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Pentylenetetrazole: A review 戊烯四唑:综述。
IF 4.4 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-28 DOI: 10.1016/j.neuint.2024.105841

Pentylenetetrazole (PTZ), a tetrazole derivative, is commonly used as a chemical agent to induce neurological disorders and replicate the characteristics of human epileptic seizures in animal models. This review offers a comprehensive analysis of the behavioral, neurophysiological, and neurochemical changes induced by PTZ. The epileptogenic and neurotoxic mechanisms of PTZ are associated with an imbalance between the GABAergic and glutamatergic systems. At doses exceeding 60 mg/kg, PTZ exerts its epileptic effects by non-competitively antagonizing GABAA receptors and activating NMDA receptors, resulting in an increased influx of cations such as Na+ and Ca2+. Additionally, PTZ promotes oxidative stress, microglial activation, and the synthesis of pro-inflammatory mediators, all of which are features characteristic of glutamatergic excitotoxicity. These mechanisms ultimately lead to epileptic seizures and neuronal cell death, which depend on the dosage and method of administration. The behavioral, electroencephalographic, and histological changes associated with PTZ further establish it as a valuable preclinical model for the study of epileptic seizures, owing to its simplicity, cost-effectiveness, and reproducibility.

戊四氮唑(PTZ)是一种四氮唑衍生物,常用作诱导神经系统疾病的化学制剂,并在动物模型中复制人类癫痫发作的特征。本综述全面分析了 PTZ 诱导的行为、神经生理学和神经化学变化。PTZ 的致痫和神经毒性机制与 GABA 能系统和谷氨酸能系统之间的失衡有关。当剂量超过 60 毫克/千克时,PTZ 通过非竞争性拮抗 GABAA 受体和激活 NMDA 受体,导致 Na+ 和 Ca2+ 等阳离子流入增加,从而产生癫痫效应。此外,PTZ 还会促进氧化应激、小胶质细胞活化和促炎介质的合成,所有这些都是谷氨酸能兴奋毒性的特征。这些机制最终会导致癫痫发作和神经细胞死亡,这取决于给药剂量和方法。与 PTZ 相关的行为学、脑电图和组织学变化因其简单、成本效益高和可重复性而进一步将其确立为研究癫痫发作的宝贵临床前模型。
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引用次数: 0
Post-stroke whole body vibration therapy alters the cerebral transcriptome to promote ischemic tolerance in middle-aged female rats 中风后全身振动疗法改变大脑转录组,促进中年雌性大鼠的缺血耐受性
IF 4.4 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-28 DOI: 10.1016/j.neuint.2024.105843

Low-frequency whole body vibration (WBV; 40 Hz) therapy after stroke reduces ischemic brain damage, motor, and cognitive deficits in middle-aged rats of both sexes. However, the underlying mechanisms responsible for WBV induced ischemic protections remain elusive. In the current study, we hypothesize that post-stroke WBV initiates transcriptional reprogramming in the cortex of middle-aged female rats which is responsible for the observed reduced stroke consequences. Middle-aged female Sprague-Dawley rats that remained in constant diestrus (reproductively senescent) were randomized to either sham or transient middle cerebral artery occlusion (tMCAO; 90 min) surgery. A day after induction of tMCAO, animals received either WBV or no-WBV treatment for 15 min twice a day for five days for a week. Post-treatment, cortical tissue was analyzed for gene expression using RNA sequencing (RNAseq) and gene enrichment analysis via Enrichr. The RNAseq data analysis revealed significant changes in gene expression due to WBV therapy and the differentially expressed genes are involved in variety of biological processes like neurogenesis, angiogenesis, excitotoxicity, and cell death. Specifically, observed significant up-regulation of 116 and down-regulation of 258 genes after WBV in tMCAO exposed rats as compared to the no-WBV group. The observed transcriptional reprogramming will identify the possible mechanism(s) responsible for post-stroke WBV conferred ischemic protection and future studies will be needed to confirm the role of the genes identified in the current study.

中风后的低频全身振动(WBV;40Hz)疗法可减少中年雌雄大鼠缺血性脑损伤、运动和认知障碍。然而,WBV诱导缺血性保护作用的潜在机制仍不明确。在目前的研究中,我们假设中风后 WBV 在中年雌性大鼠的大脑皮层中启动了转录重编程,这是观察到的中风后果减轻的原因。中年雌性 Sprague-Dawley 大鼠一直处于发情期(生殖衰老),我们随机对其进行假手术或瞬时大脑中动脉闭塞(tMCAO;90 分钟)手术。诱导 tMCAO 一天后,动物接受 WBV 或无 WBV 治疗,每天两次,每次 15 分钟,连续五天,为期一周。治疗后,使用 RNA 测序(RNAseq)和 Enrichr 基因富集分析对大脑皮层组织进行基因表达分析。RNAseq 数据分析显示,WBV 治疗导致基因表达发生了显著变化,差异表达的基因参与了神经发生、血管生成、兴奋毒性和细胞死亡等多种生物过程。具体而言,与无 WBV 组相比,观察到暴露于 tMCAO 的大鼠在接受 WBV 治疗后,116 个基因明显上调,258 个基因明显下调。观察到的转录重编程将确定脑卒中后 WBV 给予缺血保护的可能机制,未来的研究将需要确认当前研究中确定的基因的作用。
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引用次数: 0
Corrigendum to “Pharmacological inhibition of cGAS ameliorates postoperative cognitive dysfunction by suppressing caspase-3/GSDME-dependent pyroptosis” [Neurochem. Int. 178 (2024) 105788] 更正:"药理抑制 cGAS 可通过抑制 caspase-3/GSDME 依赖性脓毒症改善术后认知功能障碍" [Neurochem.
IF 4.4 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-25 DOI: 10.1016/j.neuint.2024.105838
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引用次数: 0
Red nucleus mGluR2 but not mGluR3 mediates inhibitory effect in the development of SNI-induced neuropathological pain by suppressing the expressions of TNF-α and IL-1β 红核 mGluR2 而非 mGluR3 通过抑制 TNF-α 和 IL-1β 的表达,在 SNI 诱导的神经病理性疼痛的发展过程中起介导抑制作用。
IF 4.4 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-22 DOI: 10.1016/j.neuint.2024.105840

Our previous study has verified that activation of group Ⅰ metabotropic glutamate receptors (mGluRⅠ) in the red nucleus (RN) facilitate the development of neuropathological pain. Here, we further discussed the functions and possible molecular mechanisms of red nucleus mGluR Ⅱ (mGluR2 and mGluR3) in the development of neuropathological pain induced by spared nerve injury (SNI). Our results showed that mGluR2 and mGluR3 both were constitutively expressed in the RN of normal rats. At 2 weeks post-SNI, the protein expression of mGluR2 rather than mGluR3 was significantly reduced in the RN contralateral to the nerve lesion. Injection of mGluR2/3 agonist LY379268 into the RN contralateral to the nerve injury at 2 weeks post-SNI significantly attenuated SNI-induced neuropathological pain, this effect was reversed by mGluR2/3 antagonist EGLU instead of selective mGluR3 antagonist β-NAAG. Intrarubral injection of LY379268 did not alter the PWT of contralateral hindpaw in normal rats, while intrarubral injection of EGLU rather than β-NAAG provoked a significant mechanical allodynia. Further studies indicated that the expressions of nociceptive factors TNF-α and IL-1β in the RN were enhanced at 2 weeks post-SNI. Intrarubral injection of LY379268 at 2 weeks post-SNI significantly suppressed the overexpressions of TNF-α and IL-1β, these effects were reversed by EGLU instead of β-NAAG. Intrarubral injection of LY379268 did not influence the protein expressions of TNF-α and IL-1β in normal rats, while intrarubral injection of EGLU rather than β-NAAG significantly boosted the expressions of TNF-α and IL-1β. These findings suggest that red nucleus mGluR2 but not mGluR3 mediates inhibitory effect in the development of SNI-induced neuropathological pain by suppressing the expressions of TNF-α and IL-1β. mGluR Ⅱ may be potential targets for drug development and clinical treatment of neuropathological pain.

我们之前的研究已经证实,红核(RN)中Ⅰ群代谢谷氨酸受体(mGluRⅠ)的激活促进了神经病理性疼痛的发生。在此,我们进一步探讨了红核mGluRⅡ(mGluR2和mGluR3)在幸免神经损伤(SNI)诱导的神经病理性疼痛发生中的功能和可能的分子机制。我们的研究结果表明,mGluR2 和 mGluR3 在正常大鼠的 RN 中均呈组成型表达。在神经损伤后 2 周,mGluR2 而不是 mGluR3 的蛋白表达在神经损伤对侧的 RN 中明显减少。在SNI后2周,向神经损伤对侧RN注射mGluR2/3激动剂LY379268可明显减轻SNI诱导的神经病理性疼痛,而mGluR2/3拮抗剂EGLU代替选择性mGluR3拮抗剂β-NAAG可逆转这种效应。在正常大鼠的后爪内注射 LY379268 不会改变对侧后爪的脉搏波速度,而在大鼠的后爪内注射 EGLU 而不是 β-NAAG 会引起明显的机械异感。进一步的研究表明,SNI 后 2 周,RN 中痛觉因子 TNF-α 和 IL-1β 的表达增强。在 SNI 后 2 周,睾丸内注射 LY379268 能显著抑制 TNF-α 和 IL-1β 的过度表达,而 EGLU 代替 β-NAAG 则能逆转这些效应。正常大鼠睾丸内注射 LY379268 不会影响 TNF-α 和 IL-1β 的蛋白表达,而睾丸内注射 EGLU 而非 β-NAAG 则会明显提高 TNF-α 和 IL-1β 的表达。这些研究结果表明,红核mGluR2而非mGluR3通过抑制TNF-α和IL-1β的表达来介导抑制SNI诱导的神经病理性疼痛的发生。
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引用次数: 0
Transthyretin Amyloidosis: Role of oxidative stress and the beneficial implications of antioxidants and nutraceutical supplementation 转甲状腺素淀粉样变性:氧化应激的作用以及抗氧化剂和营养补充剂的有益影响。
IF 4.4 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-21 DOI: 10.1016/j.neuint.2024.105837

Transthyretin (ATTR) amyloidosis constitutes a spectrum of debilitating neurodegenerative diseases instigated by systemic extracellular deposition of partially unfolded/aggregated aberrant transthyretin. The homotetrameric protein, TTR, is abundant in the plasma, and to a lesser extent the cerebrospinal fluid. Rate-limiting tetramer dissociation of the native protein is regarded as the critical step in the formation of morphologically heterogenous toxic aggregates and the onset of clinical manifestations such as polyneuropathy, cardiomyopathy, disturbances in motor and autonomic functions. Over the past few decades there has been increasing evidence suggesting that in addition to destabilization in TTR tetramer structure, oxidative stress may also play an important role in the pathogenesis of ATTR amyloidosis. In this review, an update on the impact of oxidative stress in TTR amyloidogenesis as well as TTR aggregate-mediated pathologies is discussed. The counteracting effects of antioxidants and nutraceutical agents explored in the treatment of ATTR amyloidosis based on recent evidence is also critically examined. The insights unveiled could further strengthen current understanding of the mechanisms underlying ATTR amyloidosis as well as extend the range of strategies for effective management of ATTR amyloidoses.

转甲状腺素(ATTR)淀粉样变性病是由部分未折叠/聚集的异常转甲状腺素在细胞外系统性沉积引起的一系列使人衰弱的神经退行性疾病。同型四聚体蛋白 TTR 在血浆中含量丰富,在脑脊液中含量也较少。原生蛋白的限速四聚体解离被认为是形成形态各异的毒性聚集体以及多发性神经病、心肌病、运动和自主神经功能紊乱等临床表现的关键步骤。过去几十年来,越来越多的证据表明,除了 TTR 四聚体结构的不稳定性外,氧化应激也可能在 ATTR 淀粉样变性的发病机制中扮演重要角色。本综述讨论了氧化应激在 TTR 淀粉样变性发生和 TTR 聚集体介导的病理学中的最新影响。此外,还根据最新证据对抗氧化剂和营养保健品在治疗ATTR淀粉样变性中的抗衡作用进行了批判性研究。所揭示的观点可进一步加强目前对ATTR淀粉样变性基础机制的理解,并扩大有效治疗ATTR淀粉样变性的策略范围。
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引用次数: 0
Neuroprotective Effects of Sulforaphane in a rat model of Alzheimer's Disease induced by Aβ (1–42) peptides Aβ (1-42) 肽诱导的阿尔茨海默病大鼠模型中红豆杉素的神经保护作用
IF 4.4 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-21 DOI: 10.1016/j.neuint.2024.105839

The intricate nature of Alzheimer's disease (AD) has presented significant hurdles in the development of effective interventions. Sulforaphane (SFN) is of interest due to its antioxidative, anti-inflammatory, and neuroprotective properties, which could address various aspects of AD pathology. This study explores the potential of SFN in a rat model of AD induced by Aβ (1–42) peptides. AD symptoms were triggered in rats by injecting Aβ (1–42) peptides directly into their cerebral ventricles. SFN (10 mg/kg and 20 mg/kg), Trigonelline (10 mg/kg), and Pioglitazone (10 mg/kg) were administered in Aβ (1–42) treated animals. Behavioral assessments were performed using the Novel Object Recognition tests. Various biochemical parameters, such as soluble Aβ (1–42), IRS-S312, GSK-3β, TNF-α, acetylcholinesterase, nitrite levels, lipid peroxidation, and reduced glutathione activity, were quantified using ELISA kits and spectrophotometric assays. Histopathological analyses included Hematoxylin and Eosin, Crystal Violet, Congo red, and IRS-1 Immunohistochemistry staining. Quantification was performed to assess neuronal loss and Aβ plaque burden. The novelty of this study lies in its comprehensive evaluation of SFN's impact on multiple AD-related pathways at dual doses. The Novel Object Recognition test revealed that SFN, especially at higher doses, improved memory deficits induced by Aβ (1–42). Biochemically, SFN reduced hippocampal Aβ levels, IRS-S312, GSK-3β, TNF-α, and acetylcholinesterase activity, while increasing glutathione levels, all in a dose-dependent manner. Histopathological analyses further confirmed SFN's protective role against Aβ-induced neuronal damage, amyloidosis, and changes in insulin signaling. These results highlight SFN's potential as a multifaceted therapeutic agent for AD, offering a promising avenue for treatment due to its antioxidative, anti-inflammatory, and neuroprotective properties. The inclusion of combination treatments with Trigonelline and Pioglitazone alongside SFN offers insights into potential synergistic effects, which could pave the way for developing combination therapies for AD.

阿尔茨海默病(AD)的病因错综复杂,给有效干预措施的开发带来了巨大障碍。绿萘素(SFN)因其抗氧化、抗炎和神经保护特性而备受关注,它可以解决阿尔茨海默病病理的各个方面。本研究探讨了SFN在Aβ(1-42)肽诱导的AD大鼠模型中的潜力。向大鼠脑室直接注射Aβ(1-42)肽,诱发大鼠出现AD症状。给Aβ(1-42)治疗动物注射SFN(10毫克/千克和20毫克/千克)、曲戈奈林(10毫克/千克)和吡格列酮(10毫克/千克)。行为评估采用新物体识别测试。使用酶联免疫吸附试剂盒和分光光度法对各种生化指标进行量化,如可溶性 Aβ (1-42)、IRS-S312、GSK-3β、TNF-α、乙酰胆碱酯酶、亚硝酸盐水平、脂质过氧化和还原型谷胱甘肽活性。组织病理学分析包括苏木精和伊红、刚果红和 IRS-1 免疫组织化学染色。对神经元损失和Aβ斑块负担进行量化评估。这项研究的新颖之处在于它以双重剂量全面评估了SFN对多种AD相关通路的影响。新物体识别测试显示,SFN,尤其是高剂量的SFN,可改善Aβ(1-42)诱导的记忆缺陷。在生化方面,SFN能降低海马Aβ水平、IRS-S312、GSK-3β、TNF-α和乙酰胆碱酯酶活性,同时提高谷胱甘肽水平,所有这些均呈剂量依赖性。组织病理学分析进一步证实了 SFN 对 Aβ 诱导的神经元损伤、淀粉样变性和胰岛素信号变化的保护作用。这些结果凸显了SFN作为一种多方面的AD治疗剂的潜力,它的抗氧化、抗炎和神经保护特性为治疗提供了一种前景广阔的途径。在使用SFN的同时使用曲高奈林和吡格列酮进行联合治疗,有助于深入了解潜在的协同效应,从而为开发AD联合疗法铺平道路。
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引用次数: 0
3-Nitrotyrosine shortens axons of non-dopaminergic neurons by inhibiting mitochondrial motility 3-硝基酪氨酸通过抑制线粒体的运动缩短非多巴胺能神经元的轴突。
IF 4.4 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-16 DOI: 10.1016/j.neuint.2024.105832

3-Nitrotyrosine (3-NT), a byproduct of oxidative and nitrosative stress, is implicated in age-related neurodegenerative disorders. Current literature suggests that free 3-NT becomes integrated into the carboxy-terminal domain of α-tubulin via the tyrosination/detyrosination cycle. Independently of this integration, 3-NT has been associated with the cell death of dopaminergic neurons. Given the critical role of tyrosination/detyrosination in governing axonal morphology and function, the substitution of tyrosine with 3-NT in this process may potentially disrupt axonal homeostasis, although this aspect remains underexplored. In this study, we examined the impact of 3-NT on the axons of cerebellar granule neurons, which is used as a model for non-dopaminergic neurons. Our observations revealed axonal shortening, which correlated with the incorporation of 3-NT into α-tubulin. Importantly, this axonal effect was observed prior to the onset of cellular death. Furthermore, 3-NT was found to diminish mitochondrial motility within the axon, leading to a subsequent reduction in mitochondrial membrane potential. The suppression of syntaphilin, a protein responsible for anchoring mitochondria to microtubules, restored the mitochondrial motility and axonal elongation that were inhibited by 3-NT. These findings underscore the inhibitory role of 3-NT in axonal elongation by impeding mitochondrial movement, suggesting its potential involvement in axonal dysfunction within non-dopaminergic neurons.

3-硝基酪氨酸(3-NT)是氧化和亚硝基应激的副产物,与年龄相关的神经退行性疾病有关。目前的文献表明,游离的 3-NT 会通过酪氨酸化/去酪氨酸化循环整合到 α-微管蛋白的羧基末端结构域中。与这种整合无关,3-NT 与多巴胺能神经元的细胞死亡有关。鉴于酪氨酸化/去酪氨酸化在支配轴突形态和功能方面的关键作用,在这一过程中用 3-NT 取代酪氨酸可能会破坏轴突的稳态,尽管这方面的研究仍然不足。在本研究中,我们研究了 3-NT 对小脑颗粒神经元轴突的影响,小脑颗粒神经元被用作非多巴胺能神经元的模型。我们的观察结果表明,轴突缩短与3-NT掺入α-微管蛋白有关。重要的是,这种轴突效应是在细胞死亡开始之前观察到的。此外,研究还发现 3-NT 会降低轴突内线粒体的运动性,从而导致线粒体膜电位随之降低。3-NT抑制了线粒体的运动和轴突的伸长,而抑制了负责将线粒体锚定在微管上的蛋白质--合成鞘磷脂,则恢复了线粒体的运动和轴突的伸长。这些发现强调了 3-NT 通过阻碍线粒体运动对轴突伸长的抑制作用,表明它可能参与了非多巴胺能神经元的轴突功能障碍。
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引用次数: 0
Unlocking the potential of low-molecular-weight (Poly)phenol metabolites: Protectors at the blood-brain barrier frontier 释放低分子量(多)酚代谢物的潜力:血脑屏障前沿的保护者。
IF 4.4 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-14 DOI: 10.1016/j.neuint.2024.105836

Neurodegenerative diseases (NDDs) are an increasing group of chronic and progressive neurological disorders that ultimately lead to neuronal cell failure and death. Despite all efforts throughout decades, their burden on individuals and society still casts one of the most massive socioeconomic problems worldwide.

The neuronal failure observed in NDDs results from an intricacy of events, mirroring disease complexity, ranging from protein aggregation, oxidative stress, (neuro)inflammation, and even blood-brain barrier (BBB) dysfunction, ultimately leading to cognitive and motor symptoms in patients. As a result of such complex pathobiology, to date, there are still no effective treatments to treat/halt NDDs progression.

Fortunately, interest in the bioavailable low molecular weight (LMW) phenolic metabolites derived from the metabolism of dietary (poly)phenols has been rising due to their multitargeted potential in attenuating multiple NDDs hallmarks. Even if not highly BBB permeant, their relatively high concentrations in the bloodstream arising from the intake of (poly)phenol-rich diets make them ideal candidates to act within the vasculature and particularly at the level of BBB.

In this review, we highlight the most recent - though still scarce - studies demonstrating LMW phenolic metabolites’ ability to modulate BBB homeostasis, including the improvement of tight and adherens junctional proteins, as well as their power to decrease pro-inflammatory cytokine secretion and oxidative stress levels in vitro and in vivo. Specific BBB-permeant LMW phenolic metabolites, such as simple phenolic sulfates, have been emerging as strong BBB properties boosters, pleiotropic compounds capable of improving cell fitness under oxidative and pro-inflammatory conditions. Nevertheless, further studies should be pursued to obtain a holistic overview of the promising role of LMW phenolic metabolites in NDDs prevention and management to fully harness their true therapeutic potential.

神经退行性疾病(NDDs)是一类日益增多的慢性进行性神经系统疾病,最终导致神经细胞衰竭和死亡。尽管经过几十年的努力,这些疾病对个人和社会造成的负担仍然是全球最严重的社会经济问题之一。在 NDDs 中观察到的神经元衰竭是由一系列错综复杂的事件引起的,反映了疾病的复杂性,包括蛋白质聚集、氧化应激、(神经)炎症,甚至血脑屏障(BBB)功能障碍,最终导致患者出现认知和运动症状。由于病理生物学如此复杂,迄今为止,仍没有有效的治疗方法来治疗/控制 NDDs 的进展。幸运的是,由于膳食(多)酚代谢产生的生物可利用性低分子量(LMW)酚类代谢物在减轻多种 NDDs 特征方面具有多靶点潜力,人们对它们的兴趣日益浓厚。即使它们的生物BB渗透性不高,但由于摄入富含(多)酚的膳食,它们在血液中的浓度相对较高,这使它们成为在血管中,特别是在生物BB水平发挥作用的理想候选物质。在这篇综述中,我们将重点介绍最新的研究,这些研究表明 LMW 酚类代谢物具有调节 BBB 平衡的能力,包括改善紧密连接蛋白和粘连蛋白,以及降低体外和体内促炎细胞因子分泌和氧化应激水平的能力。特定的BBB渗透性低分子量酚类代谢物(如简单的酚硫酸盐)已逐渐成为BBB的强力助推剂,这些多效化合物能够改善细胞在氧化和促炎条件下的健康状况。然而,要全面了解低分子量酚类代谢物在预防和治疗非传染性疾病中的作用,充分利用其真正的治疗潜力,还需要进一步的研究。
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引用次数: 0
Monoamine oxidase and neurodegeneration: Mechanisms, inhibitors and natural compounds for therapeutic intervention 单胺氧化酶与神经退行性变:治疗干预的机制、抑制剂和天然化合物。
IF 4.4 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-14 DOI: 10.1016/j.neuint.2024.105831

Mammalian flavoenzyme Monoamine oxidase (MAO) resides on the outer mitochondrial membrane (OMM) and it is involved in the metabolism of different monoamine neurotransmitters in brain. During MAO mediated oxidative deamination of relevant substrates, H2O2 is released as a catalytic by-product, thus serving as a major source of reactive oxygen species (ROS). Under normal conditions, MAO mediated ROS is reported to propel the functioning of mitochondrial electron transport chain and phasic dopamine release. However, due to its localization onto mitochondria, sudden elevation in its enzymatic activity could directly impact the form and function of the organelle. For instance, in the case of Parkinson's disease (PD) patients who are on l-dopa therapy, the enzyme could be a concurrent source of extensive ROS production in the presence of uncontrolled substrate (dopamine) availability, thus further impacting the health of surviving neurons. It is worth mentioning that the expression of the enzyme in different brain compartments increases with age. Moreover, the involvement of MAO in the progression of neurological disorders such as PD, Alzheimer's disease and depression has been extensively studied in recent times. Although the usage of available synthetic MAO inhibitors has been instrumental in managing these conditions, the associated complications have raised significant concerns lately. Natural products have served as a major source of lead molecules in modern-day drug discovery; however, there is still no FDA-approved MAO inhibitor which is derived from natural sources. In this review, we have provided a comprehensive overview of MAO and how the enzyme system is involved in the pathogenesis of different age-associated neuropathologic conditions. We further discussed the applications and drawbacks of the long-term usage of presently available synthetic MAO inhibitors. Additionally, we have highlighted the prospect and worth of natural product derived molecules in addressing MAO associated complications.

哺乳动物黄酶类单胺氧化酶(MAO)位于线粒体外膜(OMM)上,参与大脑中不同单胺神经递质的代谢。在 MAO 介导的相关底物氧化脱氨过程中,会释放出 H2O2 作为催化副产物,从而成为活性氧(ROS)的主要来源。据报道,在正常情况下,MAO 介导的 ROS 可促进线粒体电子传递链的运作和多巴胺的阶段性释放。然而,由于其定位在线粒体上,其酶活性的突然升高会直接影响细胞器的形态和功能。例如,帕金森病(PD)患者在接受 L-DOPA l-多巴治疗时,在底物(多巴胺)供应失控的情况下,该酶可能同时成为大量 ROS 生成的来源,从而进一步影响存活神经元的健康。值得一提的是,该酶在不同脑区的表达量会随着年龄的增长而增加。此外,MAO 与神经系统疾病(如帕金森病、阿尔茨海默病和抑郁症)进展的关系近来也得到了广泛研究。虽然现有的合成 MAO 抑制剂在控制这些疾病方面发挥了重要作用,但相关的并发症近来也引起了人们的极大关注。天然产品是现代药物研发中先导分子的主要来源;然而,目前仍没有一种从天然来源中提取的 MAO 抑制剂获得 FDA 批准。在这篇综述中,我们全面概述了 MAO 以及该酶系统如何参与不同年龄相关神经病理学疾病的发病机制。我们进一步讨论了长期使用现有合成 MAO 抑制剂的应用和缺点。此外,我们还强调了天然产物衍生分子在解决 MAO 相关并发症方面的前景和价值。
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引用次数: 0
Validating the nutraceutical and neuroprotective pharmacodynamics of flavones 验证黄酮类化合物的营养和神经保护药效学。
IF 4.4 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-13 DOI: 10.1016/j.neuint.2024.105829

Neurodegenerative disorders are generally characterized by progressive neuronal loss and cognitive decline, with underlying mechanisms involving oxidative stress, protein aggregation, neuroinflammation, and synaptic dysfunction. Currently, the available treatment options only improve the symptoms of the disease but do not stop disease progression; neurodegeneration. This underscores the urgent need for novel therapeutic strategies targeting multiple neurodegenerative pathways alongside the conventional therapeutic strategies available.

Emerging evidence demonstrates that flavones a subgroup of flavonoids found abundantly in various dietary sources, have surfaced as promising candidates for neuroprotection due to their multifaceted pharmacological properties. Flavones possess the potency to modulate these pathophysiological processes through their antioxidant, anti-inflammatory, and neurotrophic activities. Additionally, flavones have been shown to interact with various cellular targets, including receptors and enzymes, to confer neuroprotection.

Though there are ample evidence available, the nutraceutical and neuroprotective pharmacodynamics of flavones have not been very well established. Hence, the current review aims to explores the therapeutic potential of flavones as nutraceuticals with neuroprotective effects, focusing on their ability to modulate key pathways implicated in neurodegenerative diseases. The current article also aims to actuate supplementary research into flavones as potential agents for alleviating neurodegeneration and improving patient outcomes in neurodegenerative disorders globally.

神经退行性疾病通常以神经元逐渐丧失和认知能力下降为特征,其潜在机制包括氧化应激、蛋白质聚集、神经炎症和突触功能障碍。目前,现有的治疗方案只能改善疾病症状,却无法阻止疾病的进展和神经退行性变。这突出表明,除了现有的传统治疗策略外,还迫切需要针对多种神经退行性病变途径的新型治疗策略。新的证据表明,黄酮类化合物是黄酮类化合物的一个亚类,广泛存在于各种膳食来源中,由于其多方面的药理特性,黄酮类化合物已成为有希望保护神经的候选药物。黄酮类化合物具有抗氧化、抗炎和神经营养活性,能够调节这些病理生理过程。此外,黄酮类化合物还能与包括受体和酶在内的各种细胞靶点相互作用,从而起到保护神经的作用。虽然已有大量证据,但黄酮的营养保健和神经保护药效学尚未得到很好的证实。因此,本综述旨在探讨黄酮类化合物作为具有神经保护作用的营养保健品的治疗潜力,重点关注其调节神经退行性疾病相关关键通路的能力。本文还旨在推动对黄酮类化合物作为潜在药物的补充研究,以缓解神经退行性疾病,改善全球神经退行性疾病患者的预后。
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Neurochemistry international
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