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

{"title":"Cardiovascular Effects of Duloxetine: Preclinical and Clinical Findings","authors":"M. Detke,&nbsp;S. Iyengar,&nbsp;J. Henck,&nbsp;F. Bymaster,&nbsp;J. Callaghan,&nbsp;M. Knadler,&nbsp;A. Chappell,&nbsp;J. Wernicke,&nbsp;M. Thase","doi":"10.1016/j.nurx.2006.05.012","DOIUrl":"10.1016/j.nurx.2006.05.012","url":null,"abstract":"<div><h3>Background</h3><p>We summarize cardiac effects of duloxetine based on <em>in vitro</em> and animal studies, and human trials including higher doses and chronic treatment.</p></div><div><h3>Methods</h3><p>The affinity of duloxetine for cardiac ion channels was determined <em>in vitro</em> in a stably expressed human cell line. Cardiovascular parameters were evaluated in single- and repeat-dose studies in rats and dogs. In humans, cardiovascular safety was analyzed in (1) healthy volunteers receiving duloxetine up to 400 mg/d; (2) 8 placebo-controlled MDD trials of duloxetine (40-120 mg/d) for 8-9 weeks, compared with paroxetine or fluoxetine in 6 trials; (3) 52-week, open-label duloxetine study (80-120 mg/d); (4) 12-week MDD study of duloxetine versus venlafaxine.</p></div><div><h3>Results</h3><p>Duloxetine, at the maximum unbound plasma concentration observed clinically, had no adverse effect on the human cardiac ion channels tested <em>in vitro</em>. Blood pressure (BP) and heart rate (HR) were not significantly altered in conscious animals following single oral doses of 7 or 20 mg/kg in rats and 10 mg/kg in dogs. Cardiac rhythm, conduction, and HR were unaffected in dogs by up to 1 year of treatment with 3, 10, or 30 mg/kg. In healthy volunteers, duloxetine had a modest effect on BP and HR elevation with no prolongation of QTc interval. In patients with MDD, small increases in HR and BP were observed. Although there were statistically significant differences in HR from baseline to endpoint between duloxetine <em>versus</em> fluoxetine or paroxetine, changes were clinically insignificant. In the study of duloxetine (60-120 mg/day) and venlafaxine (75-225 mg/day) in MDD, no statistically significant differences occurred in elevated HR and BP except for significantly more venlafaxine patients with sustained systolic BP during the first 6 weeks.</p></div><div><h3>Discussion</h3><p>Consistent with the lack of effect on human cardiac ion channel binding <em>in vitro</em>, and the lack of effect on conduction parameters in repeat-dose dog studies, no QTc prolongation was seen in humans. Consistent with the HR and BP findings in animals, humans had a few small effects with these measures. In summary, duloxetine has a good cardiovascular safety profile, possibly due to its lack of affinity for crucial cardiac ion channels and/or other unknown factors.</p><p>Funding provided by Eli Lilly and Company.</p></div>","PeriodicalId":87195,"journal":{"name":"NeuroRx : the journal of the American Society for Experimental NeuroTherapeutics","volume":"3 3","pages":"Pages 407-408"},"PeriodicalIF":0.0,"publicationDate":"2006-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.nurx.2006.05.012","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"54958804","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":"Antiepileptic Drugs Do Not Affect 5-HT1A Receptor Binding Measured by Positron Emission Topography","authors":"W. Theodore,&nbsp;G. Giovacchini,&nbsp;A. Bagic,&nbsp;P. Herscovitch,&nbsp;R. Carson","doi":"10.1016/j.nurx.2006.05.019","DOIUrl":"10.1016/j.nurx.2006.05.019","url":null,"abstract":"<div><h3>Objective</h3><p>To study the effect of antiepileptic drugs on 5-HT_1A receptor binding in patients with temporal lobe epilepsy.</p></div><div><h3>Background</h3><p>5-HT_1A receptor binding is reduced in patients with temporal lobe epilepsy. Animal models show serotonergic effects of antipepileptic drugs including carbamazepine and lamotrigine.</p></div><div><h3>Methods</h3><p>We studied 31 patients and 10 normal controls. Patients with structural lesions, progressive neurological disorders, or taking other medications were excluded. None had a seizure for at least two days before PET. [¹⁸F]FCWAY PET was performed on a GE Advance scanner with continuous EEG monitoring. Functional images of the distribution volume (<em>V</em>) were generated. Anatomic regions of interest were applied to coregistered PET images, after correction for partial volume effect.</p></div><div><h3>Results</h3><p>Patients had significantly higher [¹⁸F]FCWAY free fraction (<em>f</em>₁) than controls. 5HT1A receptor binding was reduced in temporal lobe epileptic foci after partial volume correction. There were no AED effects on interictal [¹⁸F]FCWAY binding after correction for plasma free fraction. [¹⁸F]FCWAY <em>V</em>/<em>f</em>₁ reduction in epileptic foci was not affected by AEDs.</p></div><div><h3>Conclusions</h3><p>Antiepileptic drugs do not appear to have significant effects on 5HT1A receptor binding. Plasma free fractions should be measured when PET receptor studies are performed in patients with epilepsy.</p></div>","PeriodicalId":87195,"journal":{"name":"NeuroRx : the journal of the American Society for Experimental NeuroTherapeutics","volume":"3 3","pages":"Page 410"},"PeriodicalIF":0.0,"publicationDate":"2006-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.nurx.2006.05.019","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"54959145","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":"Survey on Patient and Physician Attitudes about Parkinson Clinical Trials","authors":"","doi":"10.1016/j.nurx.2006.05.033","DOIUrl":"https://doi.org/10.1016/j.nurx.2006.05.033","url":null,"abstract":"<div><p>In March 2005, Harris Interactive® completed a study examining physicians’ and patients’ attitudes towards Parkinson’s disease clinical trials. The study was commissioned on behalf of <em>PDtrials*</em> by the Michael J. Fox Foundation for Parkinson’s Research.</p><p>Five hundred physicians (250 primary care physicians/gerontologists and 250 neurologists) and 518 people with Parkinson’s participated in the study. Nearly 80% of patients surveyed stated that they would be somewhat, very, or extremely likely to participate in a clinical trial if one were available in their area. However, seven in ten are not at all or not very aware of clinical trials and only 11% reported that their doctor ever suggested that they participate in a trial.</p><p>The survey also found that, among physicians who treat people with Parkinson’s, 96% agree that clinical trials are necessary to find better treatments for the disease. However, the majority have discussed clinical trials with just 10% or less of their patients and never referred a patient to a clinical trial.</p><p>Only 14% of primary care physicians, 21% of neurologists, and 18% of patients surveyed indicated that they are somewhat or very satisfied with the amount of information available about clinical trials for Parkinson’s disease.</p><p>The Harris Interactive study confirms the assumption that there is a clinical trials information gap and the critical role of <em>PDtrials</em>, a national initiative dedicated to increasing education and awareness about clinical research by providing information to help people with Parkinson’s learn and make informed decisions about participating in clinical trials.</p><p>*<em>PDtrials</em> is led by the Parkinson’s Disease Foundation in collaboration with the American Parkinson Disease Association, The Michael J. Fox Foundation for Parkinson’s Research, the National Parkinson Foundation, the Parkinson’s Action Network, The Parkinson Alliance and WE MOVE. The campaign is advised by the National Institute of Neurological Disorders and Stroke (NIH), the Parkinson Study Group, the Parkinson Pipeline Project and the Parkinson’s Institute.</p></div>","PeriodicalId":87195,"journal":{"name":"NeuroRx : the journal of the American Society for Experimental NeuroTherapeutics","volume":"3 3","pages":"Page 415"},"PeriodicalIF":0.0,"publicationDate":"2006-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.nurx.2006.05.033","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138305833","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":"Evaluation of Polyethylene Glycol as a Neuroprotective Strategy for Acute Spinal Cord Injury","authors":"D. Baptiste,&nbsp;M. Fehlings","doi":"10.1016/j.nurx.2006.05.028","DOIUrl":"10.1016/j.nurx.2006.05.028","url":null,"abstract":"<div><p>The pathophysiology of traumatic spinal cord injury (SCI) involves abnormal activation of the proteolytical enzymes calpain-1 and caspase-3. In the present study we examined the effect of a single intravenous injection of the putative neuroprotective compound polyethylene glycol (PEG) on cytoskeletal protection following cervical SCI in mature Wistar rats.</p><p>PEG (2000 Da; 30% w/w in sterile lactate ringers (SLR)) or SLR vehicle was administered in the rat tail vein at times 1 or 4 hours after a 35g clip extradural compression injury at C7/T1. To assess the neuroprotective efficacy of PEG in the acute setting postinjury, we measured the levels of dephosphorylated neurofilament 200 (NF200) together with the accumulation of spectrin break down product 150 (SBDP 150) at times 2, 4, 8, or 24 hours post-SCI using Western blot approaches to assess calpain-1 activity. Western blots were also used to assess caspase-3 activity at 24 hours post-SCI via measurement of the accumulation of processed 17-kDa caspase-3 fragments. The mean ± SEM relative optical density values for dephosphorylated NF200 corresponding to the SLR and PEG treatments at times 2, 4, 8, and 24 hours post-SCI were 0.64 ± 0.049 and 0.48 ± 0.166, 0.3 ± 0.028 and 0.48 ± 0.134, 0.33 ± 0.077 and 0.46 ± 0.076, and 0.24 ± 0.018 and 0.38 ± 0.040, respectively. Moreover, the levels of dephosphorylated NF200 were significantly greater following PEG-treatment by 24 hours post-SCI (<em>p</em> = 0.0362). Moreover, PEG-mediated preservation of dephosphorylated NF200 was correlated with reduced calpain-1 activity at 2 and 4 hours post-SCI. Furthermore, PEG treatment resulted in reduced levels of accumulated 17-kDa caspase-3 fragments.</p><p>In conclusion, these data obtained in a clinically relevant model of cervical SCI suggest that PEG protects the injured cord by preserving cytoskeletal protein NF200, possibly through reducing calpain-1 and caspase-3 activities. Moreover, the protective effects afforded by PEG may occur within a relevant therapeutic window of opportunity, as the efficacy of PEG treatments occurred even when the drug was administered 4 hours postinjury. These data are critical in establishing the therapeutic potential for translation of PEG into the clinical arena.</p></div>","PeriodicalId":87195,"journal":{"name":"NeuroRx : the journal of the American Society for Experimental NeuroTherapeutics","volume":"3 3","pages":"Page 413"},"PeriodicalIF":0.0,"publicationDate":"2006-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.nurx.2006.05.028","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"54959755","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":"An Analysis of Correlations Among 4 Outcome Scales Employed in Clinical Trials of Patients With Major Depressive Disorder","authors":"Q. Jiang,&nbsp;S. Ahmed,&nbsp;R. Pedersen,&nbsp;J. Musgnung,&nbsp;R. Entsuah","doi":"10.1016/j.nurx.2006.05.025","DOIUrl":"10.1016/j.nurx.2006.05.025","url":null,"abstract":"<div><h3>Introduction</h3><p>The objective of this analysis was to identify and assess any correlations among 4 widely used rating scales—the17-item Hamilton Depression Rating Scale (HAM-D₁₇), the Montgomery-Asberg Depression Scale (MADRS), the Clinical Global Impression-Severity (CGI-S) and -Improvement (CGI-I)—in clinical trials with patients with major depressive disorder (MDD).</p></div><div><h3>Methods</h3><p>Data from 22 randomized, double-blind, placebo-controlled venlafaxine studies (10 ER studies, 11 IR studies, 1 with both formulations) in adult patients with MDD were pooled and examined from baseline through the first 8 weeks of treatment. For all rating scales, Pearson correlation coefficients were calculated between change scores and by treatment arm for patients at each visit. Correlations between binary outcomes (response defined as CGI-I and CGI-S ≤ 2, 50% decrease in HAM-D₁₇ and MADRS) were determined.</p></div><div><h3>Results</h3><p>At pretreatment visits, for the HAM-D₁₇, MADRS, and CGI-S, respectively, 5117, 4871, and 5103 observations were available, with mean scores of 23.0, 29.1, and 4.4. Pretreatment correlations ranged from 0.52 (CGI-S and HAM-D₁₇), 0.53 (CGI-S and MADRS), and 0.62 (HAM-D₁₇ and MADRS). Correlations between scales increased at each visit and, at 8 weeks, ranged from 0.87 (CGI-S and CGI-I) to 0.93 (HAM-D₁₇ and MADRS). Correlation coefficients in treatment arm subgroup analyses and between change scores were comparable. Correlation coefficients between binary outcomes were lower, ranging from 0.42 (CGI-I and CGI-S) to 0.61 (HAM-D₁₇ and MADRS) at week 1 and from 0.61 (CGI-I and CGI-S) to 0.81 (HAM-D₁₇ and MADRS) at week 8. All correlation coefficients were significant (<em>P</em> &lt; 0.0001).</p></div><div><h3>Conclusions</h3><p>Correlations among the four commonly used outcome scales were high; however, correlations among binary outcomes based on the scales were lower. The highest correlations were between the HAM-D₁₇ and the MADRS, which share several items and have similar modes of administration and rating. The modest but consistently lower correlations between the CGI-S and CGI-I scales were unexpected because these scales are sometimes considered interchangeable.</p></div>","PeriodicalId":87195,"journal":{"name":"NeuroRx : the journal of the American Society for Experimental NeuroTherapeutics","volume":"3 3","pages":"Pages 411-412"},"PeriodicalIF":0.0,"publicationDate":"2006-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.nurx.2006.05.025","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"54959551","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":"Liquid Chromatography with Tandem Mass Spectrometry-Based Proteomic Discovery in Aging and Alzheimer’s Disease","authors":"Thomas J. Montine,&nbsp;Randall L. Woltjer,&nbsp;Catherine Pan,&nbsp;Kathleen S. Montine,&nbsp;Jing Zhang","doi":"10.1016/j.nurx.2006.05.002","DOIUrl":"10.1016/j.nurx.2006.05.002","url":null,"abstract":"<div><h3>Summary</h3><p>Systems biology offers enormous potential to understand the complexity of human brain aging and neurodegenerative diseases. Proteomics has an important role in these investigations because of its unique strengths and because of the potential central pathogenic contribution of pathological protein to several of these diseases. Here we have reviewed the methods and presented some examples of liquid chromatography–electrospray ionization–tandem mass spectrometry–based proteomics, with and without quantification using isotope-coded affinity tags, in the investigation of aging and Alzheimer’s disease. As protocols and methods for improved quantitative high-throughput proteomics constantly improve, this approach will likely continue to provide deeper insight into human brain aging and neurodegenerative diseases.</p></div>","PeriodicalId":87195,"journal":{"name":"NeuroRx : the journal of the American Society for Experimental NeuroTherapeutics","volume":"3 3","pages":"Pages 336-343"},"PeriodicalIF":0.0,"publicationDate":"2006-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.nurx.2006.05.002","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"26122302","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":"Utility of Correlation Measures in Analysis of Gene Expression","authors":"Anthony Almudevar ,&nbsp;Lev B. Klebanov ,&nbsp;Xing Qiu ,&nbsp;Peter Salzman ,&nbsp;Andrei Y. Yakovlev","doi":"10.1016/j.nurx.2006.05.037","DOIUrl":"10.1016/j.nurx.2006.05.037","url":null,"abstract":"<div><h3>Summary</h3><p>The role of the correlation structure of gene expression data are two-fold: It is a source of complications and useful information at the same time. Ignoring the strong stochastic dependence between gene expression levels in statistical methodologies for microarray data analysis may deteriorate their performance. However, there is a host of valuable information in the correlation structure that deserves a closer look. A proper use of correlation measures can remedy deficiencies of currently practiced methods that are focused too heavily on strong effects in terms of differential expression of genes. The present paper discusses the utility of correlation measures in microarray data analysis and gene regulatory network reconstruction, along with various pitfalls in both research areas that have been uncovered in methodological studies. These issues have broad applicability to all genomic studies examining the biology, diagnosis, and treatment of neurological disorders.</p></div>","PeriodicalId":87195,"journal":{"name":"NeuroRx : the journal of the American Society for Experimental NeuroTherapeutics","volume":"3 3","pages":"Pages 384-395"},"PeriodicalIF":0.0,"publicationDate":"2006-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.nurx.2006.05.037","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"26122306","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 Cognitive Phenotype of Down Syndrome: Insights from Intracellular Network Analysis","authors":"Avi Ma’ayan ,&nbsp;Katheleen Gardiner ,&nbsp;Ravi Iyengar","doi":"10.1016/j.nurx.2006.05.036","DOIUrl":"10.1016/j.nurx.2006.05.036","url":null,"abstract":"<div><h3>Summary</h3><p>Down syndrome (DS) is caused by trisomy of chromosome 21. All individuals with DS exhibit some level of cognitive dysfunction. It is generally accepted that these abnormalities are a result of the upregulation of genes encoded by chromosome 21. Many chromosome 21 proteins are known or predicted to function in critical neurological processes, but typically they function as modulators of these processes, not as key regulators. Thus, upregulation in DS is expected to cause only modest perturbations of normal processes. Systematic approaches such as intracellular network construction and analysis have not been generally applied in DS research. Networks can be assembled from high-throughput experiments or by text-mining of experimental literature. We survey some new developments in constructing such networks, focusing on newly developed network analysis methodologies. We propose how these methods could be integrated with creation and manipulation of mouse models of DS to advance our understanding of the perturbed cell signaling pathways in DS. This understanding could lead to potential therapeutics.</p></div>","PeriodicalId":87195,"journal":{"name":"NeuroRx : the journal of the American Society for Experimental NeuroTherapeutics","volume":"3 3","pages":"Pages 396-406"},"PeriodicalIF":0.0,"publicationDate":"2006-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.nurx.2006.05.036","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"26122308","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":"Evaluation of Duloxetine Effectiveness in the Management of DPNP with Respect to Baseline Characteristics","authors":"Y. Pritchett,&nbsp;J. Xu,&nbsp;B. Rotz,&nbsp;A. Chappell,&nbsp;J. Wernicke","doi":"10.1016/j.nurx.2006.05.010","DOIUrl":"10.1016/j.nurx.2006.05.010","url":null,"abstract":"<div><h3>Objective</h3><p>To examine impact of age, gender, origin, duration of diabetic neuropathy, type of diabetes, and pain severity on treatment outcome of duloxetine (DLX) in the management of diabetic peripheral neuropathic pain (DPNP).</p></div><div><h3>Methods</h3><p>Data from 3 12-week, multicenter, double-blind, placebo-controlled studies (1-3) were pooled. In Study 1, 457 patients with DPNP were randomly assigned to DLX 20 mg QD, 60 mg QD, 60 mg BID, or placebo. In Studies 2 and 3, 334 and 348 patients, respectively, were randomly assigned to DLX 60 mg QD, 60 mg BID, or placebo. DLX 20 mg QD was not included in the analyses due to its ineffectiveness found in Study 1. Primary efficacy measure was the weekly mean score of 24-Hour Average Pain Severity collected by patient’s diary on 11-point Likert scale. Subgroup impact was evaluated for combined DLX doses with references to placebo group.</p></div><div><h3>Results</h3><p>DLX 60 mg QD and 60 mg BID significantly improved weekly mean scores of 24-Hour Average Pain Severity in each study (<em>p</em> &lt; 0.001). There were no statistical significant (<em>p</em> &lt; 0.1) interactions of treatment with age (&lt;65 or ≥65), gender (male or female), origin (Caucasian or other), duration of diabetic neuropathy (&lt;2, 2–&lt;6, or ≥6 years), type of diabetes (Type I or Type II) with an exception for pain severity (BPI average pain &lt;6 or ≥6). DLX effect was observed for both severe and less severe groups with more separation on the severe group. The superiority of DLX over placebo was observed within almost each of the stratum with the exception of Type I patient group, which demonstrated the advantage of DLX treatment with <em>p</em> = 0.123. The magnitude of change was slightly higher in Type II patients than in those with Type I; however, Type I group sample size was much smaller which may account for the statistical insignificance. DLX was safe and well tolerated with less than 20% discontinuation due to AEs, while showing no interference with diabetic control.</p></div><div><h3>Conclusion</h3><p>These studies suggested that DLX was effective and safe in the treatment of DPNP, and its effectiveness was invariant with respect to baseline conditions.</p><p>Funding provided by Eli Lilly and Company.</p></div>","PeriodicalId":87195,"journal":{"name":"NeuroRx : the journal of the American Society for Experimental NeuroTherapeutics","volume":"3 3","pages":"Page 407"},"PeriodicalIF":0.0,"publicationDate":"2006-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.nurx.2006.05.010","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"54958678","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":"Characterization of Soluble Fas Receptor as a Neuroprotective Agent following Acute Spinal Cord Injury","authors":"S. Robins,&nbsp;M. Fehlings","doi":"10.1016/j.nurx.2006.05.027","DOIUrl":"10.1016/j.nurx.2006.05.027","url":null,"abstract":"<div><p>Spinal cord injury (SCI) is a devastating form of neurotrauma, affecting any population, and is a major cause of morbidity and mortality in children and young adults. The pathophysiology of SCI consists of a primary mechanical insult that triggers a secondary cascade of cellular damage. A key event in this pathology is delayed apoptotic cell death at and adjacent to the injury site, leading to progressive neurodegeneration. Several molecular pathways have been attributed to apoptosis after SCI. The Fas receptor pathway plays an integral role in the initiation of apoptosis through receptor-ligand binding of target cells and has been observed after CNS trauma and in several neurodegenerative diseases. Previous work in our lab has revealed that subarachnoid infusion of a soluble form of the Fas receptor (sFasR) is neuroprotective, as shown by long-term behavioral evaluation and neuronal tracing. We hypothesize that inhibition of the Fas receptor pathway is neuroprotective in the acutely injured spinal cord and results in reduction of neuronal and oligodendroglial cell death and enhanced axonal integrity across the lesion site. In this study, we used a 35g and 50g clip compression injury model at C7-T1 followed by intrathecal administration of sFasR using osmotic minipumps and catheterization at the site of injury. Using Western blotting and immunohistochemistry at 5 and 7 days following injury, our results reveal enhanced axonal preservation, enhanced survival of oligodendrocytes, and reduction in apoptotic cell death in sFasR-treated animals compared with controls. These results indicate that disruption of the Fas pathway in acute injury can lead to enhanced axonal and tissue preservation, which mirrors well with the improved long-term recovery observed previously in our lab. Moreover, this work shows the potential of soluble Fas receptor administration to be a therapeutic option for individuals suffering from acute SCI.</p></div>","PeriodicalId":87195,"journal":{"name":"NeuroRx : the journal of the American Society for Experimental NeuroTherapeutics","volume":"3 3","pages":"Page 412"},"PeriodicalIF":0.0,"publicationDate":"2006-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.nurx.2006.05.027","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"54959734","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}