Current drug targets. CNS and neurological disorders最新文献_第3页

Small transthyretin (TTR) ligands as possible therapeutic agents in TTR amyloidoses. 小转甲状腺素(TTR)配体作为TTR淀粉样变性的可能治疗药物。

Current drug targets. CNS and neurological disorders Pub Date : 2005-10-01 DOI: 10.2174/156800705774322076

M R Almeida, L Gales, A M Damas, I Cardoso, M J Saraiva

{"title":"Small transthyretin (TTR) ligands as possible therapeutic agents in TTR amyloidoses.","authors":"M R Almeida, L Gales, A M Damas, I Cardoso, M J Saraiva","doi":"10.2174/156800705774322076","DOIUrl":"https://doi.org/10.2174/156800705774322076","url":null,"abstract":"In transthyretin (TTR) amyloidosis TTR variants deposit as amyloid fibrils giving origin, in most cases, to peripheral polyneuropathy, cardiomyopathy, carpal tunnel syndrome and/or amyloid deposition in the eye. More than eighty TTR variants are known, most of them being pathogenic. The mechanism of TTR fibril formation is still not completely elucidated. However it is widely accepted that the amino acid substitutions in the TTR variants contribute to a destabilizing effect on the TTR tetramer molecule, which in particular conditions dissociate into non native monomeric intermediates that aggregate and polymerize in amyloid fibrils that further elongate. Since this is a multi-step process there is the possibility to impair TTR amyloid fibril formation at different stages of the process namely by tetramer stabilization, inhibition of fibril formation or fibril disruption. Till now the only efficient therapy available is liver transplant when performed in an early phase of the onset of the disease symptoms. Since this is a very invasive therapy alternatives are desirable. In that sense, several compounds have been proposed to impair amyloid formation or disruption. Based on the proposed mechanism for TTR amyloid fibril formation we discuss the action of some of the proposed TTR stabilizers such as derivatives of some NSAIDs (diflunisal, diclofenac, flufenamic acid, and derivatives) and the action of amyloid disrupters such as 4'-iodo-4'-deoxydoxorubicin (I-DOX) and tetracyclines. Among all these compounds, TTR stabilizers seem to be the most interesting since they would impair very early the process of amyloid formation and could also have a prophylactic effect.","PeriodicalId":11063,"journal":{"name":"Current drug targets. CNS and neurological disorders","volume":"4 5","pages":"587-96"},"PeriodicalIF":0.0,"publicationDate":"2005-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2174/156800705774322076","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25671893","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: 56

Neuronal plasticity, stress and depression: involvement of the cytoskeletal microtubular system? 神经元可塑性、应激和抑郁:细胞骨架微管系统的参与?

Current drug targets. CNS and neurological disorders Pub Date : 2005-10-01 DOI: 10.2174/156800705774322012

M Bianchi, J J Hagan, C A Heidbreder

{"title":"Neuronal plasticity, stress and depression: involvement of the cytoskeletal microtubular system?","authors":"M Bianchi, J J Hagan, C A Heidbreder","doi":"10.2174/156800705774322012","DOIUrl":"https://doi.org/10.2174/156800705774322012","url":null,"abstract":"In susceptible individuals, stressors can increase the risk of onset of depression and recent brain imaging studies have shown morphometric alterations in the limbic system of patients affected by depression. The volume loss observed in the hippocampus of depressed individuals suggests a possible involvement of structural neuronal plasticity in the pathogenesis of depression. Stressful conditions in animals can result in impaired structural neuronal plasticity in the hippocampus, characterised by retraction of apical dendrites and decreased neurogenesis. The intrinsic dynamic instability of the cytoskeletal microtubular system is essential for neuronal remodelling and plasticity. We have recently shown that both acute and chronic stress decrease microtubular dynamics in the rat hippocampus. Other authors have demonstrated that proteins functionally involved in the regulation of microtubule dynamics can be altered by stress in the rodent hippocampus. Furthermore, the existence of a link between stress-induced microtubular changes and depression is further strengthened by evidence showing that both acute and chronic treatment with antidepressant drugs can affect the expression of microtubular proteins. The present review will introduce a growing body of evidence suggesting that stress-induced alterations in neuronal plasticity might be considered the final result of activation and/or inhibition of molecular cascades regulating the dynamics of the microtubular system. In addition, the prospect of targeting microtubules as a pharmacotherapeutic approach to treat mood disorders will be discussed.","PeriodicalId":11063,"journal":{"name":"Current drug targets. CNS and neurological disorders","volume":"4 5","pages":"597-611"},"PeriodicalIF":0.0,"publicationDate":"2005-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2174/156800705774322012","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25671894","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: 73

Protein kinase C isozymes: memory therapeutic potential. 蛋白激酶C同工酶:记忆治疗潜力。

Current drug targets. CNS and neurological disorders Pub Date : 2005-10-01 DOI: 10.2174/156800705774322120

Miao-Kun Sun, Daniel L Alkon

{"title":"Protein kinase C isozymes: memory therapeutic potential.","authors":"Miao-Kun Sun, Daniel L Alkon","doi":"10.2174/156800705774322120","DOIUrl":"https://doi.org/10.2174/156800705774322120","url":null,"abstract":"PKC plays an important role in many types of learning and memory. Evidence has been provided that PKC activation and translocation are induced in associative learning tasks. PKC inhibition, on the other hand, impairs learning and memory, consistent with the observations that transgenic animal models with a particular PKC isoform deficit exhibit impaired capacity in cognition. The dramatic impact of PKC pharmacology on learning and memory is further emphasized by a regulatory role of PKC isozymes in amyloid production and accumulation. Recent study reveals that PKC activation greatly reduces neurotoxic amyloid production and accumulation. PKC activators, therefore, may have important therapeutic values in the treatment of dementia, especially when fine-tuning of selective isoform activity can be effectively achieved pharmacologically, with further development of isozymes-specific agents. The success of antidementia therapy with agents that act on PKC signaling cascades depends on whether such agents at their effective doses would significantly disrupt or interfere with other vital functions that rely on a narrow range of PKC activities.","PeriodicalId":11063,"journal":{"name":"Current drug targets. CNS and neurological disorders","volume":"4 5","pages":"541-52"},"PeriodicalIF":0.0,"publicationDate":"2005-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2174/156800705774322120","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25671889","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: 15

Editorial [Hot Topic: Cognition Therapeutics (Guest Editor: Miao-Kun Sun)] 社论[热点话题:认知治疗学(特邀编辑:孙妙坤)]

Current drug targets. CNS and neurological disorders Pub Date : 2005-09-30 DOI: 10.2174/156800705774322094

Miao‐kun Sun

引用次数: 0

Old and new drug targets in diabetic retinopathy: from biochemical changes to inflammation and neurodegeneration. 糖尿病视网膜病变的新旧药物靶点:从生化变化到炎症和神经变性。

Current drug targets. CNS and neurological disorders Pub Date : 2005-08-01 DOI: 10.2174/1568007054546162

E C Leal, A R Santiago, A F Ambrósio

{"title":"Old and new drug targets in diabetic retinopathy: from biochemical changes to inflammation and neurodegeneration.","authors":"E C Leal, A R Santiago, A F Ambrósio","doi":"10.2174/1568007054546162","DOIUrl":"https://doi.org/10.2174/1568007054546162","url":null,"abstract":"Diabetic Retinopathy (DR) is a major complication of diabetes and is a leading cause of blindness in western countries. DR has been considered a microvascular disease, and the blood-retinal barrier breakdown is a hallmark of this disease. The available treatments are scarce and not very effective. Despite the attempts to control blood glucose levels and blood pressure, many diabetic patients are affected by DR, which progresses to more severe forms of disease, where laser photocoagulation therapy is needed. DR has a huge psychological impact in patients and tremendous economic and social costs. Taking this into account, the scientific community is committed to find a treatment to DR. Understanding the cellular and molecular mechanisms underlying the pathogenesis of DR will facilitate the development of strategies to prevent, or at least to delay the progression of the disease. The involvement of the polyol pathway, advanced glycation end products, protein kinase C and oxidative stress in the pathogenesis of DR is well-documented, and several clinical trials have been conducted to test the efficacy of various drugs. More recent findings also demonstrate that DR has characteristics of chronic inflammatory disease and neurodegenerative disease, which increases the opportunity of intervention at the pharmacological level. This review presents past and recent evidences demonstrating the involvement of different molecules and processes in DR, and how different approaches and pharmacological tools have been used to prevent retinal cell dysfunction.","PeriodicalId":11063,"journal":{"name":"Current drug targets. CNS and neurological disorders","volume":"4 4","pages":"421-34"},"PeriodicalIF":0.0,"publicationDate":"2005-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2174/1568007054546162","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25250267","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: 49

What can adenosine neuromodulation do for neuroprotection? 腺苷神经调节对神经保护有什么作用?

Current drug targets. CNS and neurological disorders Pub Date : 2005-08-01 DOI: 10.2174/1568007054546090

J A Ribeiro

{"title":"What can adenosine neuromodulation do for neuroprotection?","authors":"J A Ribeiro","doi":"10.2174/1568007054546090","DOIUrl":"https://doi.org/10.2174/1568007054546090","url":null,"abstract":"The possibility of repairing brain lesions is a crucial issue. Knowing how regeneration occurs allows novel concepts in the process of protecting the nervous system, in other words to induce and to develop neuroprotection. Brain insults cause irreversible tissue damage by at least three mechanisms: First, through consequences of mechanical disruption of neurons or their projections; secondly, through biochemical or metabolic changes that are initiated by the insult; and finally, through inflammatory reactions or gliotic changes. The cellular elements and the chemical neuro-mediators involved in brain injury act via interconnections between the cellular elements and their secretions; the immune system and the nervous system are highly regulated in normal physiology, which benefits the organism. When these cells suffer insults in the central nervous system (CNS), the connections between the systems are altered; these systems act together to strangulate the tissue, depriving it of the local control over microcirculation and necessary oxygen, rendering membrane potentials useless to modulate neuronal function. Surgical interventions during the stages of brain injury continue to progress as do biochemical and bioelectric therapeutics during the chronic and rehabilitation stages. There is some hope, too, for effective neuropharmacological intervention. The fact that chemical mediators are already part of normal physiology, whether during development or adulthood, means that their activity can be modified by specific agonists and antagonists to restore homeostasis or to promote the safe pathways that can lead to regeneration. This is the orientation of much of current basic and clinical research. During the past decade considerable experimental and clinical data have been accumulated regarding cellular and biochemical events associated with brain repair.","PeriodicalId":11063,"journal":{"name":"Current drug targets. CNS and neurological disorders","volume":"4 4","pages":"325-9"},"PeriodicalIF":0.0,"publicationDate":"2005-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2174/1568007054546090","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25250261","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: 54

Liposomal and viral vectors for gene therapy of the central nervous system. 用于中枢神经系统基因治疗的脂质体和病毒载体。

Current drug targets. CNS and neurological disorders Pub Date : 2005-08-01 DOI: 10.2174/1568007054546144

Maria C Pedroso de Lima, M Teresa Girao da Cruz, Ana L C Cardoso, Sérgio Simoes, Luís Pereira de Almeida

{"title":"Liposomal and viral vectors for gene therapy of the central nervous system.","authors":"Maria C Pedroso de Lima, M Teresa Girao da Cruz, Ana L C Cardoso, Sérgio Simoes, Luís Pereira de Almeida","doi":"10.2174/1568007054546144","DOIUrl":"https://doi.org/10.2174/1568007054546144","url":null,"abstract":"Due to the presence of the blood-brain barrier, the central nervous system (CNS) is not easily accessible to systemically delivered macromolecules with therapeutic activity such as growth factors, cytokines or enzymes. Therefore, the expression of exogenously administered genes in the brain has been proposed for a wide variety of inherited and acquired diseases of the CNS, for which classical pharmacotherapy is unavailable or not easily applicable. Gene therapy to the CNS has been the target of a great number of studies aiming at finding a viable therapeutic strategy for the treatment of neurological disorders. This approach has already been used as a promising tool for brain protection and repair from neuronal insults and degeneration in several animal models, and is currently being applied in clinical trials. The choice of an appropriate vector system for transferring the desired gene into the affected brain area is an important issue for developing a safe and efficient gene therapy approach for the CNS. In this review, we focus on the various types of vectors that have been used for gene delivery into the CNS. Particular emphasis is given to their mode of preparation, biological activity, safety and in vivo behavior. Examples illustrating the potential of both viral and non-viral vectors in therapeutic applications to brain disorders are provided. In addition, the use of lentiviral vectors for in vivo modeling of genetic disorders of the CNS is discussed.","PeriodicalId":11063,"journal":{"name":"Current drug targets. CNS and neurological disorders","volume":"4 4","pages":"453-65"},"PeriodicalIF":0.0,"publicationDate":"2005-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2174/1568007054546144","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25248453","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: 22

Molecular targets and therapeutic strategies in Huntington's disease. 亨廷顿舞蹈病的分子靶点和治疗策略。

Current drug targets. CNS and neurological disorders Pub Date : 2005-08-01 DOI: 10.2174/1568007054546081

A Cristina Rego, Luís Pereira de Almeida

引用次数: 23

Organotypic hippocampal slice cultures for studies of brain damage, neuroprotection and neurorepair. 用于脑损伤、神经保护和神经修复研究的器官型海马切片培养。

Current drug targets. CNS and neurological disorders Pub Date : 2005-08-01 DOI: 10.2174/1568007054546108

Jens Noraberg, Frantz Rom Poulsen, Morten Blaabjerg, Bjarne Winther Kristensen, Christian Bonde, Maria Montero, Morten Meyer, Jan Bert Gramsbergen, Jens Zimmer

{"title":"Organotypic hippocampal slice cultures for studies of brain damage, neuroprotection and neurorepair.","authors":"Jens Noraberg, Frantz Rom Poulsen, Morten Blaabjerg, Bjarne Winther Kristensen, Christian Bonde, Maria Montero, Morten Meyer, Jan Bert Gramsbergen, Jens Zimmer","doi":"10.2174/1568007054546108","DOIUrl":"https://doi.org/10.2174/1568007054546108","url":null,"abstract":"Slices of developing brain tissue can be grown for several weeks as so-called organotypic slice cultures. Here we summarize and review studies using hippocampal slice cultures to investigate mechanisms and treatment strategies for the neurodegenerative disorders like stroke (cerebral ischemia), Alzheimer's disease (AD) and epilepsia. Studies of non-excitotoxic neurotoxic compounds and the experimental use of slice cultures in studies of HIV neurotoxicity, traumatic brain injury (TBI) and neurogenesis are included. For cerebral ischemia, experimental models with oxygen-glucose deprivation (OGD) and exposure to glutamate receptor agonists (excitotoxins) are reviewed. For epilepsia, focus is on induction of seizures with effects on neuronal loss, axonal sprouting and neurogenesis. For Alzheimer's disease, the review centers on the use of beta-amyloid (Abeta) in different models, while the section on repair is focused on neurogenesis and cell migration. The culturing techniques, set-up of models, and analytical tools, including markers for neurodegeneration, like the fluorescent dye propidium iodide (PI), are reviewed and discussed. Comparisons are made between hippocampal slice cultures and other in vitro models using dispersed cell cultures, experimental in vivo models, and in some instances, clinical trials. New techniques including slice culturing of hippocampal tissue from transgenic mice as well as more mature brain tissue, and slice cultures coupled to microelectrode arrays (MEAs), on-line biosensor monitoring, and time-lapse fluorescence microscopy are also presented.","PeriodicalId":11063,"journal":{"name":"Current drug targets. CNS and neurological disorders","volume":"4 4","pages":"435-52"},"PeriodicalIF":0.0,"publicationDate":"2005-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2174/1568007054546108","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25248452","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: 241

Role of nitric oxide and calpain activation in neuronal death and survival. 一氧化氮和钙蛋白酶激活在神经元死亡和存活中的作用。

Current drug targets. CNS and neurological disorders Pub Date : 2005-08-01 DOI: 10.2174/1568007054546126

Inês M Araújo, Caetana M Carvalho

{"title":"Role of nitric oxide and calpain activation in neuronal death and survival.","authors":"Inês M Araújo, Caetana M Carvalho","doi":"10.2174/1568007054546126","DOIUrl":"https://doi.org/10.2174/1568007054546126","url":null,"abstract":"Dysregulation of intracellular calcium homeostasis is a common hallmark of degenerating neurons, at some point in the cell death cascade. It is also a feature of many neurological disorders, including stroke, epilepsy, trauma and several neurodegenerative diseases, commonly associated with the phenomenon of excitotoxicity. Nitric oxide (NO) is a signaling gaseous molecule formed in the brain as a part of the normal intracellular calcium signalling, playing highly diversified roles in cellular physiology. For the past 20 years, numerous studies have demonstrated that NO can acts as a neurotoxin in several disorders of the nervous system. More recent evidence shows that NO can also act as a neuroprotective agent. Calcium-dependent proteases, like calpains, were also shown to be activated in several conditions of the nervous system that involve excitotoxic neurodegeneration, and have been receiving increasing attention as therapeutical targets in recent years. In this review, we bring together the recent literature concerning the involvement of NO and calpains in neuronal survival and death. The biological pathways involved with NO and calpains may be good drug targets to alter neurodegenerative diseases.","PeriodicalId":11063,"journal":{"name":"Current drug targets. CNS and neurological disorders","volume":"4 4","pages":"319-24"},"PeriodicalIF":0.0,"publicationDate":"2005-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2174/1568007054546126","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25250260","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: 37