Since there is evidence of psychedelics influencing tonic GABA currents, and opioid and psychoplastogen-mediated neuroadaptations in the medial prefrontal cortex (PrL) underlying its functional effects, we performed patch-clamp recordings on PrL slices of drug-naïve rats with an acute application or chronic incubation with DM506. Tonic GABA current was decreased in slices incubated with DM506 for 2 h. qPCR analysis did not reveal any differences in the mRNA levels of GABAA receptor α and δ subunits at AD14 in heroin and saline self-administered animals that received vehicle or DM506 at AD1. Overall, our data indicate that DM506 attenuates cue-induced heroin seeking and inhibits tonic GABA current in the prelimbic cortex.

阿片类药物使用障碍是一个重大的公共卫生危机,表现为持续的觅药行为和高复发率。现有的治疗方法大多依赖于使用小分子药物靶向阿片受体,但无法持续缓解症状。精神兴奋药是一类新型的非阿片类药物,可对神经元的可塑性产生快速而持续的影响,从而产生治疗效果。Ibogalogs是伊博格生物碱的合成衍生物,没有致幻或不良副作用。在本研究中,我们考察了 DM506(一种新型伊博格罗碱,没有任何心脏毒性或致幻作用)对海洛因自我给药后线索诱导的寻求行为的治疗潜力。单次全身给药剂量为40毫克/千克时,DM506能显著降低雌雄大鼠在海洛因自我给药后戒断第1天(AD1)的线索诱导寻求行为。在AD14时再次检测线索诱导的寻求时,我们发现接受DM506的雄性大鼠继续显示出线索诱导的寻求减少,而雌性大鼠则没有观察到这种效应。由于有证据表明迷幻药会影响内侧前额叶皮层(PrL)的强直性GABA电流,以及阿片类和精神原介导的神经适应,这是其功能效应的基础,因此我们对急性应用或慢性孵育DM506的未服药大鼠的PrL切片进行了贴片钳记录。qPCR分析没有发现在AD14时,海洛因和生理盐水自我给药动物的GABAA受体α和δ亚基的mRNA水平有任何差异。总之,我们的数据表明,DM506 可减轻线索诱导的海洛因寻求,并抑制前边缘皮层的强直 GABA 电流。
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引用次数: 0
IL-17A enhances the inflammatory response of glaucoma through Act1/TRAF6/NF-κB pathway IL-17A 通过 Act1/TRAF6/NF-κB 通路增强青光眼的炎症反应
IF 4.2 3区 医学 Q2 Neuroscience Pub Date : 2024-06-01 DOI: 10.1016/j.neuint.2024.105787
Yunfan Zheng , Zhenni Mou , Sisi Tan, Xiaochen Wang, Jingchang Yuan, Hong Li

Objectives

To investigate the possible roles of Interleukin 17A (IL-17A) and IL-17A neutralizing antibodies (IL-17Ab) in glaucoma and the potential mechanisms.

Methods

The two glaucoma animal models, chronic ocular hypertension (COH) and N-methyl-D-aspartate (NMDA)-induced retinal ganglion cell (RGC) damage, were established and treated with intravitreal injection of IL-17A or IL-17Ab. Intraocular pressure (IOP) was measured by a rebound tonometer. The retina and RGC injury were evaluated by HE staining, TUNLE assay and Brn3a immunofluorescence staining. The frequency of IL-17A+CD4+T cells in peripheral blood was detected by flow cytometry. The expression of glial fibrillary acidic protein (GFAP) was detected by immunofluorescence staining, Western Blot and qPCR in retina. The RNA and protein expression of Act1/TRAF6/NF-κB were detected by Western Blot and qPCR in retina.

Results

The expression of IL-17A increased in glaucoma models. After intravitreal injection of IL-17A, in the retina, the number of RGCs decreased, the apoptosis of RGCs increased, the Müller cell gliosis was more obvious. In addition, peripheral inflammation aggravated. Whereas the intravitreal injection of IL-17Ab alleviated the relevant manifestations and peripheral inflammation, reduced the gliosis of Müller cells. In the COH model, IOP increased after the injection of IL-17A, while the intravitreal injection of IL-17Ab led to a decrease in IOP. Furthermore, IL-17A promotes the apoptosis of RGCs by binding to IL-17A receptor, activating Act1/TRAF6/NF-κB pathways.

Conclusion

IL-17A plays a role in and aggravates RGC damage in glaucoma. IL-17Ab can neutralize the pro-inflammatory effect of IL-17A and have a protective function in glaucoma. These findings reveal the importance of IL-17A in the pathogenesis of glaucoma, which will shed light on a novel direction for the prevention and treatment of glaucoma, and also provide a reference for further research on other retinal diseases.

目的 研究白细胞介素17A(IL-17A)和IL-17A中和抗体(IL-17Ab)在青光眼中的可能作用及其潜在机制。方法 建立了两种青光眼动物模型,即慢性眼压过高(COH)和N-甲基-D-天冬氨酸(NMDA)诱导的视网膜神经节细胞(RGC)损伤,并用IL-17A或IL-17Ab进行玻璃体内注射治疗。用回弹式眼压计测量眼压(IOP)。视网膜和RGC损伤通过HE染色、TUNLE检测和Brn3a免疫荧光染色进行评估。流式细胞术检测了外周血中IL-17A+CD4+T细胞的频率。通过免疫荧光染色、Western Blot 和 qPCR 检测视网膜中神经胶质纤维酸性蛋白(GFAP)的表达。通过 Western Blot 和 qPCR 检测视网膜中 Act1/TRAF6/NF-κB 的 RNA 和蛋白表达。静脉注射IL-17A后,视网膜中RGC数量减少,RGC凋亡增加,Müller细胞胶质病变更加明显。此外,外周炎症加剧。而玻璃体内注射IL-17Ab可减轻相关表现和外周炎症,减轻Müller细胞的胶质增生。在 COH 模型中,注射 IL-17A 后眼压升高,而玻璃体内注射 IL-17Ab 则使眼压降低。此外,IL-17A通过与IL-17A受体结合,激活Act1/TRAF6/NF-κB通路,促进RGC的凋亡。IL-17Ab能中和IL-17A的促炎作用,对青光眼有保护作用。这些发现揭示了IL-17A在青光眼发病机制中的重要作用,为青光眼的预防和治疗指明了新的方向,也为其他视网膜疾病的进一步研究提供了参考。
{"title":"IL-17A enhances the inflammatory response of glaucoma through Act1/TRAF6/NF-κB pathway","authors":"Yunfan Zheng ,&nbsp;Zhenni Mou ,&nbsp;Sisi Tan,&nbsp;Xiaochen Wang,&nbsp;Jingchang Yuan,&nbsp;Hong Li","doi":"10.1016/j.neuint.2024.105787","DOIUrl":"10.1016/j.neuint.2024.105787","url":null,"abstract":"<div><h3>Objectives</h3><p>To investigate the possible roles of Interleukin 17A (IL-17A) and IL-17A neutralizing antibodies (IL-17Ab) in glaucoma and the potential mechanisms.</p></div><div><h3>Methods</h3><p>The two glaucoma animal models, chronic ocular hypertension (COH) and N-methyl-D-aspartate (NMDA)-induced retinal ganglion cell (RGC) damage, were established and treated with intravitreal injection of IL-17A or IL-17Ab. Intraocular pressure (IOP) was measured by a rebound tonometer. The retina and RGC injury were evaluated by HE staining, TUNLE assay and Brn3a immunofluorescence staining. The frequency of IL-17A<sup>+</sup>CD4<sup>+</sup>T cells in peripheral blood was detected by flow cytometry. The expression of glial fibrillary acidic protein (GFAP) was detected by immunofluorescence staining, Western Blot and qPCR in retina. The RNA and protein expression of Act1/TRAF6/NF-κB were detected by Western Blot and qPCR in retina.</p></div><div><h3>Results</h3><p>The expression of IL-17A increased in glaucoma models. After intravitreal injection of IL-17A, in the retina, the number of RGCs decreased, the apoptosis of RGCs increased, the Müller cell gliosis was more obvious. In addition, peripheral inflammation aggravated. Whereas the intravitreal injection of IL-17Ab alleviated the relevant manifestations and peripheral inflammation, reduced the gliosis of Müller cells. In the COH model, IOP increased after the injection of IL-17A, while the intravitreal injection of IL-17Ab led to a decrease in IOP. Furthermore, IL-17A promotes the apoptosis of RGCs by binding to IL-17A receptor, activating Act1/TRAF6/NF-κB pathways.</p></div><div><h3>Conclusion</h3><p>IL-17A plays a role in and aggravates RGC damage in glaucoma. IL-17Ab can neutralize the pro-inflammatory effect of IL-17A and have a protective function in glaucoma. These findings reveal the importance of IL-17A in the pathogenesis of glaucoma, which will shed light on a novel direction for the prevention and treatment of glaucoma, and also provide a reference for further research on other retinal diseases.</p></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":null,"pages":null},"PeriodicalIF":4.2,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141232061","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
Molecular mechanisms of the ambroxol action in Gaucher disease and GBA1 mutation-associated Parkinson disease 氨溴索作用于戈谢病和GBA1突变相关帕金森病的分子机制
IF 4.2 3区 医学 Q2 Neuroscience Pub Date : 2024-05-24 DOI: 10.1016/j.neuint.2024.105774
Zuzanna Cyske, Lidia Gaffke, Estera Rintz, Karolina Wiśniewska, Grzegorz Węgrzyn, Karolina Pierzynowska

Glucocerebrosidase (GCase), encoded by the GBA1 gene, is one of the lysosomal enzymes responsible for hydrolyzing the glycosphingolipids. Deficiency in GCase activity (in patients with two defective alleles of GBA1) leads to glucosylceramide storage in lysosomes which in turn results in the development of the Gaucher diseases, a lysosomal storage disorder, while a heterozygous state may be correlated with the GBA1 mutation-associated Parkinson disease. One of the proposed forms of therapy for these two conditions is the use of pharmacological chaperones which work by facilitating the achievement of the correct conformation of abnormally folded enzymes. Several compounds with chaperone activities against GCase have already been tested, one of which turned out to be ambroxol. Studies conducted on the action of this compound have indeed indicated its effectiveness in increasing GCase levels and activity. However, some data have begun to question its activity as a chaperone against certain GCase variants. Then, a number of articles appeared pointing to other mechanisms of action of ambroxol, which may also contribute to the improvement of patients' condition. This paper summarizes the biological mechanisms of action of ambroxol in Gaucher disease and GBA1 mutation-associated Parkinson disease, focused on its activity as a chaperone, modulator of ERAD pathways, inducer of autophagy, and pain reliever in cellular and animal models as well as in patients. The effects of these activities on the reduction of disease markers and symptoms in patients are also discussed. Consideration of all the properties of ambroxol can help in the appropriate choice of therapy and the determination of the effective drug dose.

由 GBA1 基因编码的葡糖脑苷脂酶(GCase)是一种溶酶体酶,负责水解糖磷脂。GCase 活性缺陷(GBA1 的两个等位基因缺陷患者)会导致葡萄糖甘油酰胺在溶酶体中储存,进而导致溶酶体储存障碍性疾病戈谢病的发生,而杂合状态可能与 GBA1 基因突变相关的帕金森病有关。针对这两种疾病提出的治疗方法之一是使用药理伴侣,其作用是促进折叠异常的酶获得正确的构象。已经测试了几种对 GCase 具有伴侣活性的化合物,其中一种是氨溴索。对这种化合物的作用进行的研究确实表明,它能有效提高 GCase 的水平和活性。然而,一些数据开始质疑它作为伴侣剂对某些 GCase 变体的活性。随后,一些文章指出了氨溴索的其他作用机制,这些机制也可能有助于改善患者的病情。本文总结了氨溴索在戈谢病和GBA1突变相关帕金森病中的生物学作用机制,重点介绍了氨溴索在细胞和动物模型以及患者体内作为伴侣、ERAD通路调节剂、自噬诱导剂和止痛剂的活性。此外,还讨论了这些活性对减少疾病标志物和患者症状的影响。考虑氨溴索的所有特性有助于选择适当的疗法和确定有效的药物剂量。
{"title":"Molecular mechanisms of the ambroxol action in Gaucher disease and GBA1 mutation-associated Parkinson disease","authors":"Zuzanna Cyske,&nbsp;Lidia Gaffke,&nbsp;Estera Rintz,&nbsp;Karolina Wiśniewska,&nbsp;Grzegorz Węgrzyn,&nbsp;Karolina Pierzynowska","doi":"10.1016/j.neuint.2024.105774","DOIUrl":"10.1016/j.neuint.2024.105774","url":null,"abstract":"<div><p>Glucocerebrosidase (GCase), encoded by the <em>GBA1</em> gene, is one of the lysosomal enzymes responsible for hydrolyzing the glycosphingolipids. Deficiency in GCase activity (in patients with two defective alleles of <em>GBA1</em>) leads to glucosylceramide storage in lysosomes which in turn results in the development of the Gaucher diseases, a lysosomal storage disorder, while a heterozygous state may be correlated with the <em>GBA1</em> mutation-associated Parkinson disease. One of the proposed forms of therapy for these two conditions is the use of pharmacological chaperones which work by facilitating the achievement of the correct conformation of abnormally folded enzymes. Several compounds with chaperone activities against GCase have already been tested, one of which turned out to be ambroxol. Studies conducted on the action of this compound have indeed indicated its effectiveness in increasing GCase levels and activity. However, some data have begun to question its activity as a chaperone against certain GCase variants. Then, a number of articles appeared pointing to other mechanisms of action of ambroxol, which may also contribute to the improvement of patients' condition. This paper summarizes the biological mechanisms of action of ambroxol in Gaucher disease and <em>GBA1</em> mutation-associated Parkinson disease, focused on its activity as a chaperone, modulator of ERAD pathways, inducer of autophagy, and pain reliever in cellular and animal models as well as in patients. The effects of these activities on the reduction of disease markers and symptoms in patients are also discussed. Consideration of all the properties of ambroxol can help in the appropriate choice of therapy and the determination of the effective drug dose.</p></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":null,"pages":null},"PeriodicalIF":4.2,"publicationDate":"2024-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141141400","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
Ferroptosis: A new strategy for targeting Alzheimer’s disease 铁突变:针对阿尔茨海默病的新策略
IF 4.2 3区 医学 Q2 Neuroscience Pub Date : 2024-05-23 DOI: 10.1016/j.neuint.2024.105773
Rong Rong Qiang , Yang Xiang , Lei Zhang , Xin Yue Bai , Die Zhang , Yang Jing Li , Yan Ling Yang , Xiao Long Liu

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by a complex pathogenesis, which involves the formation of amyloid plaques and neurofibrillary tangles. Many recent studies have revealed a close association between ferroptosis and the pathogenesis of AD. Factors such as ferroptosis-associated iron overload, lipid peroxidation, disturbances in redox homeostasis, and accumulation of reactive oxygen species have been found to contribute to the pathological progression of AD. In this review, we explore the mechanisms underlying ferroptosis, describe the link between ferroptosis and AD, and examine the reported efficacy of ferroptosis inhibitors in treating AD. Finally, we discuss the potential challenges to ferroptosis inhibitors use in the clinic, enabling their faster use in clinical treatment.

阿尔茨海默病(AD)是一种神经退行性疾病,发病机制复杂,包括淀粉样蛋白斑块和神经纤维缠结的形成。最近的许多研究表明,铁蛋白沉积与阿兹海默症的发病机制密切相关。研究发现,与铁变态反应相关的铁超载、脂质过氧化、氧化还原平衡紊乱和活性氧积累等因素导致了AD的病理进展。在这篇综述中,我们探讨了铁蛋白沉积的内在机制,描述了铁蛋白沉积与 AD 之间的联系,并研究了铁蛋白沉积抑制剂治疗 AD 的疗效。最后,我们讨论了在临床中使用铁蛋白沉积抑制剂可能面临的挑战,以便更快地将其用于临床治疗。
{"title":"Ferroptosis: A new strategy for targeting Alzheimer’s disease","authors":"Rong Rong Qiang ,&nbsp;Yang Xiang ,&nbsp;Lei Zhang ,&nbsp;Xin Yue Bai ,&nbsp;Die Zhang ,&nbsp;Yang Jing Li ,&nbsp;Yan Ling Yang ,&nbsp;Xiao Long Liu","doi":"10.1016/j.neuint.2024.105773","DOIUrl":"10.1016/j.neuint.2024.105773","url":null,"abstract":"<div><p>Alzheimer's disease (AD) is a neurodegenerative disorder characterized by a complex pathogenesis, which involves the formation of amyloid plaques and neurofibrillary tangles. Many recent studies have revealed a close association between ferroptosis and the pathogenesis of AD. Factors such as ferroptosis-associated iron overload, lipid peroxidation, disturbances in redox homeostasis, and accumulation of reactive oxygen species have been found to contribute to the pathological progression of AD. In this review, we explore the mechanisms underlying ferroptosis, describe the link between ferroptosis and AD, and examine the reported efficacy of ferroptosis inhibitors in treating AD. Finally, we discuss the potential challenges to ferroptosis inhibitors use in the clinic, enabling their faster use in clinical treatment.</p></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":null,"pages":null},"PeriodicalIF":4.2,"publicationDate":"2024-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141092473","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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