Abstract:
OBJECTIVE:To design a new class of selective neuronal nitric oxide synthase (NOS) inhibitors, and demonstrate that administration in a rabbit model for cerebral palsy (CP) prevents hypoxia-ischemia-induced deaths and reduces the number of newborn kits exhibiting signs of CP. METHODS:We used a novel computer-based drug design method called fragment hopping to identify new chemical entities, synthesized them, and conducted in vitro enzyme inhibition studies with the three isozymes of NOS and in vivo experiments to monitor cardiovascular effects on pregnant rabbit dams, NOS activity, and NO(x) (NO and NO(2)) concentration in fetal brain, and assess neurobehavioral effects on kits born to saline- and compound treated dams. RESULTS:The computer-based design led to the development of powerful and highly selective compounds for inhibition of neuronal NOS over the other isozymes. After maternal administration in a rabbit model of CP, these compounds were found to distribute to fetal brain, to be nontoxic, without cardiovascular effects, inhibit fetal brain NOS activity in vivo, reduce NO concentration in fetal brain, and dramatically ameliorate deaths and number of newborn kits exhibiting signs of CP. INTERPRETATION:This approach may lead to new preventive strategies for CP.
journal_name
Ann Neuroljournal_title
Annals of neurologyauthors
Ji H,Tan S,Igarashi J,Li H,Derrick M,Martásek P,Roman LJ,Vásquez-Vivar J,Poulos TL,Silverman RBdoi
10.1002/ana.21555subject
Has Abstractpub_date
2009-02-01 00:00:00pages
209-17issue
2eissn
0364-5134issn
1531-8249journal_volume
65pub_type
杂志文章abstract::A 10-year-old boy developed progressive dystonia and dementia. His symptoms had begun at age 2 1/2 years, and he had been unable to walk by 8 years. At age 10 he was severely dystonic, unable to use his hands to feed himself, and almost anarthric . He had dysphagia and urinary incontinence, and functioned at a 4-year-...
journal_title:Annals of neurology
pub_type: 杂志文章
doi:10.1002/ana.410150408
更新日期:1984-04-01 00:00:00
abstract:OBJECTIVE:To conduct complex segregation analyses of Parkinson's disease (PD). METHODS:Data on the familial aggregation of PD remain conflicting. We conducted a historical cohort study of 1,234 relatives of 162 patients with PD representative of people of Olmsted County, MN, and of 3,009 relatives of 411 patients with...
journal_title:Annals of neurology
pub_type: 杂志文章
doi:10.1002/ana.20844
更新日期:2006-05-01 00:00:00
abstract::Patients with multiple sclerosis (MS) frequently have selective depletion of the CD45R+CD4+ T-cell subset during active phases of disease. To study the relationship between changes in this subset and the onset of objective clinical exacerbations of disease, a longitudinal study was undertaken. Two CD4+ T-cell subsets ...
journal_title:Annals of neurology
pub_type: 杂志文章
doi:10.1002/ana.410240204
更新日期:1988-08-01 00:00:00
abstract::We demonstrate that the 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase inhibitors atorvastatin and simvastatin enhance functional outcome and induce brain plasticity when administered after stroke to rats. With atorvastatin treatment initiated 1 day after stroke, animals exhibited significant increases in ...
journal_title:Annals of neurology
pub_type: 杂志文章
doi:10.1002/ana.10555
更新日期:2003-06-01 00:00:00
abstract::Persons affected with tuberous sclerosis complex (TSC) develop a wide range of neurological abnormalities including aberrant neuronal migration and seizures. In an effort to model TSC-associated central nervous system abnormalities in mice, we generated two independent lines of astrocyte-specific Tsc1 conditional knoc...
journal_title:Annals of neurology
pub_type: 杂志文章
doi:10.1002/ana.10283
更新日期:2002-09-01 00:00:00
abstract::Gustatory sweating is an autonomic disorder that frequently occurs after parotid gland surgery. We investigated the action of intracutaneous injections of botulinum toxin (BTX) (1.0-2.0 mouse units/2.25-cm2 skin area) in 45 patients (mean age, 52 years) with gustatory sweating. The area of hyperhidrosis was determined...
journal_title:Annals of neurology
pub_type: 临床试验,杂志文章
doi:10.1002/ana.410420619
更新日期:1997-12-01 00:00:00
abstract:OBJECTIVE:We aimed to determine the risk of short- and long-term stroke, as well as accidental injury, in patients discharged from an emergency department who were given a diagnosis of a peripheral vestibular disorder. METHODS:In this population-based, retrospective, cohort study, we identified all adult patients who ...
journal_title:Annals of neurology
pub_type: 杂志文章
doi:10.1002/ana.24521
更新日期:2016-01-01 00:00:00
abstract:OBJECTIVE:To examine changes in the response properties of meningeal nociceptors that might lead to migraine pain and examine endogenous processes that could play a role in mediating them using a clinically relevant model of migraine triggering, namely infusion of the nitric oxide (NO) donor nitroglycerin (NTG). METHO...
journal_title:Annals of neurology
pub_type: 杂志文章
doi:10.1002/ana.23873
更新日期:2013-06-01 00:00:00
abstract::A patient with an intracranial hemorrhage showed differential impairment among arithmetic types (impaired in multiplication but not in subtraction). A functional magnetic resonance imaging (fMRI) experiment using normal volunteers also revealed a differential activation between the two arithmetic types. The fMRI resul...
journal_title:Annals of neurology
pub_type: 杂志文章
doi:
更新日期:2000-10-01 00:00:00
abstract:OBJECTIVE:Multiple Sclerosis (MS) is an inflammatory demyelinating disease of the human central nervous system. Although the clinical impact of gray matter pathology in MS brains is unknown, 30 to 40% of MS patients demonstrate memory impairment. The molecular basis of this memory dysfunction has not yet been investiga...
journal_title:Annals of neurology
pub_type: 杂志文章
doi:10.1002/ana.22337
更新日期:2011-03-01 00:00:00
abstract::Microelectrode recording methods for stereotactic localization of the subthalamic nucleus (STN) and surrounding structures are described. These methods accurately define targets for chronic deep brain stimulation in the treatment of Parkinson's disease. Mean firing rates and a burst index were determined for all recor...
journal_title:Annals of neurology
pub_type: 杂志文章
doi:10.1002/ana.410440407
更新日期:1998-10-01 00:00:00
abstract::We describe a kindred with 7 confirmed and 2 probable cases of subacute dementia accompanied by myoclonus. The inheritance pattern is consistent with autosomal dominance and shows anticipation. The pathological changes involve marked gliosis with neuronal loss of the dorsomedial and midline thalamic nuclei, with lesse...
journal_title:Annals of neurology
pub_type: 杂志文章
doi:10.1002/ana.410200209
更新日期:1986-08-01 00:00:00
abstract::Two families with a point mutation in mtDNA associated with myoclonic epilepsy and ragged-red fiber disease showed pronounced clinical heterogeneity. The mothers of the two families had adult-onset myopathy with ragged-red fibers, partial deficiency of cytochrome c oxidase, and sensory neuropathy. Members of the first...
journal_title:Annals of neurology
pub_type: 杂志文章
doi:10.1002/ana.410330613
更新日期:1993-06-01 00:00:00
abstract::We report four children with idiopathic stroke syndromes who were assayed for human leukocyte antigen (HLA) class I markers and found to have HLA-B51 in common. This finding suggests that there may be a genetic predisposition for "idiopathic" childhood stroke, and host factors, possibly in concert with environmental f...
journal_title:Annals of neurology
pub_type: 杂志文章
doi:10.1002/ana.410310618
更新日期:1992-06-01 00:00:00
abstract::We hypothesized that automated assessment of collaterals on computed tomography perfusion can predict the rate of infarct growth during transfer from a primary to a comprehensive stroke center for endovascular stroke treatment. We identified consecutive patients (N = 28) and assessed their collaterals based on the hyp...
journal_title:Annals of neurology
pub_type: 杂志文章
doi:10.1002/ana.25320
更新日期:2018-10-01 00:00:00
abstract:OBJECTIVE:We examined the association of nutrient intake with microstructural white matter integrity, and the role of white matter integrity in the association between nutrient consumption and cognition. METHODS:This cross-sectional analysis included 239 elderly (age ≥ 65 years) participants of a multiethnic cohort. W...
journal_title:Annals of neurology
pub_type: 杂志文章
doi:10.1002/ana.24674
更新日期:2016-06-01 00:00:00
abstract::Understanding of the organization and function of a newly identified neuronal messenger molecule, nitric oxide, has progressed rapidly. Nitric oxide synthase has been purified and molecularly cloned from brain. Its localization is exclusively neuronal and endothelial. The catalytic activity of nitric oxide synthase ac...
journal_title:Annals of neurology
pub_type: 杂志文章,评审
doi:10.1002/ana.410320302
更新日期:1992-09-01 00:00:00
abstract::A number of reports have suggested an increasing incidence of primary brain tumors, especially malignant astrocytomas, in the elderly population. To investigate this issue, we analyzed the incidence and temporal trends of primary intracranial neoplasms diagnosed in the population of Rochester, Minnesota, over the 40 y...
journal_title:Annals of neurology
pub_type: 杂志文章
doi:10.1002/ana.410370113
更新日期:1995-01-01 00:00:00
abstract::The detection of 14-3-3 protein by Western immunoblot is a sensitive and specific cerebrospinal fluid marker of Creutzfeldt-Jakob disease (CJD). We developed a quantitative enzyme-linked immunosorbent assay (ELISA) that reliably detects 14-3-3 in cerebrospinal fluid. In a prospective study of 147 cerebrospinal fluid s...
journal_title:Annals of neurology
pub_type: 杂志文章
doi:
更新日期:2000-09-01 00:00:00
abstract::A 37-year-old woman with primary Sjögren syndrome developed mixed cryoglobulinemia and systemic vasculitis. Subarachnoid hemorrhage occurred as a result of necrotizing anterior spinal arteritis. Although rarely seen in mixed cryoglobulinemia, central nervous system complications have recently been documented in Sjögre...
journal_title:Annals of neurology
pub_type: 杂志文章
doi:10.1002/ana.410110614
更新日期:1982-06-01 00:00:00
abstract:OBJECTIVE:To develop and validate a questionnaire for assessing cutaneous allodynia (CA), and to estimate the prevalence and severity of CA in the migraine population. METHODS:Migraineurs (n = 11,388) completed the Allodynia Symptom Checklist, assessing the frequency of allodynia symptoms during headache. Response opt...
journal_title:Annals of neurology
pub_type: 杂志文章
doi:10.1002/ana.21211
更新日期:2008-02-01 00:00:00
abstract::One hundred fifty autopsy brains from patients with clinically diagnosed Alzheimer's disease (AD) were examined pathologically. The brains were received consecutively over a 3-year period from numerous sources as part of a research program in which one brain half was frozen for biochemical studies and the other half w...
journal_title:Annals of neurology
pub_type: 杂志文章
doi:10.1002/ana.410240110
更新日期:1988-07-01 00:00:00
abstract::In vivo phosphorus nuclear magnetic resonance spectroscopy (31P NMR) was used to evaluate the pattern of phosphate compounds in seven newborn babies (mean gestational age, 32 weeks; birth weight, 1,430 gm; age, 37 days) with a history of perinatal asphyxia. Spectra were collected in a 1.9 Tesla superconductive magnet ...
journal_title:Annals of neurology
pub_type: 杂志文章
doi:10.1002/ana.410160509
更新日期:1984-11-01 00:00:00
abstract::The ability to distinguish adaptive cortical reorganization may help to target future therapeutic strategies after neurological insult. We investigated cortical plasticity by prospectively applying visual functional magnetic resonance imaging (fMRI) and optic nerve MRI to 20 patients with acute optic neuritis at basel...
journal_title:Annals of neurology
pub_type: 杂志文章
doi:10.1002/ana.20448
更新日期:2005-05-01 00:00:00
abstract::Previous work has shown that lesions in the lateral cerebellum involving the dentate nucleus impair both reaching and pinching movements in humans and monkeys. This study addressed the question of whether disruption of the cerebellar-thalamo-cortical pathway at the level of the thalamus would produce behavioral defici...
journal_title:Annals of neurology
pub_type: 杂志文章
doi:10.1002/ana.410380608
更新日期:1995-12-01 00:00:00
abstract:OBJECTIVE:The study was undertaken to determine whether normobaric hypoxia causes elevated brain volume and intracranial pressure in individuals with symptoms consistent with acute mountain sickness (AMS). METHODS:Thirteen males age = (26 (sd 6)) years were exposed to normobaric hypoxia (12% O2 ) and normoxia (21% O2 ...
journal_title:Annals of neurology
pub_type: 杂志文章
doi:10.1002/ana.24171
更新日期:2014-06-01 00:00:00
abstract:OBJECTIVE:Rapid reversal of the anticoagulatory effect of vitamin K antagonists represents the primary emergency treatment for oral anticoagulant-related intracerebral hemorrhage (OAC-ICH). Predicting the amount of prothrombin complex concentrate (PCC) needed to reverse OAC in individual patients is difficult, and repe...
journal_title:Annals of neurology
pub_type: 临床试验,杂志文章
doi:10.1002/ana.21965
更新日期:2010-06-01 00:00:00
abstract::In 2006, Yamanaka's group pioneered a method for reprogramming somatic cells by introducing definite transcription factors, which enabled the generation of induced pluripotent stem cells (iPSCs) with pluripotency comparable to that of embryonic stem cells. These iPSCs are attracting considerable attention for their po...
journal_title:Annals of neurology
pub_type: 杂志文章,评审
doi:10.1002/ana.23596
更新日期:2012-08-01 00:00:00
abstract:OBJECTIVE:Epilepsy is a common neurological disorder characterized by recurrent seizures often unresponsive to pharmacological treatment. Brain inflammation is considered a crucial etiopathogenetic mechanism of epilepsy that could be targeted to control seizures. Specific inflammatory mediators overexpressed in human e...
journal_title:Annals of neurology
pub_type: 杂志文章
doi:10.1002/ana.23567
更新日期:2012-07-01 00:00:00
abstract::The value of various enhancement techniques as opposed to nonenhanced CT scanning was compared in 15 baboons with cerebral infarction secondary to embolization of the left middle cerebral artery. The most prominent CT findings in infarction included an area of low absorption in the opercula--basal ganglia--centrum sem...
journal_title:Annals of neurology
pub_type: 杂志文章
doi:10.1002/ana.410050108
更新日期:1979-01-01 00:00:00