Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

ADMA (asymmetric omega-NG,NG-dimethylarginine), an endogenous inhibitor of NOS (NO synthase), has been shown to be an independent predictor of cerebrovascular disorders. DDAH2 (dimethylarginine dimethylaminohydrolase 2) promotes the metabolism of ADMA and plays a key role in the regulation of the acute inflammatory response. We hypothesized that genetic variation in DDAH2 might alter the susceptibility to ICH (intracerebral haemorrhage). The hypothesis was tested in two independent case-control studies. We used a haplotype-tagging SNP (single nucleotide polymorphism) approach to identify tag SNPs in DDAH2. The SNPs were genotyped in 1603 stroke patients and 1525 control subjects. The study was replicated in another independent case-control study including 322 stroke patients and 891 control subjects. A promoter variant -449C/G (rs805305) in DDAH2 was identified and found to be in complete linkage disequilibrium with the only tag SNP (rs707916) in the region containing DDAH2. Genotype analyses were conducted for both dominant and additive models. The C allele of the -449 locus resulted in a significantly reduced risk of ICH {dominant model: OR (odds ratio), 0.51 [95% CI (confidence interval), 0.38-0.68], P=6.60x10-6; additive model: OR, 0.64 (95% CI, 0.52-0.80), P=5.21x10-5} than the wild-type genotype. No association was observed between the DDAH2 variant and atherothrombotic stroke. The findings were replicated in the second independent population. In conclusion, our results suggest that the DDAH2 common variant may play a protective role in the development of ICH, implicating that the DDAH2/ADMA pathway may act as a critical regulator of cerebral small-vessel disorders.
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PMID:Common genetic variation in DDAH2 is associated with intracerebral haemorrhage in a Chinese population: a multi-centre case-control study in China. 1925 61

The development of the atherosclerosis is based on multifactorial causes. In addition to the traditional risk factors, gene polymorphisms can play a role in the disease. Therefore in this study we investigated whether the eNOS and MTHFR gene polymorphisms is associated with myocardial infarction and stroke in patients with or without diabetes. We have identified polymorphisms in the NOS 3 gene and one of these polymorphisms, Glu(298-->)Asp, was found to be a major risk factor for carotid artery disease and myocardial infarction. Our results indicate that the MTHFR G677T allele is significantly associated with MI. MTHFR 677 G/T genotyping may be of clinical importance as a prognostic and therapeutic marker, although further studies are needed to substantiate this hypothesis.
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PMID:Methylentetrahydrofolate reductase and nitric oxide synthase polymorphism in patients with atherosclerosis and diabetes. 1933 Apr 66

In adult stroke models, 4-phenyl-1-(4-phenylbutyl) piperidine (PPBP), a sigma receptor agonist, attenuates activity of neuronal nitric oxide synthase (nNOS), blunts ischemia-induced nitric oxide production, and provides neuroprotection. Here, we tested the hypothesis that PPBP attenuates neuronal damage in a model of global hypoxia-ischemia (H-I) in newborn piglets. Piglets subjected to hypoxia followed by asphyxic cardiac arrest were treated with saline or two dosing regimens of PPBP after resuscitation. Sigma-1 receptors were found in striatal neurons. PPBP dose-dependently protected neurons in putamen at 4 days of recovery from H-I. Immunoblots of putamen extracts at 3 h of recovery showed that PPBP decreased H-I-induced recruitment of nNOS in the membrane fraction and reduced the association of nNOS with NMDA receptor NR2 subunit. The latter effect was associated with changes in the coupling of nNOS to postsynaptic density-95 (PSD-95), but not NR2-PSD-95 interactions. Moreover, PPBP suppressed NOS activity in the membrane fraction and reduced H-I-induced nitrative and oxidative damage to proteins and nucleic acids. These findings indicate that PPBP protects striatal neurons in a large animal model of neonatal H-I and that the protection is associated with decreased coupling of nNOS to PSD-95.
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PMID:Sigma receptor ligand 4-phenyl-1-(4-phenylbutyl)-piperidine modulates neuronal nitric oxide synthase/postsynaptic density-95 coupling mechanisms and protects against neonatal ischemic degeneration of striatal neurons. 1988 43

This article describes the design and initial implementation of the Neurological Outcome Scale for Traumatic Brain Injury (NOS-TBI) as an adaptation of the National Institutes of Health Stroke Scale (NIHSS), specifically for clinical and research use in patients with TBI, including (1) the addition of items specific to TBI, (2) adjustment to the scoring algorithm to allow quantification of deficits in patients who are comatose/vegetative or agitated, and (3) the reassignment of items (i.e., limb ataxia) that are problematic in TBI as supplemental items. The feasibility of using the NOS-TBI is discussed and limitations of the scale are highlighted. This scale offers (1) a cost-effective, brief, practicable, standardized, and quantifiable method of communicating and analyzing neurological deficits in a way that traditional neurological assessment alone cannot currently provide, and (2) a measure that non-physicians can administer. The NOS-TBI may serve a role in clinical practice in patients with TBI similar to the way the NIHSS has functioned for patients following stroke, by serving as a tool for initial stratification of injury severity, and as an outcome measure in clinical trials.
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PMID:Feasibility of the Neurological Outcome Scale for Traumatic Brain Injury (NOS-TBI) in adults. 2021 May 93

The Neurological Outcome Scale for Traumatic Brain Injury (NOS-TBI) is a measure adapted from the National Institutes of Health Stroke Scale (NIHSS), and is intended to capture essential neurological deficits impacting individuals with traumatic brain injury (TBI) (see Wilde et al., 2010 ). In the present study we evaluate the measure's construct validity via comparison with a quantified neurological examination performed by a neurologist. Spearman rank-order correlation between the NOS-TBI and the neurological examination was rho = 0.76, p < 0.0001, suggesting a high degree of correspondence (construct validity) between these two measures of neurological function. Additionally, items from the NOS-TBI compared favorably to the neurological examination items, with correlations ranging from 0.60 to 0.99 (all p < 0.0001). On formal neurological examination, some degree of neurological impairment was observed in every participant in this cohort of individuals undergoing rehabilitation for TBI, and on the NOS-TBI neurological impairment was evident in all but one participant. This study documents the presence of measurable neurological sequelae in a sample of patients with TBI in a post-acute rehabilitation setting, underscoring the need for formal measurement of the frequency and severity of neurological deficits in this population. The results suggest that the NOS-TBI is a valid measure of neurological functioning in patients with TBI.
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PMID:The Neurological Outcome Scale for Traumatic Brain Injury (NOS-TBI): I. Construct validity. 2021 May 94

A standardized measure of neurological dysfunction specifically designed for TBI currently does not exist and the lack of assessment of this domain represents a substantial gap. To address this, the Neurological Outcome Scale for Traumatic Brain Injury (NOS-TBI) was developed for TBI outcomes research through the addition to and modification of items specifically relevant to patients with TBI, based on the National Institutes of Health Stroke Scale. In a sample of 50 participants (mean age = 33.3 years, SD = 12.9) <or=18 months (mean = 3.1, SD = 3.2) following moderate (n = 8) to severe (n = 42) TBI, internal consistency of the NOS-TBI was high (Cronbach's alpha = 0.942). Test-retest reliability also was high (rho = 0.97, p < 0.0001), and individual item kappas between independent raters were excellent, ranging from 0.83 to 1.0. Overall inter-rater agreement between independent raters (Kendall's coefficient of concordance) for the NOS-TBI total score was excellent (W = 0.995). Convergent validity was demonstrated through significant Spearman rank-order correlations between the NOS-TBI and the concurrently administered Disability Rating Scale (rho = 0.75, p < 0.0001), Rancho Los Amigos Scale (rho = -0.60, p < 0.0001), Supervision Rating Scale (rho = 0.59, p < 0.0001), and the FIM (rho = -0.68, p < 0.0001). These results suggest that the NOS-TBI is a reliable and valid measure of neurological functioning in patients with moderate to severe TBI.
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PMID:The Neurological Outcome Scale for Traumatic Brain Injury (NOS-TBI): II. Reliability and convergent validity. 2021 May 95

Identification of the signaling pathways that mediate neuronal survival signaling could lead to new therapeutic targets for neurologic disorders and stroke. Sublethal doses of NMDA can induce robust endogenous protective mechanisms in neurons. Through differential analysis of primary library expression and microarray analyses, here we have shown that nuclear factor I, subtype A (NFI-A), a member of the NFI/CAAT-box transcription factor family, is induced in mouse neurons by NMDA receptor activation in a NOS- and ERK-dependent manner. Knockdown of NFI-A induction using siRNA substantially reduced the neuroprotective effects of sublethal doses of NMDA. Further analysis indicated that NFI-A transcriptional activity was required for the neuroprotective effects of NMDA receptor activation. Additional evidence of the neuroprotective effects of NFI-A was provided by the observations that Nfia(-/-) neurons were highly sensitive to NMDA-induced excitotoxicity and were more susceptible to developmental cell death than wild-type neurons and that Nfia(+/-) mice were more sensitive to NMDA-induced intrastriatal lesions than were wild-type animals. These results identify NFI-A as what we believe to be a novel neuroprotective transcription factor with implications in neuroprotection and neuronal plasticity following NMDA receptor activation.
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PMID:NMDA-induced neuronal survival is mediated through nuclear factor I-A in mice. 2051 44

Stroke-prone spontaneously hypertensive rats (SHRSP) demonstrate impaired endothelium-dependent relaxation and often develop brain injuries. We investigated whether the regulatory mechanism for endothelial NOS (eNOS) phosphorylation and activation is altered in the cerebral cortex of SHRSP at a younger age. Western blot analysis revealed a low ratio of phosphor-eNOS (Ser1177) to total eNOS in SHRSP at 10 weeks of age. In addition, urinary nitric oxide metabolites (ie, nitrate and nitrite) were decreased compared with normal control WKY rats. Likewise, Akt phosphorylation (especially Ser473) was significantly reduced, with no changes in total Akt. Furthermore, the amount of the phosphatidylinositol 3-kinase (PI3K) was upstream of Akt was diminished, although attenuation of the PI3K/Akt pathway was not an effect of mTOR, another downstream target of Akt. Our findings indicate that abnormalities of the PI3K/Akt pathway in the cerebral cortex are involved in the impaired eNOS phosphorylation and activation in SHRSP.
J Stroke Cerebrovasc Dis
PMID:Phosphorylated endothelial NOS Ser1177 via the PI3K/Akt pathway is depressed in the brain of stroke-prone spontaneously hypertensive rat. 2081 49

Tetrahydrobiopterin (BH4) is an essential cofactor for all three nitric oxide synthase (NOS isoforms), which plays an important role in vascular diseases. GTP cyclohydrolase 1 (GCH 1) is the first-step and rate-limiting enzyme for BH4 biosynthesis in its de novo pathway. Common GCH1 gene variant C+243T in the 3'-untranslated region predicts NO excretion. The present study examined the predictive role of GCH 1 gene 3'-UTR C+243T variant in the long-term outcome of ischemic stroke. A total of 142 patients with first-onset ischemic stroke were recruited and detected for genotype of GCH1 3'-UTR C+243T by a TaqMan SNP Genotyping assay. Subsequent vascular events and death were determined over a 5-year follow-up period. The frequency of GCH1 3'-UTR +243 C/T or T/T genotype was significantly increased in patients with endpoint events as compared with those without events (74% vs 57.8%, P=0.06). Cox regression survival analysis indicated that an increased probability of death or new vascular events was found in patients with GCH1 3'-UTR +243 C/T or T/T genotype compared with those with GCH1 3'-UTR C/C genotype (40.6% vs 25.5%), GCH1 3'-UTR +243 C/T or T/T genotype relative to GCH1 3'-UTR C/C genotype was associated with the increased risk of death or vascular events even after adjustment for other risk factors (OR=2.171, 95% CI: 1.066-4.424, P=0.033). It was concluded that GCH1 3'-UTR C+243T variant was an independent predictor of worsening long-term outcomes in patients with first-onset ischemic stroke.
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PMID:GTP cyclohydrolase 1 gene 3'-UTR C+243T variant predicts worsening outcome in patients with first-onset ischemic stroke. 2118 56

Inducible arginine oxidation and subsequent NO production by correspondent synthase (iNOS) are important cellular answers to proinflammatory signals. Prolonged NO production has been proved in higher organisms to cause stroke or septic shock. Several classes of potent NOS inhibitors have been reported, most of them targeting the arginine binding site of the oxygenase domain. Here we disclose the SAR and the rational design of potent and selective iNOS inhibitors which may be useful as anti-inflammatory drugs.
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PMID:Novel nanomolar imidazo[4,5-b]pyridines as selective nitric oxide synthase (iNOS) inhibitors: SAR and structural insights. 2168 57


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