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

{"title":"The Role of Microglia and NADPH Oxidase in Traumatic Spinal Cord Injury","authors":"K. Byrnes,&nbsp;B. Stoica,&nbsp;S. Di Giovanni,&nbsp;A. De Biase,&nbsp;S. Knoblach,&nbsp;E. Hoffman,&nbsp;A. Faden","doi":"10.1016/j.nurx.2006.05.014","DOIUrl":"10.1016/j.nurx.2006.05.014","url":null,"abstract":"<div><p>Spinal cord injury (SCI) results in delayed biochemical changes that contribute to secondary tissue damage and dysfunction. The microglial-induced inflammatory response, long implicated in secondary tissue damage after SCI, includes release of various factors known to be toxic to neurons. However, the response of microglia and their subsequent role remains controversial and poorly understood. The present study evaluated the acute and chronic gene expression profiles in rats after traumatic SCI. Using anchor genes selected from the literature because of their relationship to microglial-induced inflammation, high density microarray expression profiles were examined after contusion. Two temporally correlated clusters were identified: one was expressed immediately after injury, peaking between 4 and 24 hours and declining to baseline or below baseline levels; the second was expressed chronically after injury, and remained elevated up to 6 months after injury. Expression profiles for genes of each group were confirmed using real-time quantitative PCR, immunoblotting, and immunohistochemistry. One of the genes chronically expressed from 24 hours to 6 months postinjury was p22^phox, a component of the NADPH oxidase enzyme. To investigate the role of this chronically expressed gene after SCI and the effect of modification of its activity, the NADPH oxidase inhibitor apocynin was added to purified microglia cultures and microglial activation after LPS stimulation was investigated. Inhibition of p22^phox/NADPH oxidase resulted in significant suppression of microglial proliferation, nitric oxide production, and microglial-induced neurotoxicity. This study demonstrates the potential utility of microarray technology in identifying possible targets for future therapeutics. Additionally, it identifies p22^phox and NADPH as potential components of microglial-induced neurotoxicity, with implications for neuroprotective therapy.</p></div>","PeriodicalId":87195,"journal":{"name":"NeuroRx : the journal of the American Society for Experimental NeuroTherapeutics","volume":"3 3","pages":"Page 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.2006.05.014","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"54958891","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":"NIH Countermeasures Against Chemical Threats (CounterACT) Research Program","authors":"D. Jett","doi":"10.1016/j.nurx.2006.05.016","DOIUrl":"10.1016/j.nurx.2006.05.016","url":null,"abstract":"<div><p>The NIH is taking a leadership role in pursuing the development of new and improved medical countermeasures designed to prevent, diagnose, and treat the conditions caused by potential and existing chemical agents of terrorism. In addition, many of the same chemicals posing a threat as terrorist agents may also be released from transportation and storage facilities by industrial accidents or during a natural disaster. The NIH has developed a comprehensive Countermeasures Against Chemical Threats (CounterACT) Research Network that includes Research Centers of Excellence, individual research projects, Small Business Grants and Contracts, and other programs (see <span>http://www.ninds.nih.gov/funding/research/counterterrorism/index.htm</span><svg><path></path></svg><span><span>). The network will conduct basic, translational, and clinical research aimed at the discovery and/or identification of better therapeutic and diagnostic medical countermeasures against chemical threat agents. The overarching goal of this research program is to enhance our diagnostic and treatment response capabilities during an emergency. The civilian chemical threat spectrum now includes chemical warfare agents, toxic industrial chemicals, toxins and other chemicals. Many of the highest priority chemical threat agents target the nervous system and require new and improved neurotherapeutics that can be used as safe and rapid medical countermeasures during a mass casualty<span> situation. Examples of these chemical agents include anticholinesterase<span> nerve “gases” such as sarin or VX, metabolic poisons such as cyanide, and biological </span></span></span>neurotoxins<span> such as saxitoxin. The type of research supported within the CounterACT research program includes: (1) mechanistic research to identify targets for therapeutic/diagnostic development, (2) development of </span></span><em>in vitro</em> and animal models for efficacy screening of therapeutics and diagnostic tools, (3) efficacy screening of therapeutics/diagnostics using new and validated <em>in vitro</em> and animal models, (4) advanced efficacy studies with appropriate animal models including nonhuman primates, and (5) clinical studies, including trials, when appropriate. Special consideration will be given to research relevant to people who are particularly vulnerable, including the young, the elderly, and individuals with pre-existing medical conditions.</p><p>Interested parties are encouraged to contact Dr. David A. Jett, via email at <span><span>[email protected]</span></span><svg><path></path></svg> or by telephone at (301) 496-6035 for more information and funding opportunities within the NIH CounterACT research program.</p></div>","PeriodicalId":87195,"journal":{"name":"NeuroRx : the journal of the American Society for Experimental NeuroTherapeutics","volume":"3 3","pages":"Page 409"},"PeriodicalIF":0.0,"publicationDate":"2006-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.nurx.2006.05.016","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"54959052","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":"Hypothermic Neuroprotection","authors":"A.J. Gunn ,&nbsp;M. Thoresen","doi":"10.1016/j.nurx.2006.01.007","DOIUrl":"10.1016/j.nurx.2006.01.007","url":null,"abstract":"<div><p>The possibility that hypothermia during or after resuscitation from asphyxia at birth, or cardiac arrest in adults, might reduce evolving damage has tantalized clinicians for a very long time. It is now known that severe hypoxia-ischemia may not necessarily cause immediate cell death, but can precipitate a complex biochemical cascade leading to the delayed neuronal loss. Clinically and experimentally, the key phases of injury include a latent phase after reperfusion, with initial recovery of cerebral energy metabolism but EEG suppression, followed by a secondary phase characterized by accumulation of cytotoxins, seizures, cytotoxic edema, and failure of cerebral oxidative metabolism starting 6 to 15 h post insult. Although many of the secondary processes can be injurious, they appear to be primarily epiphenomena of the ‘execution’ phase of cell death. Studies designed around this conceptual framework have shown that moderate cerebral hypothermia initiated as early as possible before the onset of secondary deterioration, and continued for a sufficient duration in relation to the severity of the cerebral injury, has been associated with potent, long-lasting neuroprotection in both adult and perinatal species. Two large controlled trials, one of head cooling with mild hypothermia, and one of moderate whole body cooling have demonstrated that post resuscitation cooling is generally safe in intensive care, and reduces death or disability at 18 months of age after neonatal encephalopathy. These studies, however, show that only a subset of babies seemed to benefit. The challenge for the future is to find ways of improving the effectiveness of treatment.</p></div>","PeriodicalId":87195,"journal":{"name":"NeuroRx : the journal of the American Society for Experimental NeuroTherapeutics","volume":"3 2","pages":"Pages 154-169"},"PeriodicalIF":0.0,"publicationDate":"2006-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.nurx.2006.01.007","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25920166","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 Pharmacological Treatment Options for Pediatric Migraine: An Evidence-Based Appraisal","authors":"Donald W. Lewis MD,&nbsp;Paul Winner DO","doi":"10.1016/j.nurx.2006.01.002","DOIUrl":"10.1016/j.nurx.2006.01.002","url":null,"abstract":"<div><p>The treatment of children and adolescents who suffer from migraine headaches must be individually tailored, flexible, and balanced with a blend of bio-behavioral measures, agents for acute treatment and, if needed, daily preventive medicines. While controlled data is limited, there is now enough evidence available to provide a rational framework to build treatment plans appropriate for the pediatric population. Essentially, the pharmacological management of pediatric migraine divides into agents for the acute attacks and agents used daily to prevent or reduce the frequency of attacks. For the acute treatment, the most rigorously studied agents are ibuprofen, acetaminophen, and the nasal spray forms of sumatriptan and zolmitriptan, all of which have shown both safety and efficacy in controlled trials. For preventive treatment the calcium channel blocker flunarezine has the best efficacy profile in controlled trials, but is not available in the U.S. A growing body of data, mostly uncontrolled, is emerging regarding the use of several anti-epileptic agents (e.g. topiramate, disodium valproate, levateracetam), as well as the antihistamine cyproheptadine and the anti-depressant amitriptyline.</p></div>","PeriodicalId":87195,"journal":{"name":"NeuroRx : the journal of the American Society for Experimental NeuroTherapeutics","volume":"3 2","pages":"Pages 181-191"},"PeriodicalIF":0.0,"publicationDate":"2006-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.nurx.2006.01.002","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25920167","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":"Traumatic Injury to the Immature Brain: Inflammation, Oxidative Injury, and Iron-Mediated Damage as Potential Therapeutic Targets","authors":"Mathew B. Potts ,&nbsp;Seong-Eun Koh ,&nbsp;William D. Whetstone ,&nbsp;Breset A. Walker ,&nbsp;Tomoko Yoneyama ,&nbsp;Catherine P. Claus ,&nbsp;Hovhannes M. Manvelyan ,&nbsp;Linda J. Noble-Haeusslein","doi":"10.1016/j.nurx.2006.01.006","DOIUrl":"10.1016/j.nurx.2006.01.006","url":null,"abstract":"<div><p>Traumatic brain injury (TBI) is the leading cause of morbidity and mortality among children and both clinical and experimental data reveal that the immature brain is unique in its response and vulnerability to TBI compared to the adult brain. Current therapies for pediatric TBI focus on physiologic derangements and are based primarily on adult data. However, it is now evident that secondary biochemical perturbations play an important role in the pathobiology of pediatric TBI and may provide specific therapeutic targets for the treatment of the head-injured child. In this review, we discuss three specific components of the secondary pathogenesis of pediatric TBI – inflammation, oxidative injury, and iron-induced damage – and potential therapeutic strategies associated with each. The inflammatory response in the immature brain is more robust than in the adult and characterized by greater disruption of the blood-brain barrier and elaboration of cytokines. The immature brain also has a muted response to oxidative stress compared to the adult due to inadequate expression of certain antioxidant molecules. In addition, the developing brain is less able to detoxify free iron after TBI-induced hemorrhage and cell death. These processes thus provide potential therapeutic targets that may be tailored to pediatric TBI, including anti-inflammatory agents such as minocycline, antioxidants such as glutathione peroxidase, and the iron chelator deferoxamine.</p></div>","PeriodicalId":87195,"journal":{"name":"NeuroRx : the journal of the American Society for Experimental NeuroTherapeutics","volume":"3 2","pages":"Pages 143-153"},"PeriodicalIF":0.0,"publicationDate":"2006-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.nurx.2006.01.006","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25920164","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":"Therapy of X-Linked Adrenoleukodystrophy","authors":"Hugo W. Moser M.D","doi":"10.1016/j.nurx.2006.01.004","DOIUrl":"10.1016/j.nurx.2006.01.004","url":null,"abstract":"<div><p>Current therapies for X-linked adrenoleukodystrophy (X-ALD) include replacement therapy with adrenal steroids, which is mandatory for all patients with impaired adrenal function but does not alter neurological progression significantly; dietary therapy with “Lorenzo’s Oil,” which appears to have a preventive effect in asymptomatic boys whose brain MRI is normal; and hematopoietic stem cell transplantation in patients in the early stage of the cerebral inflammatory phenotype. Application of these interventions requires careful assessment of the patients’ phenotype, which often changes over time. Family screening provides important opportunities for disease prevention.</p></div>","PeriodicalId":87195,"journal":{"name":"NeuroRx : the journal of the American Society for Experimental NeuroTherapeutics","volume":"3 2","pages":"Pages 246-253"},"PeriodicalIF":0.0,"publicationDate":"2006-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.nurx.2006.01.004","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25919539","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":"Intervention for Autistic Spectrum Disorders","authors":"Pauline A. Filipek ,&nbsp;Robin Steinberg-Epstein ,&nbsp;Teri M. Book","doi":"10.1016/j.nurx.2006.01.014","DOIUrl":"10.1016/j.nurx.2006.01.014","url":null,"abstract":"<div><h3>Summary</h3><p>A comprehensive approach to the assessment of any child with autism must be matched specifically to each individual child and family. This premise holds for medical therapies and special education services as well as psychopharmacologic interventions. Behavioral, as opposed to pharmacologic, treatment is the hallmark of effective intervention for autism. Physicians involved in the care of children with autism need to become familiar with educational law and intervention recommendations. Goals should include improved functional verbal and nonverbal communication and social skills, increased engagement in developmentally appropriate activities, improved fine and gross motor skills, and the development of independent academic and organizations skills, as well as replacement of problem behaviors with developmentally appropriate behaviors.. Medicating children with autism is difficult, but is often necessary for chronic behavioral difficulties. In the absence of clear and present guidelines, we have attempted to use evidence and clinical experience to suggest an algorithm based on symptom clusters. Although children with autism may be responsive to medications at lower doses and more susceptible to side effects than other children, medical intervention can produce a significant improvement in the quality of life for the child and family. Careful thought leading to correct identification of target behaviors can appropriately direct better alternatives for medication. Although these approaches are costly and time-consuming endeavors, the expenditure of such efforts is the only available pathway to improve the potential outcomes for individuals with autism as well as decrease the lifetime societal costs for each individual.</p></div>","PeriodicalId":87195,"journal":{"name":"NeuroRx : the journal of the American Society for Experimental NeuroTherapeutics","volume":"3 2","pages":"Pages 207-216"},"PeriodicalIF":0.0,"publicationDate":"2006-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.nurx.2006.01.014","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25920168","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":"Therapeutics in Duchenne Muscular Dystrophy","authors":"Jonathan B. Strober MD","doi":"10.1016/j.nurx.2006.01.005","DOIUrl":"10.1016/j.nurx.2006.01.005","url":null,"abstract":"<div><h3>Summary</h3><p>Duchenne muscular dystrophy (DMD) is a fatal disorder affecting approximately 1 in 3500 live born males, characterized by progressive muscle weakness. Several different strategies are being investigated in developing a cure for this disorder. Until a cure is found, therapeutic and supportive care is essential in preventing complications and improving the afflicted child’s quality of life. Currently, corticosteroids are the only class of drug that has been extensively studied in this condition, with controversy existing over the use of these drugs, especially in light of the multiple side effects that may occur. The use of nutritional supplements has expanded in recent years as researchers improve our abilities to use gene and stem cell therapies, which will hopefully lead to a cure soon. This article discusses the importance of therapeutic interventions in children with DMD, the current debate over the use of corticosteroids to treat this disease, the growing use of natural supplements as a new means of treating these boys and provides an update on the current state of gene and stem cell therapies.</p></div>","PeriodicalId":87195,"journal":{"name":"NeuroRx : the journal of the American Society for Experimental NeuroTherapeutics","volume":"3 2","pages":"Pages 225-234"},"PeriodicalIF":0.0,"publicationDate":"2006-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.nurx.2006.01.005","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25919537","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":"Advances in Treatment of Pediatric Brain Tumors","authors":"Patricia L. Robertson M.D.","doi":"10.1016/j.nurx.2006.01.001","DOIUrl":"10.1016/j.nurx.2006.01.001","url":null,"abstract":"<div><p>The long-term survival of children with brain tumor has improved considerably in the last three decades, owing to advances in neuroimaging, neurosurgical, and radiation therapy modalities, coupled with the application of conventional chemotherapy. MRI, MR spectroscopy and diffusion-weighted MRI have contributed to more accurate diagnosis, prognostication and better treatment planning. Neurosurgical treatment has been advanced by the use of functional MRI, and intraoperative image-guided stereotactic techniques and electrophysiologic monitoring. The use of 3-D conformal and intensity-modulated radiation therapy, stereotactic radiosurgery, and radiosensitizing agents has made radiation therapy safer and more effective. Conventional chemotherapy, administered either alone or combined with radiation therapy has improved survival and quality of life of children with brain tumors. These improved outcomes have also occurred, due, in part, to their treatment on collaborative national and international studies. Recent promising diagnostic and therapeutic strategies have resulted from advances in understanding molecular brain tumor biology. Important new approaches include the refinement of drug-delivery strategies, the evaluation of biologic markers to stratify patients for optimal treatment and to exploit these molecular differences using “targeted” therapeutic strategies. These approaches include blocking tumor cell drug resistance mechanisms, immunotherapy, inhibition of molecular signal transduction pathways important in tumorigenesis, anti-angiogenic therapy, and gene therapy. The thrust of such approaches for children with brain tumors is especially directed at reducing the toxicity of therapy and improving quality-of-life, as well as increasing disease-free survival.</p></div>","PeriodicalId":87195,"journal":{"name":"NeuroRx : the journal of the American Society for Experimental NeuroTherapeutics","volume":"3 2","pages":"Pages 276-291"},"PeriodicalIF":0.0,"publicationDate":"2006-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.nurx.2006.01.001","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25919542","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":"Pediatric Multiple Sclerosis","authors":"Dorothée Chabas,&nbsp;Ari J. Green,&nbsp;Emmanuelle Waubant","doi":"10.1016/j.nurx.2006.01.011","DOIUrl":"10.1016/j.nurx.2006.01.011","url":null,"abstract":"<div><h3>Summary</h3><p>Multiple sclerosis (MS) occurs at all ages of the pediatric population. Childhood MS may represent up to 10% of all MS cases. Establishing the diagnosis of MS in a child is complicated by the limited diagnostic criteria and the possibility of significant clinical and magnetic resonance imaging (MRI) overlap with acute disseminated encephalomyelitis and other pediatric diseases. Although the clinical profile of MS appears similar to that seen in adults, several features may differ and specific issues arise in children. Sex ratios are different between young children with MS and adolescents—implicating a role for sex hormones in disease pathogenesis and/or modification of disease expression. Younger patients with MS are more likely to have seizures, brainstem, and cerebellar symptoms than adults. Children with MS may have fewer T2 hyperintense areas on MRI scans, therefore not meeting MRI criteria established for adults. It is possible that the pediatric MS course is more indolent than in adult patients but the disease may lead to significant disability at a younger age, e.g., while patients are students, young professionals, or want to start a family. There has been no controlled clinical trial in children with disease modifying therapies approved for adult MS due to the limited number of patients under the age of 18 years compared with the adult contingent. As a result, children are receiving adult therapies in an arbitrary manner and our understanding of pediatric treatment effect and tolerability is limited. Available data on tolerability of approved drugs for adults is reviewed.</p></div>","PeriodicalId":87195,"journal":{"name":"NeuroRx : the journal of the American Society for Experimental NeuroTherapeutics","volume":"3 2","pages":"Pages 264-275"},"PeriodicalIF":0.0,"publicationDate":"2006-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.nurx.2006.01.011","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25919541","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}