Current drug targets. CNS and neurological disorders最新文献_第2页

Molecular biology of the enzymes that degrade endocannabinoids. 降解内源性大麻素的酶的分子生物学。

Current drug targets. CNS and neurological disorders Pub Date : 2005-12-01 DOI: 10.2174/156800705774933050

Robyn A Puffenbarger

引用次数: 32

Pharmacological properties and therapeutic possibilities for drugs acting upon endocannabinoid receptors. 内源性大麻素受体作用药物的药理特性和治疗可能性。

Current drug targets. CNS and neurological disorders Pub Date : 2005-12-01 DOI: 10.2174/156800705774933041

Christopher J Fowler

{"title":"Pharmacological properties and therapeutic possibilities for drugs acting upon endocannabinoid receptors.","authors":"Christopher J Fowler","doi":"10.2174/156800705774933041","DOIUrl":"https://doi.org/10.2174/156800705774933041","url":null,"abstract":"Clinical trial data are beginning to emerge with respect to the therapeutic efficacy of cannabis extracts for the treatment of chronic pain. Although there is some evidence of efficacy, a major issue concerns the narrow margin between doses producing therapeutic effects and those producing the \"highs\" associated with cannabis misuse. In addition, long-term use is associated with an increased risk of psychiatric illness. These negative aspects constrain the doses of cannabis extracts and psychoactive cannabinoids that can be given to patients, and raise the risk that properly conducted clinical trials with too low dosages will impact negatively on subsequent drug development in this field. However, recent research has opened up a number of avenues whereby compounds acting directly upon cannabinoid (CB) receptors may have therapeutic potential. In this review, two such areas are discussed, namely a) the possible use of peripherally acting CB agonists and CB2 receptor-selective agonists for the treatment of pain, and b) the possible utility of CB2 receptor agonists for the prevention of stress-induced exacerbations of skin disorders such as psoriasis. A second area of drug development at present is that of CB1 receptor antagonists/inverse agonists, spearheaded by rimonabant, for the treatment of obesity and as an aid for smoking cessation. An important aspect of these compounds is their efficacy and selectivity, and this is discussed in detail in the present review.","PeriodicalId":11063,"journal":{"name":"Current drug targets. CNS and neurological disorders","volume":"4 6","pages":"685-96"},"PeriodicalIF":0.0,"publicationDate":"2005-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2174/156800705774933041","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25768682","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: 17

Low density lipoprotein receptor-related proteins (LRPs), Alzheimer's and cognition. 低密度脂蛋白受体相关蛋白(LRPs)，阿尔茨海默病和认知。

Current drug targets. CNS and neurological disorders Pub Date : 2005-10-01 DOI: 10.2174/156800705774322102

M E Harris-White, S A Frautschy

{"title":"Low density lipoprotein receptor-related proteins (LRPs), Alzheimer's and cognition.","authors":"M E Harris-White, S A Frautschy","doi":"10.2174/156800705774322102","DOIUrl":"https://doi.org/10.2174/156800705774322102","url":null,"abstract":"This review will focus primarily on the role of the low density lipoprotein receptor-related protein (LRP-1) in neuronal synapse formation and function in Alzheimer's Disease (AD). We review the role that its ligands may have in cognition or AD: apolipoprotein E (ApoE), alpha2-macroglobulin, Transforming Growth Factor-Beta (TGFbeta, Tissue Plasminogen Activator (tPA), insulin growth factor binding protein-3 (IGFBP-3), which all bind LRP-1 and apolipoprotein J (ApoJ), which is a ligand for LRP-2. After reviewing its role as a signaling receptor, we discuss the connection between LRP and the NMDA glutamate receptor via the post synaptic density 95 (PSD-95) neuronal scaffold protein and the implications it may have for memory and cognition. Finally, we discuss the evidence supporting a role for LRP in AD. Although the evidence for LRP as a genetic risk factor is weak, many of its ligands impose genetic risk, and have been implicated in AD pathogenic cascades. We discuss the role of LRP in amyloid precursor protein (APP) processing and production of beta-amyloid (Abeta. We identify LRP ligands that accelerate aggregation of toxic Abeta species. LRP mediates crucial pathways in AD pathogenesis such as Abeta clearance, Abeta uptake, intraneuronal Abeta accumulation and Abeta-associated neuron death. Interestingly, the TGFbeta -V receptor is LRP-1. Data show that one critical ligand TGFbeta2, associated with neurodegeneration in amyloid diseases, induces LRP expression in PC12 cells. Data from rodent infusion models demonstrate the impact of TGFbeta2 in modifying Abeta- induced Long Term Potentiation (LTP) responses, presynaptic proteins, lipid peroxidation, gliosis and staining for neuronal nuclei. The evidence supports a complex and significant role of LRP in cognition and AD.","PeriodicalId":11063,"journal":{"name":"Current drug targets. CNS and neurological disorders","volume":"4 5","pages":"469-80"},"PeriodicalIF":0.0,"publicationDate":"2005-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2174/156800705774322102","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25673173","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: 66

Cannabinoids. 大麻类。

Current drug targets. CNS and neurological disorders Pub Date : 2005-10-01 DOI: 10.2174/156800705774322111

Franjo Grotenhermen

{"title":"Cannabinoids.","authors":"Franjo Grotenhermen","doi":"10.2174/156800705774322111","DOIUrl":"https://doi.org/10.2174/156800705774322111","url":null,"abstract":"Since the discovery of an endogenous cannabinoid system, research into the pharmacology and therapeutic potential of cannabinoids has steadily increased. Two subtypes of G-protein coupled cannabinoid receptors, CB(1) and CB(1), have been cloned and several putative endogenous ligands (endocannabinoids) have been detected during the past 15 years. The main endocannabinoids are arachidonoyl ethanolamide (anandamide) and 2-arachidonoyl glycerol (2-AG), derivatives of arachidonic acid, that are produced \"on demand\" by cleavage of membrane lipid precursors. Besides phytocannabinoids of the cannabis plant, modulators of the cannabinoid system comprise synthetic agonists and antagonists at the CB receptors and inhibitors of endocannabinoid degradation. Cannabinoid receptors are distributed in the central nervous system and many peripheral tissues, including immune system, reproductive and gastrointestinal tracts, sympathetic ganglia, endocrine glands, arteries, lung and heart. There is evidence for some non-receptor dependent mechanisms of cannabinoids and for endocannabinoid effects mediated by vanilloid receptors. Properties of CB receptor agonists that are of therapeutic interest include analgesia, muscle relaxation, immunosuppression, anti-inflammation, antiallergic effects, improvement of mood, stimulation of appetite, antiemesis, lowering of intraocular pressure, bronchodilation, neuroprotection and antineoplastic effects. The current main focus of clinical research is their efficacy in chronic pain and neurological disorders. CB receptor antagonists are under investigation for medical use in obesity and nicotine addiction. Additional potential was proposed for the treatment of alcohol and heroine dependency, schizophrenia, conditions with lowered blood pressure, Parkinson's disease and memory impairment in Alzheimer's disease.","PeriodicalId":11063,"journal":{"name":"Current drug targets. CNS and neurological disorders","volume":"4 5","pages":"507-30"},"PeriodicalIF":0.0,"publicationDate":"2005-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2174/156800705774322111","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25673176","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

Abeta immunotherapy and other means to remove amyloid. 免疫疗法和其他方法去除淀粉样蛋白。

Current drug targets. CNS and neurological disorders Pub Date : 2005-10-01 DOI: 10.2174/156800705774322067

Edith G McGeer, Patrick L McGeer

引用次数: 13

Memantine: a therapeutic approach in treating Alzheimer's and vascular dementia. 美金刚:治疗阿尔茨海默病和血管性痴呆的一种治疗方法。

Current drug targets. CNS and neurological disorders Pub Date : 2005-10-01 DOI: 10.2174/156800705774322021

Horst J Koch, Gökhan Uyanik, David Fischer-Barnicol

{"title":"Memantine: a therapeutic approach in treating Alzheimer's and vascular dementia.","authors":"Horst J Koch, Gökhan Uyanik, David Fischer-Barnicol","doi":"10.2174/156800705774322021","DOIUrl":"https://doi.org/10.2174/156800705774322021","url":null,"abstract":"Memantine has been clinically used in the treatment of organic disorders in Germany for over ten years and has now been approved in Europe and also in the US for moderate to severe Alzheimer's disease. The rationale for this indication is strongly related to the physiological and pathological role of glutamate in neurotransmission. Glutamate is an agonist of NMDA, kainate and AMPA (ionotropic) receptors, where its influence on NMDA receptors plays an important role with regard to neuronal plasticity effecting memory and learning. Excessive levels of glutamate result in neurotoxicity, in part by overactivation of NMDA receptors. Memantine acts as an uncompetitive antagonist of NMDA receptors and therefore compensates for this overactivation. Furthermore, memantine is a neuroprotective agent in various animal models based on both neurodegenerative and vascular processes, as it ameliorates cognitive and memory deficits. Memantine was effective and safe in several clinical studies, particularly in Alzheimer's disease. The compound is completely absorbed after oral intake and undergoes little metabolism. Having a low probability for drug-drug interactions, memantine, in principle, is suited for elderly patients exposed to multiple therapeutic therapies.","PeriodicalId":11063,"journal":{"name":"Current drug targets. CNS and neurological disorders","volume":"4 5","pages":"499-506"},"PeriodicalIF":0.0,"publicationDate":"2005-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2174/156800705774322021","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25673175","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: 23

Neuroactive flavonoids interacting with GABAA receptor complex. 神经活性类黄酮与GABAA受体复合物相互作用。

Current drug targets. CNS and neurological disorders Pub Date : 2005-10-01 DOI: 10.2174/156800705774322030

Feng Wang, Michael Shing, Yan Huen, Shui Ying Tsang, Hong Xue

{"title":"Neuroactive flavonoids interacting with GABAA receptor complex.","authors":"Feng Wang, Michael Shing, Yan Huen, Shui Ying Tsang, Hong Xue","doi":"10.2174/156800705774322030","DOIUrl":"https://doi.org/10.2174/156800705774322030","url":null,"abstract":"Classical benzodiazepines (BZs) are the most widely prescribed drugs acting on the central nervous system (CNS). They exert their therapeutic effects via binding to the BZ-site of GABAA receptors, and allosterically modulating the chloride flux through the ion channel complex. Given the multiple actions of classical BZs, the serious limitations to their usefulness have directed much research into development of novel ligands for the BZ-site with retained therapeutic effectiveness and minimal side effects. From the studies of CNS-active chemical constituents of medicinal herbs, some members of the family of flavonoids were demonstrated to have moderate binding affinities for the BZ-site. In vivo studies revealed that these compounds were mostly partial agonists of GABAA receptors, and only a few flavonoids were shown to possess antagonistic activities. At effective anxiolytic doses, the actions of partial agonistic flavonoids were often not accompanied by sedative and myorelaxant side effects. Based on structure-activity relationship (SAR) studies, incorporation of electronegative groups to the C6 and C3' on the flavone backbone was found to yield significant increases in the binding affinities for the BZ-site. It was also shown that 2'-hydroxyl was a critical moiety on flavonoids with regard to BZ-site binding. These have guided the identification of several synthetic flavonoids with high BZ-site binding affinity and in vivo activity, and further quantitative SAR studies resulted in the development of several pharmacophore models. This review attempts to summarize these findings, which has led to the establishment of flavonoids as potential therapeutics for GABAA receptor-mediated disorders.","PeriodicalId":11063,"journal":{"name":"Current drug targets. CNS and neurological disorders","volume":"4 5","pages":"575-85"},"PeriodicalIF":0.0,"publicationDate":"2005-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2174/156800705774322030","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25671892","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: 67

CREB, synapses and memory disorders: past progress and future challenges. CREB，突触和记忆障碍:过去的进展和未来的挑战。

Current drug targets. CNS and neurological disorders Pub Date : 2005-10-01 DOI: 10.2174/156800705774322058

Sheena A Josselyn, Peter V Nguyen

{"title":"CREB, synapses and memory disorders: past progress and future challenges.","authors":"Sheena A Josselyn, Peter V Nguyen","doi":"10.2174/156800705774322058","DOIUrl":"https://doi.org/10.2174/156800705774322058","url":null,"abstract":"In neurons, appropriate long-term adaptive responses to changes in the environment require the conversion of extracellular stimuli into discrete intracellular signals. Many of these signals involve the regulation of gene expression. The cAMP responsive element binding protein (CREB) is a nuclear transcription factor that modulates transcription of genes containing cAMP responsive elements (CRE sites) in their promoters. CREB is a key part of many intracellular signaling events that critically regulate many neural functions. Numerous studies on invertebrates and vertebrates demonstrate that CREB is critical for long-term memory. Here, we review the key features of CREB-dependent transcription and critically evaluate the data examining the roles of CREB in different forms of plasticity, including long-term memory in mammals. Because learning and memory have been linked to specific types of synaptic plasticity in several species, we also review studies on the role of CREB in long-term facilitation in Aplysia and in hippocampal long-term potentiation (LTP). Several human cognitive disorders have been linked to alterations of CREB-regulated gene expression. Therefore, we explore the possibility of targeting CREB function in developing novel treatment strategies. Finally, we highlight areas of research on CREB that are ripe for further advancement.","PeriodicalId":11063,"journal":{"name":"Current drug targets. CNS and neurological disorders","volume":"4 5","pages":"481-97"},"PeriodicalIF":0.0,"publicationDate":"2005-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2174/156800705774322058","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25673174","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: 188

Increasing testosterone levels and effects on cognitive functions in elderly men and women: a review. 老年男性和女性睾酮水平升高及其对认知功能的影响:综述。

Current drug targets. CNS and neurological disorders Pub Date : 2005-10-01 DOI: 10.2174/156800705774322049

E Hogervorst, S Bandelow, S D Moffat

{"title":"Increasing testosterone levels and effects on cognitive functions in elderly men and women: a review.","authors":"E Hogervorst, S Bandelow, S D Moffat","doi":"10.2174/156800705774322049","DOIUrl":"https://doi.org/10.2174/156800705774322049","url":null,"abstract":"Low testosterone (T) levels may predispose to Alzheimer disease (AD), but it is unclear whether this is a co-morbid effect due to cachexia, subclinical hyperthyroidism or other co-morbidity. The biological plausibility for potential protective effects of T on brain functions is substantial. In addition, higher levels of gonadotropins found in older cases with AD suggest that low levels of T are not due to brain degeneration and that the hypothalamic-pituitary-gonadal (HPG) axis is still intact. Men genetically at risk for AD were also already found to have lower levels of T. However, despite having lower levels of T, women do not show accelerated cognitive decline with age when compared to men. In addition, castration has not necessarily shown a decline in cognitive functions; some studies even found improvement of memory recall. Age may be an important factor when assessing optimal levels of T and several studies suggest that free or bioavailable T may be a better marker than total T levels when investigating associations of androgen activity with cognitive function. Small-scale T intervention trials in elderly men with and without dementia suggest that some cognitive deficits may be reversed, at least in part, by short term T supplementation. Age and prior hypogonadism may play an important role in therapy success and these factors should be investigated in more detail in future large scale randomized controlled studies. For elderly women, T treatment does not seem to have additional benefits over estrogen treatment for postmenopausal complaints and cognitive decline and may increase cardiovascular disease.","PeriodicalId":11063,"journal":{"name":"Current drug targets. CNS and neurological disorders","volume":"4 5","pages":"531-40"},"PeriodicalIF":0.0,"publicationDate":"2005-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2174/156800705774322049","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25673177","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: 58

Cholesterol and apoe: a target for Alzheimer's disease therapeutics. 胆固醇和载脂蛋白:阿尔茨海默病治疗的目标。

Current drug targets. CNS and neurological disorders Pub Date : 2005-10-01 DOI: 10.2174/156800705774322085

Daniela Fenili, Joanne McLaurin

引用次数: 10