NeuroRx : the journal of the American Society for Experimental NeuroTherapeutics最新文献

{"title":"Challenges in the Development of Novel Treatment Strategies for Neuropathic Pain","authors":"Michael H. Ossipov,&nbsp;Frank Porreca Ph.D.","doi":"10.1602/neurorx.2.4.650","DOIUrl":"10.1602/neurorx.2.4.650","url":null,"abstract":"<div><p>Neuropathic pain might best be considered as a collection of various pain states with a common feature, that being symptoms suggestive of dysfunction of peripheral nerves. The development of therapeutic options for the treatment of neuropathic pain is complicated significantly by several factors. Neuropathic pain may arise from widely diverse etiologies such as physical trauma, disease, infection, or chemotherapy. Symptoms indicative of neuropathic pain may also arise in individuals with no evidence of any type of nerve trauma (idiopathic). Although neuropathic pain is a substantial health care issue, it is relatively uncommon and only occurs in a small fraction (&lt;10%) of individuals with these initiating factors. Moreover, the efficacy of treatment protocols, even against the same type of symptoms, differ depending on the underlying initiating cause of the neuropathy. Although these observations strongly suggest that there are predisposing factors that may impart susceptibility to the development of neuropathic pain, no common predisposing factors or genetic markers have been satisfactorily identified. Because of these vagaries, treatment of neuropathic pain has been based on trial and error. However, recent progress in the understanding of neurophysiologic changes that accompany peripheral nerve dysfunction indicate that regulation of ion channels that maintain membrane potentials or generate action potentials may provide an important therapeutic approach. Neuropathic pain is accompanied by increased activity of peripheral nociceptors, which is produced in part by changes in levels of specific calcium and sodium channels. The identification of sodium and/or calcium channels subtypes that are expressed almost exclusively on nocicpetors may provide a way of regulating the activity of exaggerated nociceptor function without altering other sensory modalities. Thus, the selective targeting of ion channels may represent a viable therapeutic target for the management of the neuropathic pain state, regardless of etiology.</p></div>","PeriodicalId":87195,"journal":{"name":"NeuroRx : the journal of the American Society for Experimental NeuroTherapeutics","volume":"2 4","pages":"Pages 650-661"},"PeriodicalIF":0.0,"publicationDate":"2005-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1602/neurorx.2.4.650","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25864691","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":"Animal Models of Kennedy Disease","authors":"Diane E. Merry","doi":"10.1602/neurorx.2.3.471","DOIUrl":"10.1602/neurorx.2.3.471","url":null,"abstract":"<div><p>Since the identification of the polyglutamine repeat expansion responsible for Kennedy disease (KD) more than a decade ago, several laboratories have created animal models for KD. The slowly progressive nature of KD, its X-linked dominant mode of inheritance, and its recently elucidated hormone dependence have made the modeling of this lower motor neuron disease uniquely challenging. Several models have been generated in which variations in specificity, age of onset, and rate of progression have been achieved. Animal models that precisely reproduce the motor neuron specificity, delayed onset, and slow progression of disease may not support preclinical therapeutics testing, whereas models with rapidly progressing symptoms may preclude the ability to fully elucidate pathogenic pathways. <em>Drosophila</em> models of KD provide unique opportunities to use the power of genetics to identify pathogenic pathways at work in KD. This paper reviews the new wealth of transgenic mouse and <em>Drosophila</em> models for KD. Whereas differences, primarily in neuropathological findings, exist in these models, these differences may be exploited to begin to elucidate the most relevant pathological features of KD.</p></div>","PeriodicalId":87195,"journal":{"name":"NeuroRx : the journal of the American Society for Experimental NeuroTherapeutics","volume":"2 3","pages":"Pages 471-479"},"PeriodicalIF":0.0,"publicationDate":"2005-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1602/neurorx.2.3.471","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25780643","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":"Drosophila Models of Neurodegenerative Disease","authors":"Tzu-Kang Sang,&nbsp;George R. Jackson","doi":"10.1602/neurorx.2.3.438","DOIUrl":"10.1602/neurorx.2.3.438","url":null,"abstract":"<div><p>Over the last two decades, a number of mutations have been identified that give rise to neurodegenerative disorders, including familial forms of Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Although in most cases sporadic cases vastly outnumber familial forms of such diseases, study of such inherited forms has the potential to provide powerful clues regarding the pathophysiological basis of neurodegeneration. One powerful approach to analyzing disease mechanisms is the development of transgenic animal models, most notably in the mouse. However, development and analysis of such models can be costly and time consuming. Development of improved transgenic technologies have contributed to the development of <em>Drosophila</em> models of a number of neurodegenerative disorders that have shown striking similarities to the human diseases. Moreover, genetic screens using such models have begun to unravel aspects of the pathophysiological basis of neurodegenerative disorders. Here, we provide a general overview of fly models pertinent to trinucleotide repeat expansion disorders, Alzheimer's, and Parkinson's diseases, and highlight key genetic modifiers that have been identified to date using such models.</p></div>","PeriodicalId":87195,"journal":{"name":"NeuroRx : the journal of the American Society for Experimental NeuroTherapeutics","volume":"2 3","pages":"Pages 438-446"},"PeriodicalIF":0.0,"publicationDate":"2005-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1602/neurorx.2.3.438","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25780714","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":"Toxin-Induced Models of Parkinson's Disease","authors":"Jordi Bové,&nbsp;Delphine Prou,&nbsp;Céline Perier,&nbsp;Dr. Serge Przedborski","doi":"10.1602/neurorx.2.3.484","DOIUrl":"10.1602/neurorx.2.3.484","url":null,"abstract":"<div><p>Parkinson's disease (PD) is a common neurodegenerative disease that appears essentially as a sporadic condition. It results mainly from the death of dopaminergic neurons in the substantia nigra. PD etiology remains mysterious, whereas its pathogenesis begins to be understood as a multifactorial cascade of deleterious factors. Most insights into PD pathogenesis come from investigations performed in experimental models of PD, especially those produced by neurotoxins. Although a host of natural and synthetic molecules do exert deleterious effects on dopaminergic neurons, only a handful are used in living laboratory animals to recapitulate some of the hallmarks of PD. In this review, we discuss what we believe are the four most popular parkinsonian neurotoxins, namely 6-hydroxydopamine (6-OHDA), 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), rotenone, and paraquat. The main goal is to provide an updated summary of the main characteristics of each of these four neurotoxins. However, we also try to provide the reader with an idea about the various strengths and the weaknesses of these neurotoxic models.</p></div>","PeriodicalId":87195,"journal":{"name":"NeuroRx : the journal of the American Society for Experimental NeuroTherapeutics","volume":"2 3","pages":"Pages 484-494"},"PeriodicalIF":0.0,"publicationDate":"2005-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1602/neurorx.2.3.484","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25780645","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":"Crossroads in Clinical Trials","authors":"Lisa J. Bain","doi":"10.1602/neurorx.2.3.525","DOIUrl":"10.1602/neurorx.2.3.525","url":null,"abstract":"If clinical trials are the engine that powers the development of new interventions for neurologic and other diseases, volunteer participants in those trials are the fuel. Yet as attendees at the Advocacy Forum of the 7th Annual Meeting of the American Society for Experimental NeuroTherapeutics (ASENT) heard, the fuel supply is low. “We are facing a national public health crisis. Trust and the incidence of volunteerism in clinical research is declining,” said Ken Getz, founder and chairman of the Center for Information and Study on Clinical Research Participation (CISCRP) and a Research Fellow at the Tufts Center for the Study of Drug Development. “Over the past 25 years, as the volume of clinical research has grown dramatically, we have as a community failed to engage the public and prospective volunteers in the process.”","PeriodicalId":87195,"journal":{"name":"NeuroRx : the journal of the American Society for Experimental NeuroTherapeutics","volume":"2 3","pages":"Pages 525-528"},"PeriodicalIF":0.0,"publicationDate":"2005-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1602/neurorx.2.3.525","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25780648","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":"Animal Models of Neurological Disorders","authors":"Marie-Françoise Chesselet (Guest Editor)","doi":"10.1602/neurorx.2.3.395","DOIUrl":"10.1602/neurorx.2.3.395","url":null,"abstract":"","PeriodicalId":87195,"journal":{"name":"NeuroRx : the journal of the American Society for Experimental NeuroTherapeutics","volume":"2 3","pages":"Page 395"},"PeriodicalIF":0.0,"publicationDate":"2005-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1602/neurorx.2.3.395","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25780710","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":"Animal Models of Focal Dystonia","authors":"Craig Evinger","doi":"10.1602/neurorx.2.3.513","DOIUrl":"10.1602/neurorx.2.3.513","url":null,"abstract":"<div><p>Animal models indicate that the abnormal movements of focal dystonia result from disordered sensorimotor integration. Sensorimotor integration involves a comparison of sensory information resulting from a movement with the sensory information expected from the movement. Unanticipated sensory signals identified by sensorimotor processing serve as signals to modify the ongoing movement or the planning for subsequent movements. Normally, this process is an effective mechanism to modify neural commands for ongoing movement or for movement planning. Animal models of the focal dystonias spasmodic torticollis, writer's cramp, and benign essential blepharospasm reveal different dysfunctions of sensorimotor integration through which dystonia can arise. Animal models of spasmodic torticollis demonstrate that modifications in a variety of regions are capable of creating abnormal head postures. These data indicate that disruption of neural signals in one structure may mutate the activity pattern of other elements of the neural circuits for movement. The animal model of writer's cramp demonstrates the importance of abnormal sensory processing in generating dystonic movements. Animal models of blepharospasm illustrate how disrupting motor adaptation can produce dystonia. Together, these models show mechanisms by which disruptions in sensorimotor integration can create dystonic movements.</p></div>","PeriodicalId":87195,"journal":{"name":"NeuroRx : the journal of the American Society for Experimental NeuroTherapeutics","volume":"2 3","pages":"Pages 513-524"},"PeriodicalIF":0.0,"publicationDate":"2005-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1602/neurorx.2.3.513","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25780585","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 Use of the R6 Transgenic Mouse Models of Huntington's Disease in Attempts to Develop Novel Therapeutic Strategies","authors":"Jia Yi Li,&nbsp;Natalija Popovic,&nbsp;Patrik Brundin","doi":"10.1602/neurorx.2.3.447","DOIUrl":"10.1602/neurorx.2.3.447","url":null,"abstract":"<div><p>Huntington's disease (HD) is a genetic neurodegenerative disorder. Since identification of the disease-causing gene in 1993, a number of genetically modified animal models of HD have been generated. The first transgenic mouse models, R6/1 and R6/2 lines, were established 8 years ago. The R6/2 mice have been the best characterized and the most widely used model to study pathogenesis of HD and therapeutic interventions. In the present review, we especially focus on the characteristics of R6 transgenic mouse models and, in greater detail, describe the different therapeutic strategies that have been tested in these mice. We also, at the end, critically assess the relevance of the HD mouse models compared with the human disease and discuss how they can be best used in the future.</p></div>","PeriodicalId":87195,"journal":{"name":"NeuroRx : the journal of the American Society for Experimental NeuroTherapeutics","volume":"2 3","pages":"Pages 447-464"},"PeriodicalIF":0.0,"publicationDate":"2005-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1602/neurorx.2.3.447","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25780642","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":"Abstracts from ASENT 2005 Annual Meeting","authors":"","doi":"10.1602/neurorx.2.3.533","DOIUrl":"10.1602/neurorx.2.3.533","url":null,"abstract":"s from the ASENT 2005 Annual Meeting March 3–5, 2005 Dopamine D3 Receptor Gene and Olanzapine Response in Schizophrenia J. P. Houston, S. C. Kirkwood, D. J. Fu, D. H. Adams, M. Farmen, A. C. M. Downing, N. Mukhopadhyay, and A. Breier Eli Lilly and Company, Indianapolis, Indiana Introduction: Several single nucleotide polymorphisms (SNPs) for dopamine D3 receptor gene (DRD-3) have been associated with differential anti-psychotic response, including ser-9-gly (rs6280). Methods: We assessed response in 82 patients with schizophrenia retrospectively genotyped for SNPs of neuroreceptor genes associated with olanzapine activity. Baseline-to-endpoint reduction in Positive and Negative Syndrome Scale (PANSS)positive sub-scores over 6 weeks of olanzapine treatment was assessed by repeated measures ANOVA. Categorical response was an endpoint rating of mild or minimal or less on each PANSS-positive item. Results: PANSS-positive reduction for 3 DRD-3 SNPs differed significantly by allelic and genotypic analyses respectively at chromosome 3 positions rs1800828 (p 0.238 and 0.0130), rs6280 (p 0.022 and 0.0045), and rs3732790 (dbSNP) (p 0.0006 and 0.0130). For each SNP, one homozygous genotype was associated with greatest response (N 10, 24, and 42, respectively) compared with the rest of the 82 patients. Of patients homozygous for the more responsive ser-9-gly SNP vs. others, 45.8% vs. 17.24% (p 0.0116) had at most minimal PANSSpositive symptoms, and 79.2% vs. 58.6% (p 0.127) had at most mild PANSS-positive symptoms at endpoint. Conclusions: DRD-3 receptor gene SNPs predicted statistically and clinically significant acute positive symptom reduction with olanzapine in substantial subsets of patients with schizophrenia. Differential Rates of Clinical Trial Discontinuation as a Measure of Treatment Effectiveness among Antipsychotic Medications B. J. Kinon, H. Liu-Seifert, and D. H. Adams Eli Lilly and Company, Indianapolis, Indiana Objective: Antipsychotic treatment discontinuation may be used to measure overall treatment effectiveness. Few studies systematically assess early treatment discontinuation differences among antipsychotics. We investigate olanzapine discontinuation compared to other atypical antipsychotics. Methods: A post hoc, pooled analysis of 4 randomized, 24–28 week, double-blind clinical trials included 822 olanzapine-treated and 805 risperidone-, quetiapine-, or ziprasidonetreated patients. Discontinuation rates and the probability of staying in treatment were compared between olanzapine and the other atypicals combined. Results: Poor response/symptom worsening was the primary reason for discontinuation regardless of medication. There was a significant treatment difference in the rate of discontinuation due to poor response/symptom worsening (olanzapine 14.23% vs. other atypicals 24.60%, p 0.001). There was no treatment difference in the rate of discontinuation due to medication intolerability (olanzapine 5.60% vs. other atypicals 7.45%, p 0.13)","PeriodicalId":87195,"journal":{"name":"NeuroRx : the journal of the American Society for Experimental NeuroTherapeutics","volume":"2 3","pages":"Pages 533-538"},"PeriodicalIF":0.0,"publicationDate":"2005-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1602/neurorx.2.3.533","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"67390970","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":"Genetic Mouse Models of Parkinsonism: Strengths and Limitations","authors":"Sheila M. Fleming,&nbsp;Pierre-Olivier Fernagut,&nbsp;Marie-Françoise Chesselet M.D., Ph.D","doi":"10.1602/neurorx.2.3.495","DOIUrl":"10.1602/neurorx.2.3.495","url":null,"abstract":"<div><p>Parkinson's disease (PD) is a progressive neurodegenerative disorder. Patients with PD display a combination of motor symptoms including resting tremor, rigidity, bradykinesia, and postural instability that worsen over time. These motor symptoms are related to the progressive loss of dopamine neurons in the substantia nigra pars compacta. PD patients also suffer from nonmotor symptoms that may precede the cardinal motor symptoms and that are likely related to pathology in other brain regions. Traditional toxin models of PD have focused on the nigrostriatal pathway and the loss of dopamine neurons in this region, and these models have been important in our understanding of PD and in the development of symptomatic treatments for the disease. However, they are limited in that they do not reproduce the full pathology and progression seen in PD, thus creating a need for better models. The recent discovery of specific genes causing familial forms of PD has contributed to the development of novel genetic mouse models of PD. This review discusses the validity, benefits, and limitations of these new models.</p></div>","PeriodicalId":87195,"journal":{"name":"NeuroRx : the journal of the American Society for Experimental NeuroTherapeutics","volume":"2 3","pages":"Pages 495-503"},"PeriodicalIF":0.0,"publicationDate":"2005-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1602/neurorx.2.3.495","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25780646","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}