Therapeutic targets for neurological diseases最新文献

{"title":"SRSF1-dependent nuclear export of C9ORF72 repeat transcripts: targeting toxic gain-of-functions induced by protein sequestration as a selective therapeutic strategy for neuroprotection","authors":"L. Castelli, Ya-Hui Lin, L. Ferraiuolo, Alvaro Sanchez-Martinez, K. Ning, M. Azzouz, Alexander J. Whitworth, P. Shaw, Guillaume M. Hautbergue","doi":"10.14800/TTND.1619","DOIUrl":"https://doi.org/10.14800/TTND.1619","url":null,"abstract":"Microsatellite repeat expansions cause several incurable and lethal neurodegenerative disorders including \u0000ataxias, myotonic dystrophy, Huntington's disease and C9ORF72-linked amyotrophic lateral sclerosis (ALS) and \u0000frontotemporal dementia (FTD). Abnormal repeat transcripts generated from the expanded loci are substrates \u0000of repeat-associated non-AUG (RAN) translation, an unconventional form of translation leading to the \u0000production of polymeric repeat proteins with cytotoxic and aggregating properties. The mechanisms involved in \u0000the pathogenesis of microsatellite repeat expansion disorders remain a hotly debated topic. They are shared \u0000between toxic loss/gain of functions due to intranuclear RNA foci that sequesters RNA-binding proteins and \u0000RAN translation of repeat proteins in the cytoplasm. We recently elucidated the molecular mechanism driving \u0000the nuclear export of C9ORF72 repeat transcripts and showed for the first time that this pathway can be \u0000manipulated to confer neuroprotection. Strikingly, we discovered that intron-retaining C9ORF72 repeat \u0000transcripts hijack the physiological NXF1-dependent export pathway by selective RNA-repeat sequestration of \u0000SRSF1. Antagonizing SRSF1 and the nuclear export of C9ORF72 repeat transcripts promoted in turn the \u0000survival of patient-derived motor neurons and suppressed neurodegeneration-associated motor deficits in \u0000Drosophila (Hautbergue et al. Nature Communications 2017; 8:16063). In this invited Research Highlight review, \u0000we aim to place this work in the context of our previous studies on the nuclear export of mRNAs, provide a \u0000summary of the published research and highlight the significance of these findings as a novel therapeutic \u0000strategy for neuroprotection in C9ORF72-ALS/FTD. In addition, we emphasize that protein sequestration, often \u0000thought as of inducing loss-of-function mechanisms, can also trigger unwanted protein interactions and toxic \u0000gain-of-functions.","PeriodicalId":90750,"journal":{"name":"Therapeutic targets for neurological diseases","volume":"4 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2018-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"44095015","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}

{"title":"Insights into abnormal sphingolipid metabolism in multiple sclerosis: targeting ceramide biosynthesis as a unique therapeutic strategy","authors":"S. Dasgupta, S. Ray","doi":"10.14800/TTND.1598","DOIUrl":"https://doi.org/10.14800/TTND.1598","url":null,"abstract":"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.","PeriodicalId":90750,"journal":{"name":"Therapeutic targets for neurological diseases","volume":"4 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46657246","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}

{"title":"The synthesis of polyhydroxy sterone 2β,3α,5-trihydroxy-5α-androst-6-one and its neuroprotection","authors":"Minyu Xie, Xinhua Li, Li-qiang Yuan, Yiyu Chen, Xiaolei Zhang, Wei Yin, Bing-zheng Lu, Zhu Zhu, Haitao Shi, Jingxia Zhang","doi":"10.14800/TTND.1559","DOIUrl":"https://doi.org/10.14800/TTND.1559","url":null,"abstract":"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.","PeriodicalId":90750,"journal":{"name":"Therapeutic targets for neurological diseases","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"48789402","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}

{"title":"Addictive neurons.","authors":"Sodikdjon A Kodirov","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Since the reward center is considered to be the <i>area tegmentalis ventralis</i> 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.</p>","PeriodicalId":90750,"journal":{"name":"Therapeutic targets for neurological diseases","volume":"4 ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5479441/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35118881","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Insights into abnormal sphingolipid metabolism in multiple sclerosis: targeting ceramide biosynthesis as a unique therapeutic strategy.","authors":"Somsankar Dasgupta,&nbsp;Swapan K Ray","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":90750,"journal":{"name":"Therapeutic targets for neurological diseases","volume":"4 ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/b0/09/nihms911060.PMC5933878.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36077621","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Therapeutic potential of paracrine factors and secretome-based treatment in spinal cord injury","authors":"T. Haider, H. Ankersmit","doi":"10.14800/TTND.1198","DOIUrl":"https://doi.org/10.14800/TTND.1198","url":null,"abstract":"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.","PeriodicalId":90750,"journal":{"name":"Therapeutic targets for neurological diseases","volume":"5 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2016-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"66658287","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}

{"title":"BDNF promotes the growth of human neurons in vitro through crosstalk with the Wnt/β-catenin signaling pathway","authors":"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","doi":"10.14800/TTND.1062","DOIUrl":"https://doi.org/10.14800/TTND.1062","url":null,"abstract":"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.","PeriodicalId":90750,"journal":{"name":"Therapeutic targets for neurological diseases","volume":"3 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2015-11-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"66658247","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}

{"title":"Cellular effectors and transduction pathways as therapeutic targets in cholinergic-dependent neuropsychiatric disorders","authors":"P. Szulczyk, P. Kurowski, M. Gawlak","doi":"10.14800/ttnd.1043","DOIUrl":"https://doi.org/10.14800/ttnd.1043","url":null,"abstract":"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.","PeriodicalId":90750,"journal":{"name":"Therapeutic targets for neurological diseases","volume":"3 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2015-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"66658239","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}

{"title":"Cerebellar adrenomedullin: A new target for blood pressure regulation","authors":"L. Figueira, A. Israel","doi":"10.14800/TTND.1039","DOIUrl":"https://doi.org/10.14800/TTND.1039","url":null,"abstract":"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.","PeriodicalId":90750,"journal":{"name":"Therapeutic targets for neurological diseases","volume":"3 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2015-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"66658229","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}

{"title":"Effect of sigma agonist 1, 3 di-o-tolyl-guanidine (DTG) on squizophrenia and immobility responses.","authors":"L. Garcés-Ramírez, G. Flores, F. Cruz","doi":"10.14800/TTND.942","DOIUrl":"https://doi.org/10.14800/TTND.942","url":null,"abstract":"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.","PeriodicalId":90750,"journal":{"name":"Therapeutic targets for neurological diseases","volume":"49 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2015-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"66659162","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}