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Montelukast Ameliorates Scopolamine-induced Alzheimer's Disease: Role on Cholinergic Neurotransmission, Antioxidant Defence System, Neuroinflammation and Expression of BDNF. 孟鲁司特改善东莨菪碱诱导的阿尔茨海默病:对胆碱能神经传递、抗氧化防御系统、神经炎症和BDNF表达的作用。
Pub Date : 2024-01-01 DOI: 10.2174/0118715273258337230925040049
Bhavana Yerraguravagari, Naga Pavani Penchikala, Aravinda Sai Kolusu, Grandhi Sandeep Ganesh, Prasad Konduri, Kumar V S Nemmani, Pavan Kumar Samudrala

Background: Alzheimer's disease (AD) is an overwhelming neurodegenerative disease with progressive loss of memory. AD is characterized by the deposition of the senile plaques mainly composed of β-amyloid (Aβ) fragment, BDNF decline, Cholinergic system overactivity and neuroinflammation. Montelukast (MTK), a leukotriene receptor antagonist, showed astounding neuroprotective effects in a variety of neurodegenerative disorders.

Objective: This study aims to investigate the ameliorative effects of Montelukast in the scopolamineinduced Alzheimer's disease (AD) model in rats and evaluate its activity against neuroinflammation.

Methods: Thirty rats were split into five groups: Control group (1 mL/kg normal saline, i.p.), Montelukast perse (10 mg/kg, i.p.), Disease group treated with Scopolamine (3 mg/kg, i.p.), Donepezil group (3 mg/kg, i.p.), Montelukast treatment group (10 mg/kg, i.p.) and behavioural and biochemical tests were carried out to assess the neuro protective effect.

Results: Scopolamine treatment led to a significant reduction in learning and memory and an elevation in cholinesterase levels when compared with the control group (p < 0.01). Additionally, elevated oxidative stress and Amyloid-β levels were associated with enhanced neuroinflammation (p < 0.05, p < 0.01). Furthermore, the decline in neurotrophic factor BDNF is also observed when compared with the normal control group (p < 0.01). Montelukast pre-treatment significantly attenuated learning and memory impairment and cholinesterase levels. Besides, Montelukast and standard drug donepezil administration significantly suppressed the oxidative stress markers (p < 0.01), Amyloid-β levels, neuroinflammatory mediators (p < 0.05) and caused a significant increase in BDNF levels (p < 0.05).

Conclusion: Montelukast bestowed ameliorative effects in scopolamine-induced AD animal models as per the previous studies via attenuation of memory impairment, cholinesterase neurotransmission, oxidative stress, Amyloid-β levels, neuroinflammatory mediators and enhanced BDNF levels.

背景:阿尔茨海默病(AD)是一种严重的神经退行性疾病,伴有进行性记忆丧失。AD的特征是老年斑块的沉积,主要由β-淀粉样蛋白(Aβ)片段、BDNF下降、胆碱能系统过度活动和神经炎症组成。孟鲁司特(MTK)是一种白三烯受体拮抗剂,在各种神经退行性疾病中表现出惊人的神经保护作用。目的:研究孟鲁司特对东莨菪碱诱导的阿尔茨海默病(AD)大鼠模型的改善作用,并评价其对神经炎症的活性。方法:将30只大鼠分为5组:对照组(生理盐水1 mL/kg,腹腔注射)、孟鲁司特组(10 mg/kg,腹腔注射。)、疾病组(东莨菪碱3 mg/kg,腹腔内注射)、多奈哌齐组(3 mg/kg,静脉注射)、蒙鲁司特治疗组(10 mg/kg,腹腔内)。结果:与对照组相比,东莨菪碱治疗可显著降低学习记忆和胆碱酯酶水平(p<0.01)。此外,氧化应激和淀粉样蛋白-β水平升高与神经炎症增强有关(p<0.05,p<0.01),与正常对照组相比,神经营养因子BDNF也有所下降(p<0.01)。孟鲁司特治疗显著减轻了学习记忆障碍和胆碱酯酶水平。此外,孟鲁司特和标准药物多奈哌齐给药显著抑制了氧化应激标志物(p<0.01)、淀粉样蛋白-β水平,神经炎症介质(p<0.05)并导致BDNF水平显著升高(p<0.05)结论:根据先前的研究,孟鲁司特通过减轻记忆障碍、胆碱酯酶神经传递、氧化应激、淀粉样蛋白-β水平、神经炎症介质和增强BDNF水平,在东莨菪碱诱导的AD动物模型中具有改善作用。
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引用次数: 0
Non-coding RNAs as Key Regulators of the Notch Signaling Pathway in Glioblastoma: Diagnostic, Prognostic, and Therapeutic Targets. 作为胶质母细胞瘤 Notch 信号通路关键调控因子的非编码 RNA:诊断、预后和治疗靶点。
Pub Date : 2024-01-01 DOI: 10.2174/0118715273277458231213063147
Seyed Hossein Shahcheraghi, Elmira Roshani Asl, Malihe Lotfi, Jamshid Ayatollahi, Seyed Hossein Khaleghinejad, Alaa A A Aljabali, Hamid A Bakshi, Mohamed El-Tanani, Nitin B Charbe, Ángel Serrano-Aroca, Vijay Mishra, Yachana Mishra, Rohit Goyal, Altijana Hromić-Jahjefendić, Vladimir N Uversky, Marzieh Lotfi, Murtaza M Tambuwala

Glioblastoma multiforme (GBM) is a highly invasive brain malignancy originating from astrocytes, accounting for approximately 30% of central nervous system malignancies. Despite advancements in therapeutic strategies including surgery, chemotherapy, and radiopharmaceutical drugs, the prognosis for GBM patients remains dismal. The aggressive nature of GBM necessitates the identification of molecular targets and the exploration of effective treatments to inhibit its proliferation. The Notch signaling pathway, which plays a critical role in cellular homeostasis, becomes deregulated in GBM, leading to increased expression of pathway target genes such as MYC, Hes1, and Hey1, thereby promoting cellular proliferation and differentiation. Recent research has highlighted the regulatory role of non-coding RNAs (ncRNAs) in modulating Notch signaling by targeting critical mRNA expression at the post-transcriptional or transcriptional levels. Specifically, various types of ncRNAs, including long non-coding RNAs (lncRNAs) and microRNAs (miRNAs), have been shown to control multiple target genes and significantly contribute to the carcinogenesis of GBM. Furthermore, these ncRNAs hold promise as prognostic and predictive markers for GBM. This review aims to summarize the latest studies investigating the regulatory effects of ncRNAs on the Notch signaling pathway in GBM.

多形性胶质母细胞瘤(GBM)是一种源自星形胶质细胞的高侵袭性脑恶性肿瘤,约占中枢神经系统恶性肿瘤的 30%。尽管手术、化疗和放射性药物等治疗策略取得了进展,但 GBM 患者的预后仍然不容乐观。鉴于 GBM 的侵袭性,有必要确定分子靶点并探索有效的治疗方法来抑制其增殖。Notch 信号通路在细胞稳态中发挥着关键作用,但在 GBM 中却出现失调,导致 MYC、Hes1 和 Hey1 等通路靶基因表达增加,从而促进细胞增殖和分化。最近的研究强调了非编码 RNA(ncRNA)通过在转录后或转录水平靶向关键 mRNA 表达来调节 Notch 信号转导的调控作用。具体来说,各种类型的 ncRNA(包括长非编码 RNA(lncRNA)和 microRNA(miRNA))已被证明可控制多个靶基因,并在很大程度上导致 GBM 癌变。此外,这些 ncRNA 还有望成为 GBM 的预后和预测标志物。本综述旨在总结有关 ncRNA 对 GBM 中 Notch 信号通路的调控作用的最新研究。
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引用次数: 0
The Possible Protective Effect of Taurine on Bisphenol Induced Structural Changes on the Cerebral Cortex of Rats: Histological and Immunohistochemical Study. 牛磺酸对双酚:诱导的大鼠大脑皮层结构变化的可能保护作用:组织学和免疫组化研究。
Pub Date : 2024-01-01 DOI: 10.2174/0118715273280701231227100805
Samah Kandeel, Marwa M Abd-Elsalam, Sherief Abd-Elsalam, Heba Hassan Elkaliny

Introduction: Bisphenol A (BPA) is a chemical compound that has been used in many industries, such as paints and dental sealants. Taurine is a semi-essential amino acid with antioxidant, anti-inflammatory, and anti-apoptotic actions.

Aim: This study aimed to evaluate the possible protective effect of taurine on BPA-induced structural changes in the cerebral cortex of rats using histological and immunohistochemical methods.

Methods: 35 Wistar rats (180-200 gm) were divided into control: 10 rats; Group I: 5 rats received corn oil (0.5 mL/day); Group II (Bisphenol low dose; BPAL): 5 rats received a low dose of BPA (25 mg/kg/three times/week); Group III (Bisphenol high dose; BPAH): 5 rats received a high dose of BPA (100 mg/kg/three times/week; Group IV: (BPAL + taurine): 5 rats received taurine 100 mg/kg/day and BPAL (25 mg/kg/three times/week); Group V: (BPAH + taurine): 5 rats received taurine 100 mg/kg/day and BPH (100 mg/kg/ three times/week).

Results: BPAL& BPAH groups showed significant dose-dependent histological changes of the neuropil, pyramidal, and neuroglial cells at H&E stained sections, significantly increased GFAP, caspase- 3 immunohistochemical reaction with cells positive for Ki67 with many mitotic figures. BPAL + taurine and BPAH + taurine groups showed amelioration of the previously mentioned results.

Conclusion: Taurine ameliorated the structural changes induced by BPA in the cerebral cortex of rats.

简介:双酚 A(BPA)是一种化合物,已被用于许多行业,如油漆和牙科密封剂。牛磺酸是一种半必需氨基酸,具有抗氧化、抗炎和抗细胞凋亡的作用。目的:本研究旨在使用组织学和免疫组化方法评估牛磺酸对双酚 A 诱导的大鼠大脑皮层结构变化可能产生的保护作用。材料和方法:35 只 Wistar 大鼠(180-200 gm)分为对照组:10 只;I 组:5 只大鼠接受玉米油(0.5 mL/天);II 组(双酚低剂量;BPAL):5 只大鼠接受低剂量双酚 A(25 mg/kg/三次/周);III 组(双酚高剂量;BPAH):5 只大鼠接受高剂量双酚 A(100 mg/kg/三次/周);IV 组:(BPAL + 牛磺酸):5 只大鼠接受牛磺酸 100 毫克/千克/天和 BPAL(25 毫克/千克/三次/周);第五组:(双酚 AH + 牛磺酸):结果:结果:BPAL和BPAH组大鼠的神经胶质细胞、锥体细胞和神经胶质细胞在H&E染色切片中出现了明显的剂量依赖性组织学变化,GFAP、caspase-3免疫组化反应显著增加,细胞Ki67阳性,有许多有丝分裂。BPAL + 牛磺酸组和 BPAH + 牛磺酸组的上述结果有所改善:牛磺酸可改善双酚 A 诱导的大鼠大脑皮层结构变化。
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引用次数: 0
Transdermal Therapeutic Systems for the Treatment of Alzheimer's Disease: A Patent Review. 用于治疗阿尔茨海默病的透皮治疗系统:专利审查。
Pub Date : 2024-01-01 DOI: 10.2174/0118715273275957231102044934
Letícia Basso, Silvia Cristina Fagundes, Tatiana Staudt, Karini da Rosa, Elizane Langaro, Hamid Omidian, Charise Dallazem Bertol

Background: Two classes of medications are used to treat Alzheimer's disease (AD); donepezil, galantamine, and rivastigmine are acetylcholinesterase inhibitors, and memantine is a non-competitive antagonist of the N-methyl-D-aspartate receptor. Although these are typically taken orally, there are transdermal therapeutic systems (TTSs) commercially available for rivastigmine and donepezil. The transdermal route has been preferable for guardians/caregivers due to ease of use, reduced side effects, and improved adherence to therapy.

Objective: The study aimed to obtain knowledge of the properties of these drugs and to search for patents relating to the TTS for AD using the Espacenet platform.

Methods: The search terms were "rivastigmine AND transdermal AND skin delivery AND Alzheimer's", changing the drugs "memantine", "donepezil", and "galantamine", between January 2015 and January 2022. Title and abstract were used to choose patents.

Results: TTSs present some limit factors in terms of absorption due to skin physiology and the size of the molecules with established limits of percutaneous penetration (molecular mass of 500 g/mol and log P of 5). We found 1, 4, 4, and 2 patents for galantamine, rivastigmine, donepezil, and memantine, respectively. Galantamine TTS seems to be more challenging due to the molecular mass of 287.35 g/mol and logP of 1.8. The permeator of absorption is necessary. Memantine, rivastigmine, and donepezil present logP of 3.28, 2.3, and 4.27 and molecular weights of 179.30, 250.34, and 415.96 g/mol, respectively.

Conclusion: TTSs are primarily effective for delivering small molecules. The use of absorption enhancers and irritation mitigators can be necessary to enhance the performance. The development of these technologies is essential for the convenience of patients and caregivers.

背景:两类药物用于治疗阿尔茨海默病(AD);多奈哌齐、加兰他敏和利瓦斯汀是乙酰胆碱酯酶抑制剂,美金刚是n-甲基- d -天冬氨酸受体的非竞争性拮抗剂。虽然这些药物通常口服,但也有经皮治疗系统(tss)市售,用于治疗利瓦斯丁胺和多奈哌齐。由于易于使用、减少副作用和提高治疗依从性,透皮途径对监护人/护理人员更可取。目的:利用Espacenet平台了解这些药物的性质,并检索TTS治疗AD的相关专利。方法:2015年1月至2022年1月,检索词为“利瓦司丁与透皮给药和阿尔茨海默氏症”,药物名称为“美金刚”、“多奈哌齐”、“加兰他明”。采用标题和摘要选择专利。结果:由于皮肤生理和分子大小的限制,tss在吸收方面存在一些限制因素,并具有确定的经皮渗透极限(分子质量为500 g/mol, log P为5)。我们分别发现了加兰他明、利瓦司汀、多奈哌齐和美金刚的1、4、4和2项专利。加兰他明TTS的分子质量为287.35 g/mol, logP为1.8,因此更具挑战性。吸收渗透剂是必要的。美金刚、利瓦司汀和多奈哌齐的logP分别为3.28、2.3和4.27,分子量分别为179.30、250.34和415.96 g/mol。结论:tss主要对小分子药物输送有效。使用吸收增强剂和刺激缓解剂可以是必要的,以提高性能。这些技术的发展对患者和护理人员的便利至关重要。
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引用次数: 0
Intestinal Barrier Function and Neurodegenerative Disease. 肠屏障功能与神经退行性疾病。
Pub Date : 2024-01-01 DOI: 10.2174/0118715273264097231116103948
Shijing Wu, Liangfang Yang, Yiwei Fu, Zhimin Liao, De Cai, Zhou Liu

Neurodegenerative diseases are caused by the loss of neurons and/or their myelin sheaths, which deteriorate over time and become dysfunctional. Alzheimer's disease, Parkinson's disease, and multiple sclerosis are among the most prominent neurodegenerative diseases that affect millions of older adults worldwide. Despite extensive research over several decades, controversies still surround the etiology of neurodegenerative diseases, and many of them remain incurable. Meanwhile, an increasing number of new mechanistic studies related to the microbiota-gut-brain axis have emerged, among which the relationship between the function of the intestinal barrier and neurodegenerative diseases has received widespread attention. As one of the first lines of defense between the body and the external environment, the impaired function of the intestinal barrier is closely related to the development of neurodegenerative pathologies. Among them, the microbiota-gut-brain axis disorder characterized by intestinal barrier disruption mainly includes impaired function of the intestinal microbial barrier, chemical barrier, mechanical barrier, and immune barrier. This review focuses on the structure and molecular mechanisms of the various layers of the intestinal barrier as well as their relationship with neurodegenerative lesions. In recent years, intestinal barrier repair therapies have provided new ideas for the studied disease treatment modalities. We believe that a better understanding of the role of the intestinal barrier in neurodegenerative diseases would provide new insights for the development of viable therapeutic strategies for patients.

神经退行性疾病是由神经元和/或髓鞘的丧失引起的,随着时间的推移,髓鞘会恶化并变得功能失调。阿尔茨海默病、帕金森病和多发性硬化症是影响全世界数百万老年人的最突出的神经退行性疾病。尽管几十年来进行了广泛的研究,但围绕神经退行性疾病的病因仍然存在争议,其中许多疾病仍然无法治愈。与此同时,越来越多与微生物-肠-脑轴相关的新的机制研究出现,其中肠屏障功能与神经退行性疾病的关系受到广泛关注。肠屏障作为机体与外界环境之间的第一道防线之一,其功能受损与神经退行性病变的发生密切相关。其中以肠道屏障破坏为特征的微生物-肠-脑轴紊乱主要包括肠道微生物屏障、化学屏障、机械屏障和免疫屏障功能受损。本文就肠屏障各层的结构、分子机制及其与神经退行性病变的关系作一综述。近年来,肠屏障修复疗法为所研究的疾病治疗方式提供了新的思路。我们相信,更好地了解肠屏障在神经退行性疾病中的作用,将为患者开发可行的治疗策略提供新的见解。
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引用次数: 0
Length of Survival, Outcome, and Potential Predictors in Poor-Grade Aneurysmal Subarachnoid Hemorrhage Patients Treated with Microsurgical Clipping. 微创手术夹闭治疗低级别动脉瘤蛛网膜下腔出血患者的生存时间、结果和潜在预测因素。
Pub Date : 2024-01-01 DOI: 10.2174/0118715273258678231011060312
Xanthoula Lambrianou, Christos Tzerefos, Christina Arvaniti, Anastasia Tasiou, Kostas N Fountas

Background: Poor-grade aneurysmal subarachnoid hemorrhage (aSAH) has been associated with severe morbidity and high mortality. It has been demonstrated that early intervention is of paramount importance. The aim of our study is to evaluate the functional outcome and the overall survival of early microsurgically treated patients.

Material and methods: Poor-grade aSAH patients admitted at our institution over fifteen years (January 2008 - December 2022) were included in our retrospective study. All participants underwent brain Computed Tomography Angiography (CTA). Fisher scale was used to assess the severity of hemorrhage. All our study participants underwent microsurgical clipping, and their functional outcome was assessed with the Glasgow Outcome Scale (GOS). We used logistic regression analysis to identify any parameters associated with a favorable outcome at 12 months. Cox proportional hazard analysis was also performed, identifying factors affecting the length of survival.

Results: Our study included 39 patients with a mean age of 54 years. Thirty of our participants (76.9%) were Hunt and Hess grade V, while the vast majority (94.9%) were Fisher grade 4. The observed six-month mortality rate was 48.6%. The mean follow-up time was 18.6 months. The functional outcome at six months was favorable in 6 patients (16.2%), increased to 23.5% at 12 months. Our data analysis showed that the age, as well as the employment of temporary clipping during surgery, affected the overall outcome.

Conclusion: Management of poor-grade aSAH patients has been dramatically changed. Microsurgical clipping provides promising results in carefully selected younger patients.

背景:低度动脉瘤性蛛网膜下腔出血(aSAH)与严重的发病率和高死亡率有关。事实证明,早期干预至关重要。我们研究的目的是评估早期显微外科治疗患者的功能结果和总生存率。材料和方法:在我们的回顾性研究中纳入了在我们机构住院超过15年(2008年1月至2022年12月)的aSAH低级别患者。所有参与者都接受了脑部计算机断层扫描血管造影(CTA)。Fisher量表用于评估出血的严重程度。我们所有的研究参与者都接受了显微外科夹闭术,并用格拉斯哥结果量表(GOS)评估了他们的功能结果。我们使用逻辑回归分析来确定与12个月时的良好结果相关的任何参数。还进行了Cox比例风险分析,确定了影响生存时间的因素。结果:我们的研究包括39名患者,平均年龄54岁。我们的参与者中有30人(76.9%)是Hunt和Hess五级,而绝大多数(94.9%)是Fisher四级。观察到的6个月死亡率为48.6%,平均随访时间为18.6个月。6个月时,6名患者(16.2%)的功能结果良好,12个月时增至23.5%。我们的数据分析表明,年龄以及手术过程中临时修剪的使用影响了整体结果。结论:aSAH低级别患者的管理方式发生了巨大变化。在精心挑选的年轻患者中,显微手术切除术提供了有希望的结果。
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引用次数: 0
Obesity and Depression: Common Link and Possible Targets. 肥胖症与抑郁症:肥胖症与抑郁症:共同的联系和可能的目标
Pub Date : 2024-01-01 DOI: 10.2174/0118715273291985240430074053
Srikanth Jitte, Saritha Keluth, Priya Bisht, Pranay Wal, Sanjiv Singh, Krishna Murti, Nitesh Kumar

Depression is among the main causes of disability, and its protracted manifestations could make it even harder to treat metabolic diseases. Obesity is linked to episodes of depression, which is closely correlated to abdominal adiposity and impaired food quality. The present review is aimed at studying possible links between obesity and depression along with targets to disrupt it. Research output in Pubmed and Scopus were referred for writing this manuscript. Obesity and depression are related, with the greater propensity of depressed people to gain weight, resulting in poor dietary decisions and a sedentary lifestyle. Adipokines, which include adiponectin, resistin, and leptin are secretory products of the adipose tissue. These adipokines are now being studied to learn more about the connection underlying obesity and depression. Ghrelin, a gut hormone, controls both obesity and depression. Additionally, elevated ghrelin levels result in anxiolytic and antidepressant-like effects. The gut microbiota influences the metabolic functionalities of a person, like caloric processing from indigestible nutritional compounds and storage in fatty tissue, that exposes an individual to obesity, and gut microorganisms might connect to the CNS through interconnecting pathways, including neurological, endocrine, and immunological signalling systems. The alteration of brain activity caused by gut bacteria has been related to depressive episodes. Monoamines, including dopamine, serotonin, and norepinephrine, have been widely believed to have a function in emotions and appetite control. Emotional signals stimulate arcuate neurons in the hypothalamus that are directly implicated in mood regulation and eating. The peptide hormone GLP-1(glucagon-like peptide- 1) seems to have a beneficial role as a medical regulator of defective neuroinflammation, neurogenesis, synaptic dysfunction, and neurotransmitter secretion discrepancy in the depressive brain. The gut microbiota might have its action in mood and cognition regulation, in addition to its traditional involvement in GI function regulation. This review addressed the concept that obesity-related low-grade mild inflammation in the brain contributes to chronic depression and cognitive impairments.

抑郁症是导致残疾的主要原因之一,它的长期表现会使代谢性疾病的治疗变得更加困难。肥胖与抑郁症的发作有关,而抑郁症与腹部肥胖和食物质量受损密切相关。本综述旨在研究肥胖与抑郁症之间可能存在的联系,以及消除这种联系的目标。撰写本稿件时参考了 Pubmed 和 Scopus 上的研究成果。肥胖与抑郁症有关,抑郁症患者更倾向于增加体重,从而导致不良的饮食决定和久坐不动的生活方式。脂肪因子包括脂肪连素、抵抗素和瘦素,是脂肪组织的分泌产物。目前正在对这些脂肪因子进行研究,以进一步了解肥胖与抑郁之间的内在联系。胃泌素是一种肠道激素,可控制肥胖和抑郁。此外,胃泌素水平升高会产生类似抗焦虑和抗抑郁的效果。肠道微生物群会影响人的新陈代谢功能,如从难以消化的营养成分中提取热量并储存在脂肪组织中,从而导致肥胖,肠道微生物可能会通过神经、内分泌和免疫信号系统等相互连接的途径与中枢神经系统相连。肠道细菌导致的大脑活动改变与抑郁症发作有关。人们普遍认为,包括多巴胺、血清素和去甲肾上腺素在内的单胺类物质具有控制情绪和食欲的功能。情绪信号会刺激下丘脑中的弓状神经元,这些神经元直接参与情绪调节和进食。肽类激素 GLP-1(胰高血糖素样肽-1)似乎对抑郁脑的神经炎症缺陷、神经发生、突触功能障碍和神经递质分泌差异具有医疗调节作用。肠道微生物群除了参与传统的消化道功能调节外,还可能在情绪和认知调节方面发挥作用。本综述探讨了肥胖相关的大脑低度轻度炎症会导致慢性抑郁和认知障碍的概念。
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引用次数: 0
Neurotrophin-3 Rescues Striatal Synaptic Plasticity in Model of Neurodegeneration by PLC Signaling Activation. 神经营养素-3通过激活PLC信号激活神经退行性病变模型的纹状体突触可塑性
Pub Date : 2024-01-01 DOI: 10.2174/0118715273298919240531110022
Victor G Gómez-Pineda, Elizabeth Nieto-Mendoza, Francisco M Torres-Cruz, Elizabeth Hernández-Echeagaray

Background: Neurotrophins are essential factors for neural growth and function; they play a crucial role in neurodegenerative diseases where their expression levels are altered. Our previous research has demonstrated changes in synaptic plasticity and neurotrophin expression levels in a pharmacological model of Huntington's disease (HD) induced by 3-nitropropionic acid (3-NP). In the 3-NP-induced HD model, corticostriatal Long Term Depression (LTD) was impaired, but neurotrophin- 3 (NT-3) restored striatal LTD. This study delves into the NT-3-induced signaling pathways involved in modulating and restoring striatal synaptic plasticity in cerebral slices from 3-NPinduced striatal degeneration in mice in vivo.

Methods: Phospholipase C (PLC), phosphatidylinositol-3-kinase (PI3K), and mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK) pathways activated by NT-3 were analyzed by means of field electrophysiological recordings in brain slices from control and 3-NP treated in the presence of specific inhibitors of the signaling pathways.

Results: Using specific inhibitors, PLC, PI3K, and MEK/ERK signaling pathways contribute to NT-3-mediated plasticity modulation in striatal tissue slices recorded from control animals. However, in the neurodegeneration model induced by 3-NP, the recovery of striatal LTD induced by NT-3 was prevented only by the PLC inhibitor. Moreover, the PLC signaling pathway appeared to trigger downstream activation of the endocannabinoid system, evidenced by AM 251, an inhibitor of the CB1 receptor, also hindered NT-3 plasticity recovery.

Conclusion: Our finding highlights the specific involvement of the PLC pathway in the neuroprotective effects of NT-3 in mitigating synaptic dysfunction under neurodegenerative conditions.

背景:神经营养素是神经生长和功能所必需的因子;在神经退行性疾病中,神经营养素的表达水平会发生变化,因此神经营养素在神经退行性疾病中起着至关重要的作用。我们之前的研究表明,在 3-硝基丙酸(3-NP)诱导的亨廷顿氏病药理学模型中,突触可塑性和神经营养素表达水平发生了变化。在3-硝基丙酸诱导的亨廷顿症模型中,皮质长期抑制(LTD)功能受损,但神经营养素-3(NT-3)可恢复纹状体的LTD功能。本研究探讨了NT-3诱导的信号通路,这些信号通路参与调节和恢复3-NP诱导的小鼠体内纹状体变性脑片的纹状体突触可塑性:方法:在信号通路特异性抑制剂存在的情况下,通过对对照组和3-NP处理的脑片进行场电生理记录,分析NT-3激活的磷脂酶C(PLC)、磷脂酰肌醇-3-激酶(PI3K)和丝裂原活化蛋白激酶(MEK)/细胞外信号调节激酶(ERK)通路:结果:使用特异性抑制剂,在对照组动物记录的纹状体组织切片中,PLC、PI3K和MEK/ERK信号通路有助于NT3介导的可塑性调节。然而,在 3-NP 诱导的神经变性模型中,只有 PLC 抑制剂能阻止 NT-3 诱导的纹状体 LTD 的恢复。此外,PLC 信号通路似乎触发了内源性大麻素系统的下游激活,CB1 受体抑制剂 AM 251 也阻碍了 NT-3 可塑性的恢复:我们的发现强调了 PLC 通路在减轻神经退行性病变条件下突触功能障碍的神经保护作用中的特殊参与。
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引用次数: 0
Pre-clinical Aspects and Contemporary Treatments of Parkinson's Disease. 帕金森病的临床前方面和当代治疗。
Pub Date : 2024-01-01 DOI: 10.2174/0118715273258646230920074421
Partosh Chhabra, Rishabh, Shivani Singla, Sunayna Choudhary, Shivam Kohli, Nitin Bansal, Seema Bansal

Background: After Alzheimer's disease, the second slot for the most common neurodegenerative disease, is occupied by Parkinson's disease. The symptoms of Parkinson's are classified as motor symptoms and non-motor symptoms. Motor symptoms involve rigidity, tremors, bradykinesia, and postural instability. Non-motor symptoms consist of cognitive dysfunction, salivation, lacrimation, etc. Objectives: The objectives of this study are to find out the most recent treatment options for Parkinson's disease.

Methods: Research and review papers are collected from different databases like Google Scholar, PubMed, Mendeley, Scopus, Science Open, and the Directory of Open Access Journals using different keywords such as "Parkinson's disease, biomarkers, animal models".

Results: Currently, various novel therapeutics have been emerging for PD. These may include treatments that may control the symptoms without causing any other severe side effects with already available treatments. Better therapies such as gene therapies, cell-based treatments, and regenerative therapies, which may evolve over time, can be a better therapeutic option.

Conclusion: There is a need for the development of novel and potential therapeutic strategies that offer fewer side effects to patients. Several clinical, biochemical, and imaging markers that are noteworthy in Parkinson's disease examination have been discussed here. Current work in the field of Parkinson's disease has developed a variety of significant small animal models, such as viral vector models and seeding models, including the insertion of preformed fibrils of alpha-synuclein. The brief concepts regarding risk factors, pathogenesis, clinical diagnosis, and emerging treatments of PD are discussed in this review article.

背景:继阿尔茨海默病之后,帕金森病占据了最常见的神经退行性疾病的第二位。帕金森氏症的症状分为运动症状和非运动症状。运动症状包括僵硬、震颤、运动迟缓和姿势不稳定。非运动症状包括认知功能障碍、流涎、流泪等。目的:本研究的目的是找出帕金森病的最新治疗方案。方法:从Google Scholar、PubMed、Mendeley、Scopus、Science Open和开放获取期刊目录等不同数据库中收集研究和综述论文,使用不同的关键词,如“帕金森病、生物标志物、动物模型”。这些可能包括可以控制症状而不引起任何其他严重副作用的治疗方法。更好的治疗方法,如基因治疗、细胞治疗和再生治疗,可能会随着时间的推移而发展,可能是更好的治疗选择。结论:有必要开发新的、潜在的治疗策略,减少患者的副作用。本文讨论了帕金森病检查中值得注意的几种临床、生化和影像学标志物。目前在帕金森病领域的工作已经开发了各种重要的小动物模型,如病毒载体模型和种子模型,包括插入预先形成的α-突触核蛋白原纤维。本文对帕金森病的危险因素、发病机制、临床诊断和新出现的治疗方法进行了简要的讨论。
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引用次数: 0
Exerkines: A Crosstalk between Lactate Production, Exercise and Mental Health. 运动:乳酸生产、运动和心理健康之间的对话。
Pub Date : 2024-01-01 DOI: 10.2174/0118715273250928231009054658
Alberto Souza Sá Filho, Silvio Roberto Barsanulfo, Sara Socorro Faria, Pedro Augusto Inacio, Farahnaz Ayatizadeh, Sérgio Machado

Muscle skeletal striated cells secrete a wide range of proteins called myokines or "exerkines", which in turn perform autocrine, paracrine, or endocrine functions. For being able to act in the communication between skeletal muscle, adipose tissue, and mainly the brain, exerkines play a prominent role and potential influence on health promotion. Furthermore, we detected in the literature that one of these potential therapeutic substances derived from muscle contraction is a molecule derived from glycolytic metabolism that in the past was largely marginalized, the lactate. Currently, studies are dedicated to examining the target structures for exerkines that may contribute to the maintenance and restoration of mental health. Thus, lactate appears to be recognized as a critical mediator of exercise-related changes and their health benefits, particularly in their role in communication and coordination between organs. It is inferred that the BDNF expression mechanism can be induced by lactate, which in turn derives from the activation of SIRT pathways 1 and 2 and activates the PGC1-α cascade. The behavior of lactate concentration is intensity-dependent, directly related to the type of fast-twitch fibers (type IIb) and the recruitment of these fibers would potentiate the responses in the brain. In this sense, high-intensity exercise would establish itself as an important strategy to be considered. Despite this understanding, there is still much to be done. However, lactate appears to be a highly promising exerkine for future research initiatives and a potential biomarker to reduce illness and promote mental health.

肌肉骨骼纹状细胞分泌一系列被称为肌细胞因子或“运动因子”的蛋白质,这些蛋白质反过来执行自分泌、旁分泌或内分泌功能。运动因子能够参与骨骼肌、脂肪组织,主要是大脑之间的交流,在促进健康方面发挥着重要作用和潜在影响。此外,我们在文献中发现,这些源自肌肉收缩的潜在治疗物质之一是一种源自糖酵解代谢的分子,乳酸在过去很大程度上被边缘化。目前,研究致力于检查可能有助于维持和恢复心理健康的运动因子的目标结构。因此,乳酸似乎被认为是运动相关变化及其健康益处的关键介质,特别是在其在器官之间的沟通和协调中的作用。据推测,BDNF的表达机制可以由乳酸诱导,乳酸反过来源于SIRT通路1和2的激活,并激活PGC1-α级联。乳酸浓度的行为是强度依赖性的,与快速抽搐纤维(IIb型)的类型直接相关,这些纤维的募集会增强大脑中的反应。从这个意义上说,高强度运动将成为一项需要考虑的重要策略。尽管有这样的理解,仍有许多工作要做。然而,乳酸似乎是未来研究计划中一种非常有前途的运动因子,也是减少疾病和促进心理健康的潜在生物标志物。
{"title":"Exerkines: A Crosstalk between Lactate Production, Exercise and Mental Health.","authors":"Alberto Souza Sá Filho, Silvio Roberto Barsanulfo, Sara Socorro Faria, Pedro Augusto Inacio, Farahnaz Ayatizadeh, Sérgio Machado","doi":"10.2174/0118715273250928231009054658","DOIUrl":"10.2174/0118715273250928231009054658","url":null,"abstract":"<p><p>Muscle skeletal striated cells secrete a wide range of proteins called myokines or \"exerkines\", which in turn perform autocrine, paracrine, or endocrine functions. For being able to act in the communication between skeletal muscle, adipose tissue, and mainly the brain, exerkines play a prominent role and potential influence on health promotion. Furthermore, we detected in the literature that one of these potential therapeutic substances derived from muscle contraction is a molecule derived from glycolytic metabolism that in the past was largely marginalized, the lactate. Currently, studies are dedicated to examining the target structures for exerkines that may contribute to the maintenance and restoration of mental health. Thus, lactate appears to be recognized as a critical mediator of exercise-related changes and their health benefits, particularly in their role in communication and coordination between organs. It is inferred that the BDNF expression mechanism can be induced by lactate, which in turn derives from the activation of SIRT pathways 1 and 2 and activates the PGC1-α cascade. The behavior of lactate concentration is intensity-dependent, directly related to the type of fast-twitch fibers (type IIb) and the recruitment of these fibers would potentiate the responses in the brain. In this sense, high-intensity exercise would establish itself as an important strategy to be considered. Despite this understanding, there is still much to be done. However, lactate appears to be a highly promising exerkine for future research initiatives and a potential biomarker to reduce illness and promote mental health.</p>","PeriodicalId":93947,"journal":{"name":"CNS & neurological disorders drug targets","volume":" ","pages":"1057-1060"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41242190","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","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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CNS & neurological disorders drug targets
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