Therapeutic targets for neurological diseases最新文献

SRSF1-dependent nuclear export of C9ORF72 repeat transcripts: targeting toxic gain-of-functions induced by protein sequestration as a selective therapeutic strategy for neuroprotection srsf1依赖的C9ORF72重复转录物的核输出:靶向蛋白隔离诱导的毒性功能获得作为神经保护的选择性治疗策略

Therapeutic targets for neurological diseases

Pub Date : 2018-01-15 DOI: 10.14800/TTND.1619

L. Castelli, Ya-Hui Lin, L. Ferraiuolo, Alvaro Sanchez-Martinez, K. Ning, M. Azzouz, Alexander J. Whitworth, P. Shaw, Guillaume M. Hautbergue

Microsatellite repeat expansions cause several incurable and lethal neurodegenerative disorders including ataxias, myotonic dystrophy, Huntington's disease and C9ORF72-linked amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Abnormal repeat transcripts generated from the expanded loci are substrates of repeat-associated non-AUG (RAN) translation, an unconventional form of translation leading to the production of polymeric repeat proteins with cytotoxic and aggregating properties. The mechanisms involved in the pathogenesis of microsatellite repeat expansion disorders remain a hotly debated topic. They are shared between toxic loss/gain of functions due to intranuclear RNA foci that sequesters RNA-binding proteins and RAN translation of repeat proteins in the cytoplasm. We recently elucidated the molecular mechanism driving the nuclear export of C9ORF72 repeat transcripts and showed for the first time that this pathway can be manipulated to confer neuroprotection. Strikingly, we discovered that intron-retaining C9ORF72 repeat transcripts hijack the physiological NXF1-dependent export pathway by selective RNA-repeat sequestration of SRSF1. Antagonizing SRSF1 and the nuclear export of C9ORF72 repeat transcripts promoted in turn the survival of patient-derived motor neurons and suppressed neurodegeneration-associated motor deficits in Drosophila (Hautbergue et al. Nature Communications 2017; 8:16063). In this invited Research Highlight review, we aim to place this work in the context of our previous studies on the nuclear export of mRNAs, provide a summary of the published research and highlight the significance of these findings as a novel therapeutic strategy for neuroprotection in C9ORF72-ALS/FTD. In addition, we emphasize that protein sequestration, often thought as of inducing loss-of-function mechanisms, can also trigger unwanted protein interactions and toxic gain-of-functions.

微卫星重复扩增导致几种无法治愈和致命的神经退行性疾病，包括共济失调、肌强直性营养不良、亨廷顿氏病和c9orf72相关的肌萎缩性侧索硬化症(ALS)和额颞叶痴呆(FTD)。扩增位点产生的异常重复转录物是重复相关非aug (RAN)翻译的底物，这是一种非常规的翻译形式，导致产生具有细胞毒性和聚集特性的聚合重复蛋白。微卫星重复扩增障碍的发病机制仍然是一个备受争议的话题。它们在核内RNA聚焦导致的毒性功能丧失/获得(隔离RNA结合蛋白)和细胞质中重复蛋白的RAN翻译之间是共享的。我们最近阐明了驱动C9ORF72重复转录物核输出的分子机制，并首次表明这一途径可以被操纵以赋予神经保护。引人注目的是，我们发现保留内含子的C9ORF72重复转录物通过选择性分离SRSF1的rna重复序列来劫持生理上依赖nxf1的输出途径。在果蝇中，拮抗SRSF1和C9ORF72重复转录物的核输出反过来促进了患者源性运动神经元的存活，并抑制了神经退行性相关的运动缺陷(Hautbergue等)。自然通讯2017;8:16063)。在这篇特约研究综述中，我们的目标是将这项工作放在我们之前关于mrna核输出的研究背景下，总结已发表的研究，并强调这些发现作为C9ORF72-ALS/FTD神经保护的新治疗策略的意义。此外，我们强调，通常被认为是诱导功能丧失机制的蛋白质隔离也可能引发不必要的蛋白质相互作用和毒性功能获得。

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引用次数: 2

Insights into abnormal sphingolipid metabolism in multiple sclerosis: targeting ceramide biosynthesis as a unique therapeutic strategy 多发性硬化症鞘脂代谢异常的研究：靶向神经酰胺生物合成作为一种独特的治疗策略

Therapeutic targets for neurological diseases

Pub Date : 2017-10-02 DOI: 10.14800/TTND.1598

S. Dasgupta, S. Ray

Multiple sclerosis (MS) is a fatal demyelinating disease that primarily affects axons leading to massive neurodegeneration. Many studies have reported the causes and drawn the conclusions that multiple factors such as recurrent viral infections, hereditary link, and environmental condition are involved in the pathogenesis of MS. In essence, all these reports indicate a severe change in the biochemical milieu in the central nervous system (CNS) leading to inflammation and neurodegeneration. Recent studies in our laboratory revealed aberrant sphingolipid metabolism and accumulation of toxic sphingosine in the CNS tissues in MS patients. An elevation in sphingosine in MS brain white matter and plaque indicated that sphingosine toxicity might mediate degeneration of oligodendrocytes contributing to demyelination. An intermittent increase in ceramide followed by sphingosine accumulation in spinal cords from Lewis rats with experimental autoimmune encephalitis (EAE) and also stimulation of serine-palmitoyltransferase (SPT) activity correlated with induction of apoptosis in the lumbar spinal cord in EAE animals. Cytokine-stimulated ceramide elevation in cultured human oligodendrocytes was almost completely blocked by myriocin, an inhibitor of SPT. Myriocin exposure also protected oligodendrocytes from induction of apoptosis. Sphingosine toxicity via ceramide biosynthesis contributed to oligodendrocyte degeneration in both EAE and MS. Although many clinical trials are being conducted for MS, to the best of our knowledge, there is still no sphingolipid-targeted therapy available. Hence, we propose that sphingosine toxicity via ceramide generation may be a potential therapeutic target in both EAE and MS.

多发性硬化症（MS）是一种致命的脱髓鞘疾病，主要影响轴突，导致大量神经退行性变。许多研究报道了MS的病因，并得出结论，复发性病毒感染、遗传联系和环境条件等多种因素参与了MS的发病机制。从本质上讲，所有这些报道都表明中枢神经系统（CNS）的生化环境发生了严重变化，导致炎症和神经退行性变。我们实验室最近的研究揭示了多发性硬化症患者中枢神经系统组织中异常的鞘脂代谢和有毒鞘氨醇的积累。多发性硬化症脑白质和斑块中鞘氨醇的升高表明鞘氨醇毒性可能介导导致脱髓鞘的少突胶质细胞变性。患有实验性自身免疫性脑炎（EAE）的Lewis大鼠脊髓中神经酰胺的间歇性增加，随后鞘氨醇的积累，以及丝氨酸棕榈酰转移酶（SPT）活性的刺激，与EAE动物腰椎中细胞凋亡的诱导相关。在培养的人类少突胶质细胞中，细胞因子刺激的神经酰胺升高几乎完全被SPT抑制剂肉豆蔻霉素阻断。Myriocin暴露也保护少突胶质细胞免于诱导凋亡。鞘氨醇通过神经酰胺生物合成的毒性导致EAE和MS中的少突胶质细胞变性。尽管正在对MS进行许多临床试验，但据我们所知，仍然没有鞘脂靶向治疗。因此，我们认为神经酰胺产生的鞘氨醇毒性可能是EAE和MS的潜在治疗靶点。

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引用次数: 6

The synthesis of polyhydroxy sterone 2β,3α,5-trihydroxy-5α-androst-6-one and its neuroprotection 多羟基酮2β，3α，5-三羟基-5α-雄激素-6- 1的合成及其神经保护作用

Therapeutic targets for neurological diseases

Pub Date : 2017-06-19 DOI: 10.14800/TTND.1559

Minyu Xie, Xinhua Li, Li-qiang Yuan, Yiyu Chen, Xiaolei Zhang, Wei Yin, Bing-zheng Lu, Zhu Zhu, Haitao Shi, Jingxia Zhang

Neuroactive steroids exhibit better neuroprotective properties in vitro and in vivo, and will be a potential neuroprotective effect. In this study, polyhydroxy sterone 2β,3α,5-trihydroxy-5α- androst-6-one (YC-10) was designed and synthesized from androst-5-en-3-ol by 6 steps reactions. Its absolute structure was characterized by X-SRD and its structure was characterized by NMR, IR, and MS. Its neuroprotective action was determined by MTT assay with two models of neurotoxicity. The maximum protective effect was at a concentration of 40μM for neurotoxicity induced by glutamate, and showing better cell viability in a dose-dependent manner; Moreover it cloud significantly protect the cerebellar granule neurons against neuronal death mediated by low K + , its effective protective concentration was 50μM.

神经活性类固醇在体内和体外均表现出较好的神经保护作用，具有潜在的神经保护作用。本研究以雄甾-5-烯-3-醇为原料，经6步反应设计合成了多羟基酮2β，3α，5-三羟基-5α-雄甾-6-酮(YC-10)。用X-SRD对其绝对结构进行表征，用NMR、IR、ms对其结构进行表征，用MTT法测定其神经保护作用，采用两种神经毒性模型。在浓度为40μM时，对谷氨酸神经毒性的保护作用最大，且呈剂量依赖性;低K +介导的小脑颗粒神经元死亡具有明显的保护作用，其有效保护浓度为50μM。

引用次数: 1

Addictive neurons. 成瘾性神经元

Therapeutic targets for neurological diseases

Pub Date : 2017-01-01 Epub Date: 2017-01-30

Sodikdjon A Kodirov

Since the reward center is considered to be the area tegmentalis ventralis of the hypothalamus, logically its neurons could mainly be responsible for addiction. However, the literature asserts that almost any neurons of CNS can respond to one or another addictive compound. Obviously not only addictive nicotine, but also alcohol, amphetamine, cannabis, cocaine, heroin and morphine may influence dopaminergic cells alone in VTA. Moreover, paradoxically some of these drugs ameliorate symptoms, counterbalance syndromes, cure diseases and improve health, not only those related to the CNS and in adults, but also almost all other organs and in children, e.g. epilepsy.

由于奖赏中枢被认为是下丘脑腹侧被盖区，从逻辑上讲，它的神经元可能是导致成瘾的主要原因。然而，文献断言，几乎所有中枢神经系统的神经元都能对一种或另一种成瘾化合物做出反应。显然，不仅是尼古丁会上瘾，酒精、苯丙胺、大麻、可卡因、海洛因和吗啡也会影响 VTA 中的多巴胺能细胞。此外，令人费解的是，其中一些药物还能改善症状、消除综合症、治疗疾病和改善健康状况，不仅是与中枢神经系统有关的药物和成人药物，还包括几乎所有其他器官的药物和儿童药物，例如癫痫。

引用次数: 0

Insights into abnormal sphingolipid metabolism in multiple sclerosis: targeting ceramide biosynthesis as a unique therapeutic strategy. 多发性硬化症中鞘脂代谢异常的见解:靶向神经酰胺生物合成作为独特的治疗策略。

Therapeutic targets for neurological diseases

Pub Date : 2017-01-01 Epub Date: 2017-10-02

Somsankar Dasgupta, Swapan K Ray

Multiple sclerosis (MS) is a fatal demyelinating disease that primarily affects axons leading to massive neurodegeneration. Many studies have reported the causes and drawn the conclusions that multiple factors such as recurrent viral infections, hereditary link, and environmental condition are involved in the pathogenesis of MS. In essence, all these reports indicate a severe change in the biochemical milieu in the central nervous system (CNS) leading to inflammation and neurodegeneration. Recent studies in our laboratory revealed aberrant sphingolipid metabolism and accumulation of toxic sphingosine in the CNS tissues in MS patients. An elevation in sphingosine in MS brain white matter and plaque indicated that sphingosine toxicity might mediate degeneration of oligodendrocytes contributing to demyelination. An intermittent increase in ceramide followed by sphingosine accumulation in spinal cords from Lewis rats with experimental autoimmune encephalitis (EAE) and also stimulation of serine-palmitoyltransferase (SPT) activity correlated with induction of apoptosis in the lumbar spinal cord in EAE animals. Cytokine-stimulated ceramide elevation in cultured human oligodendrocytes was almost completely blocked by myriocin, an inhibitor of SPT. Myriocin exposure also protected oligodendrocytes from induction of apoptosis. Sphingosine toxicity via ceramide biosynthesis contributed to oligodendrocyte degeneration in both EAE and MS. Although many clinical trials are being conducted for MS, to the best of our knowledge, there is still no sphingolipid-targeted therapy available. Hence, we propose that sphingosine toxicity via ceramide generation may be a potential therapeutic target in both EAE and MS.

多发性硬化症(MS)是一种致命的脱髓鞘疾病，主要影响轴突，导致大量神经变性。许多研究报道了ms的发病原因，认为反复病毒感染、遗传联系、环境条件等多种因素参与了ms的发病机制，本质上都表明中枢神经系统(central nervous system, CNS)生化环境发生了严重变化，导致炎症和神经退行性变。我们实验室最近的研究发现，MS患者的中枢神经系统组织中存在异常的鞘脂代谢和毒性鞘脂苷的积累。MS脑白质和斑块中鞘氨醇的升高表明鞘氨醇毒性可能介导少突胶质细胞变性，导致脱髓鞘。实验性自身免疫性脑炎(EAE) Lewis大鼠脊髓中神经酰胺的间歇性增加和鞘氨酸的积累，以及丝氨酸-棕榈酰转移酶(SPT)活性的刺激与EAE动物腰椎脊髓细胞凋亡的诱导相关。细胞因子刺激的神经酰胺升高在培养的人少突胶质细胞中几乎完全被肉豆蔻素(一种SPT抑制剂)阻断。肉豆蔻素暴露也保护少突胶质细胞免于诱导凋亡。神经酰胺生物合成的鞘脂毒性导致EAE和MS的少突胶质细胞变性。尽管针对MS进行了许多临床试验，但据我们所知，目前还没有针对鞘脂的治疗方法。因此，我们认为神经酰胺产生的鞘氨醇毒性可能是EAE和MS的潜在治疗靶点。

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引用次数: 0

Therapeutic potential of paracrine factors and secretome-based treatment in spinal cord injury 旁分泌因子与分泌组治疗脊髓损伤的潜力

Therapeutic targets for neurological diseases

Pub Date : 2016-03-08 DOI: 10.14800/TTND.1198

T. Haider, H. Ankersmit

Spinal cord injuries trigger multiple endogenous pathways in an effort to contain damage to the spinal cord. These secondary mechanisms are also associated with damage progression and worse neurological outcome. This Janus-faced characteristic of the secondary response to spinal cord injuries complicates potential modulation of associated pathways. During recent years, our group investigated characteristics of the secretome obtained from apoptotic PBMCs. We demonstrated this secretomes capacity to interact with and modulate multiple cellular and molecular pathways exerting therapeutic potential in diseases like myocardial infarction or stroke. In a previously published study, we were able to show that characteristics of this secretome are also beneficial in a preclinical study of spinal cord injury by modulating the secondary cascade on multiple levels.

脊髓损伤触发多种内源性通路，以抑制脊髓损伤。这些次要机制也与损伤进展和更差的神经预后有关。脊髓损伤继发反应的这种双面特征使相关通路的潜在调节复杂化。近年来，我们的研究小组研究了从凋亡的pbmc中获得的分泌组的特征。我们证明了这种分泌组能够与多种细胞和分子途径相互作用并调节，在心肌梗死或中风等疾病中发挥治疗潜力。在先前发表的一项研究中，我们能够证明该分泌组的特征在脊髓损伤的临床前研究中也是有益的，通过在多个水平上调节二级级联。

引用次数: 0

BDNF promotes the growth of human neurons in vitro through crosstalk with the Wnt/β-catenin signaling pathway BDNF通过与Wnt/β-catenin信号通路的串扰促进体外人神经元的生长

Therapeutic targets for neurological diseases

Pub Date : 2015-11-16 DOI: 10.14800/TTND.1062

Jin‐wei Yang, Jin Ru, Wei Ma, Yan Gao, Zhang Liang, Jia Liu, Jingru Cheng, Dong-Yan Wang, Tao Luo, Jian‐hui Guo, Li‐yan Li

Background: Brain-derived neurotrophic factor (BDNF) plays an important role in neuronal growth; however, the downstream regulatory mechanisms remain unclear. In this study, we investigated whether BDNF exerts its neurotrophic effects through the Wnt/β-catenin signaling pathway in human embryonic spinal cord neurons in vitro. Methods: The research was carry out by human embryonic spinal cord neurons cultured in vitro, immunofluoresence labelling, BDNF plasmid transfection and siRNA interference, RT-PCR, Real time quantitative PCR and Western Blot. Results: We found that neuronal growth (soma size and average neurite length) was increased by transfection with a BDNF overexpression plasmid. Western blotting and real-time quantitative PCR showed that expression of the BDNF pathway components TrkB, PI3K, Akt and PLC-γ were increased by BDNF overexpression. Furthermore, the Wnt signaling factors Wnt, Frizzled and Dsh and the downstream target β-catenin were upregulated, whereas GSK-3β was downregulated. In contrast, when BDNF signaling was downregulated with BDNF siRNA, the growth of neurons was decreased. Furthermore, BDNF signaling factors, Wnt pathway components and β-catenin were all downregulated, whereas GSK-3β was upregulated. Then we treated neurons with 6-bromoindirubin-3’-oxime (BIO), a small molecule GSK-3β inhibitor. BIO reduced the effects of BDNF upregulation/downregulation on soma size and average neurite length, and suppressed the impact of BDNF modulation on the Wnt signaling pathway. Conclusions: Our findings suggest that BDNF promotes the growth of neurons in vitro through crosstalk with the Wnt/β-catenin signaling pathway, and that this interaction may be mediated by GSK-3β.

背景:脑源性神经营养因子(BDNF)在神经元生长中起重要作用;然而，下游调控机制尚不清楚。在本研究中，我们研究了BDNF是否通过Wnt/β-catenin信号通路在体外人胚胎脊髓神经元中发挥神经营养作用。方法:采用体外培养的人胚胎脊髓神经元、免疫荧光标记、BDNF质粒转染和siRNA干扰、RT-PCR、Real time定量PCR和Western Blot等方法进行研究。结果:我们发现转染BDNF过表达质粒后，神经元生长(体细胞大小和平均神经突长度)增加。Western blotting和real-time定量PCR结果显示，BDNF过表达后，BDNF通路组分TrkB、PI3K、Akt和PLC-γ的表达增加。Wnt信号因子Wnt、frizzed、Dsh及下游靶蛋白β-catenin上调，GSK-3β下调。相反，当BDNF siRNA下调BDNF信号传导时，神经元的生长下降。BDNF信号因子、Wnt通路组分和β-catenin均下调，GSK-3β上调。然后用小分子GSK-3β抑制剂6-溴靛红素-3′-肟(BIO)处理神经元。BIO降低了BDNF上调/下调对体细胞大小和平均神经突长度的影响，抑制了BDNF调节对Wnt信号通路的影响。结论:BDNF通过与Wnt/β-catenin信号通路的串扰促进体外神经元的生长，这种相互作用可能是由GSK-3β介导的。

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引用次数: 3

Cellular effectors and transduction pathways as therapeutic targets in cholinergic-dependent neuropsychiatric disorders 作为胆碱能依赖性神经精神疾病治疗靶点的细胞效应物和转导途径

Therapeutic targets for neurological diseases

Pub Date : 2015-11-04 DOI: 10.14800/ttnd.1043

P. Szulczyk, P. Kurowski, M. Gawlak

The impairment of working memory and the subsequent decrease in cognitive function is a prominent feature of widespread neuropsychiatric disorders such as Alzheimer’s disease and schizophrenia and also characterizes the decrease in cognitive function that occurs during natural aging. The working memory process may partially depend on acetylcholine-evoked depolarization of prefrontal cortex layer V pyramidal neurons. Working memory and cognitive functions are improved by the activation of M1 cholinergic muscarinic receptors in prefrontal cortex neurons. The activation of muscarinic receptors to improve working memory is impractical due to serious side effects. We discuss our recent findings that acetylcholine evokes depolarization in prefrontal cortex pyramidal neurons due to M1 muscarinic receptor-mediated activation of the G protein βγ subunit-dependent transduction system and Nav1.9-type Na + channels. Our results indicate that the depolarization of pyramidal neurons can be reinforced and working memory presumably strengthened not only by the activation of M1 muscarinic receptors but also by the activation of the transduction system linked to βγ subunits and/or the activation of Nav1.9 channels.

工作记忆的损伤和随后的认知功能下降是广泛存在的神经精神疾病(如阿尔茨海默病和精神分裂症)的一个显著特征，也是自然衰老过程中认知功能下降的特征。工作记忆过程可能部分依赖于乙酰胆碱诱发的前额叶皮层V层锥体神经元去极化。前额皮质神经元M1胆碱能毒蕈碱受体的激活可改善工作记忆和认知功能。由于严重的副作用，激活毒蕈碱受体来改善工作记忆是不切实际的。我们讨论了我们最近的发现，乙酰胆碱通过M1毒毒碱受体介导的G蛋白βγ亚基依赖性转导系统和nav1.9型Na +通道的激活，引起前额叶皮层锥体神经元的去极化。我们的研究结果表明，锥体神经元的去极化和工作记忆可能不仅通过M1毒蕈碱受体的激活，还可以通过与βγ亚基相关的转导系统的激活和/或Nav1.9通道的激活来增强。

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引用次数: 0

Cerebellar adrenomedullin: A new target for blood pressure regulation 小脑肾上腺髓质素:血压调节的新靶点

Therapeutic targets for neurological diseases

Pub Date : 2015-11-04 DOI: 10.14800/TTND.1039

L. Figueira, A. Israel

Adrenomedullin (AM) and their receptor components, CRLR, RAMP1, RAMP2 and RAMP3 are widely expressed in the central nervous system, including cerebellum. Recent evidence suggests a role for cerebellar adrenomedullinergic system in blood pressure (BP) regulation. We assessed AM, RAMP1, RAMP2, RAMP3 and CRLR expression; and AM receptor signaling pathway in the cerebellar vermis of WKY and SHR rats. Our findings demonstrated that CRLR, RAMP1 and RAMP3 expression was higher in cerebellum of SHR rats, while AM and RAMP2 expression was lower than those of WKY rats, both in 8 and 16 week old rats. In regard of AM signaling pathways, we show that AM activates ERK, increases cAMP production, increases cGMP production and NO accumulation. These effects are mediated through the activation of AM 1 receptor, since AM 22-52 blunted AM action, meanwhile AM increase of cAMP production is also mediated through stimulation of AM2 and CGRP receptors. Furthermore, AM decreased TBARS production and antioxidant enzymes basal activity: catalase (CAT), gluthation peroxidase (GPx) and superoxide dismutase (SOD). During hypertension, AM signaling pathways in the cerebellar vermis are altered. Effectively, in WKY rats AM decreased the activity of three antioxidant enzymes and TBARS production, while in SHR rats AM was unable to affect these signaling pathways; AM-induced ERK1/2 activation in cerebellum of the SHR was smaller in magnitude than in WKY; and AM increased cGMP/NO production in cerebellar vermis of the WKY rats, while in SHR rats AM was unable to stimulate this signaling pathway. We anticipated a possible functional role of cerebellar AM on BP regulation. Indeed, in vivo microinjection of AM into the cerebellar vermis caused a profound, dose dependent, hypotensive effect in SHR but not in normotensive WKY rats. Co-injections of a putative AM receptor antagonist, AM 22–52 abolished the decreases in MAP evoked by AM, showing that AM acts through its AM1 receptor to reduce blood pressure. These findings demonstrate dysregulation of cerebellar AM system during hypertension, and suggest that cerebellar AM plays an important role in the regulation of BP. Likewise, they constitute a novel mechanism of BP control which has not been described so far.

肾上腺髓质素(AM)及其受体成分CRLR、RAMP1、RAMP2和RAMP3在包括小脑在内的中枢神经系统广泛表达。最近的证据表明小脑肾上腺髓质能系统在血压调节中的作用。我们检测AM、RAMP1、RAMP2、RAMP3和CRLR的表达;WKY和SHR大鼠小脑蚓AM受体信号通路的变化。我们的研究结果表明，在8周龄和16周龄的大鼠中，SHR大鼠小脑中CRLR、RAMP1和RAMP3的表达高于WKY大鼠，AM和RAMP2的表达低于WKY大鼠。在AM信号通路方面，我们发现AM激活ERK，增加cAMP的产生，增加cGMP的产生和NO的积累。这些作用是通过激活AM 1受体介导的，因为AM 22-52使AM的作用减弱，同时AM增加cAMP的产生也是通过刺激AM2和CGRP受体介导的。此外，AM降低了TBARS的产生和抗氧化酶的基础活性:过氧化氢酶(CAT)、谷胱甘肽过氧化物酶(GPx)和超氧化物歧化酶(SOD)。高血压期间，小脑蚓内AM信号通路发生改变。在WKY大鼠中，AM有效地降低了三种抗氧化酶的活性和TBARS的产生，而在SHR大鼠中，AM无法影响这些信号通路;am诱导的ERK1/2在SHR小脑的激活程度小于WKY;AM增加了WKY大鼠小脑蚓cGMP/NO的产生，而在SHR大鼠中AM不能刺激这一信号通路。我们预计小脑AM可能在血压调节中发挥功能作用。事实上，在体内将AM显微注射到小脑蚓部，在SHR中产生了深刻的、剂量依赖性的降压作用，但在正常血压的WKY大鼠中没有。联合注射一种假定的AM受体拮抗剂AM 22-52，可以消除AM引起的MAP下降，表明AM通过其AM1受体降低血压。这些发现表明高血压患者小脑AM系统失调，提示小脑AM在血压调节中起重要作用。同样，它们构成了一种新的BP控制机制，这是迄今为止尚未描述的。

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引用次数: 3

Effect of sigma agonist 1, 3 di-o-tolyl-guanidine (DTG) on squizophrenia and immobility responses. 西格玛激动剂1,3二邻甲基胍(DTG)对精神分裂症和静止反应的影响。

Therapeutic targets for neurological diseases

Pub Date : 2015-10-15 DOI: 10.14800/TTND.942

L. Garcés-Ramírez, G. Flores, F. Cruz

Recently in our laboratory we found that DTG (sigma receptor agonist 1,3-di-o-tolyl-guanidine) sub-chronic administration reduced the hyperlocomotor activity and reversed the neuronal hypotrophy in the prefrontal cortex, amygdala and nucleus accumbens, generated in rats with neonatal ventral hippocampus lesion (nVHL). We also observed that DTG reversed some of the behavioral and neuromorphological effects of nVHL rats, which supports the possibility that DTG has beneficial effects in the management of symptoms of schizophrenia. We also found that DTG had effects on immobility responses, in the unlesioned rats increased the duration of the dorsal immobility but it did not have effect on the duration of immobility elicited by clamping. However, the nVHL increased the duration of immobility elicited by clamping, but did not have effect on the duration of the dorsal immobility. It should be noted that DTG counteracted the increase in the duration of the immobility by clamping produced by nVHL. The increase in the duration of the dorsal immobility produced by DTG was counteracted by nVHL. We suggested that the differential effect on these two immobility responses, is due to they are different varieties of immobility mediated by different mechanisms. Therefore, we believe that this evidence could help us to connect, schizophrenia with immobility reaction, which may be associated or somehow present in catatonic schizophrenia Key words; immobility response, schizophrenia, neonatal ventral hippocampus lesion, sigma agonist.

最近在我们的实验室中，我们发现DTG (sigma受体激动剂1,3-二-邻甲基胍)亚慢性给药可降低新生儿腹侧海马病变(nVHL)大鼠的运动亢进活动，逆转前额皮质、杏仁核和伏隔核的神经元萎缩。我们还观察到，DTG逆转了nVHL大鼠的一些行为和神经形态学效应，这支持了DTG对精神分裂症症状管理有益的可能性。我们还发现DTG对固定反应有影响，在未损伤的大鼠中，DTG增加了背侧固定的持续时间，但对夹紧引起的固定持续时间没有影响。然而，nVHL增加了夹紧引起的固定时间，但对背侧固定时间没有影响。应该指出的是，DTG抵消了由nVHL产生的夹紧固定时间的增加。DTG引起的背侧不动持续时间的增加被nVHL抵消。我们认为，这两种不动反应的差异效应是由于它们是由不同机制介导的不同类型的不动。因此，我们认为这一证据可以帮助我们将精神分裂症与不动反应联系起来，不动反应可能与紧张性精神分裂症有关或以某种方式存在。静止反应，精神分裂症，新生儿海马腹侧病变，sigma激动剂。

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引用次数: 1