Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

NMDA receptors may play a crucial role in nerve cell death following subarachnoid hemorrhage (SAH). Changes in NMDA receptor-mediated transmission appear before neuronal death in rodent models of transient ischemia, and NMDA receptor function is known to be dependent on subunit composition. Here, we have investigated whether mRNA expression of the NMDA receptor subunits is altered in the hippocampal formation 3-5 h following experimental SAH, and correlated these early alterations to subsequent delayed cell death. SAH was induced by intraluminal perforation of the internal carotid artery intracranially, and cerebral blood flow (CBF) was bilaterally monitored by laser-Doppler flowmetry. Early changes in NMDA receptor subunit mRNA and early nerve cell death were analyzed at 3-5 h after SAH, and delayed nerve cell death was analyzed at 2-7 days after SAH. Duration of ipsilateral CBF reduction below 30% of baseline (CBF30) was predictive of ipsilateral delayed nerve cell death in the CA1 2-7 days after SAH. At CBF30 > 9 min, we found downregulation of mRNA for NR2A, NR2B, and NR3B at 3-5 h after SAH, whereas the levels of NR1 mRNA were unaffected. The downregulation of NR2A and NR2B mRNA may result in a reduced NMDA receptor function. Such reduction may be sufficient to provide neuroprotection in the dentate gyrus, where no cell death appears, but insufficient to rescue neurons in the hippocampus proper following SAH.
Brain Res Mol Brain Res 2005 Jun 13
PMID:Experimental subarachnoid hemorrhage induces changes in the levels of hippocampal NMDA receptor subunit mRNA. 1595 Jul 69

The rupture of an intracranial aneurysm (IA) results in subarachnoid hemorrhage, a catastrophic neurological condition with high morbidity and mortality. Following-up on our previous genome-wide linkage study in Japanese population, we extensively analyzed a 4.6 Mb linkage region around D7S2472 on 7q11 by genotyping 168 single nucleotide polymorphisms (SNPs). SNP association and window scan haplotype-based association studies revealed a susceptibility locus for IA on a single LD block covering the 3'-untranslated region (3'-UTR) of ELN and the entire region of LIMK1. An association study with 404 IA patients and 458 non-IA controls revealed that the ELN 3'-UTR G(+659)C SNP has the strongest association to IA (P=0.000002) and constitutes a tag-SNP for an at-risk haplotype, which contains two functional SNPs, the ELN 3'-UTR (+502) A insertion and the LIMK1 promoter C(-187)T SNP. These allelic and haplotype-based associations were confirmed in a Korean population. Ex vivo and in vitro analyses demonstrate that the functional impact of both SNPs is the decrease of transcript levels, either through accelerated ELN mRNA degradation or through decreased LIMK1 promoter activity. Elastin and LIMK1 protein are involved in the same actin depolymerization signaling pathway; therefore, these lines of evidence suggest a combined effect of the SNPs in the at-risk haplotype possibly by weakening the vascular wall and promoting the development of IA.
Hum Mol Genet 2006 May 15
PMID:A haplotype spanning two genes, ELN and LIMK1, decreases their transcripts and confers susceptibility to intracranial aneurysms. 1661 74

Cerebral aneurysms and arteriovenous malformations (AVM) are a common cause of stroke and cerebral hemorrage. Both are often discovered when they rupture, causing subarachnoid hemorrhage (SAH). SAH-induced vasospasm is mediated by enhanced vasoconstriction due to endothelin-1 (ET-1). We investigated whether endothelial cells (ECs) obtained from aneurysm and AVM express phenotypic and genotypic alterations contributing to the development of vasospasm after SAH. We isolated ECs from human AVM and aneurysm and then confirmed their EC origin by polymerase chain reaction and immunocytochemistry with endothelial markers. Experiments were also carried out with human cerebral microvascular and umbilical vein ECs (HCECs and HUVECs respectively) for comparison. We tested EC proliferation ability and microtubule formation in Matrigel at different cell passages. Five aneurysm (3 ruptured, 2 unruptured) and 3 AVM (2 ruptured, 1 unruptured) ECs were tested for ET-1 release in the culture medium. Aneurysm and AVM ECs expressed von Willebrand factor, Adrenomedullin, and exhibited a progressive reduction of proliferation and in vitro angiogenic ability after the V passage. Significantly higher levels of ET-1 have been detected in ECs from ruptured aneurysms and AVMs. We report the first successful isolation and characterization of primary EC lines from human cerebral vascular lesions. Augmented release of ET-1 is correlated with the rupture of the abnormal vessel confirming its role in vasospasm after SAH. Furthermore, ECs obtained from these vascular malformations can be used as an experimental model to study SAH-induced vasoconstriction.
Int J Mol Med 2006 Nov
PMID:Endothelial cells from human cerebral aneurysm and arteriovenous malformation release ET-1 in response to vessel rupture. 1701 10

The cellular events leading to cerebral vasospasm after subarachnoid hemorrhage (SAH) are poorly understood, although the family of protein kinase C (PKC) is already known to play crucial roles in this pathology. Hemoglobin (Hb) is one of the major causes of the cerebral vasospasm that follows SAH. In the present study we investigated whether Hb can in vitro regulate PKC expression in endothelial as opposed to smooth-muscle cells. The levels of expression of PKCalpha and PKCzeta were quantitatively determined by means of computer-assisted fluorescence microscopy in the A7r5 smooth-muscle rat cells and human umbilical endothelial cells (HUVECs). Hb significantly modified both calcium-dependent PKCalpha and calcium-independent PKCzeta expression in HUVECs and A7r5 smooth-muscle rat cells. Our data showed that, in vitro, Hb promptly and markedly modified the levels of expression of both calcium-dependent PKCalpha and calcium-independent PKCzeta. We are currently investigating the effects of specific PKC antagonists associated or not with calcium channel blockers on the expression of PKC and the in vivo severity of SAH-induced vasospasm. Our results encourage the prophylactic use of specific PKC isoform antagonists associated with calcium channel blockers early after SAH to prevent cerebral vasospasm.
Int J Mol Med 2007 Oct
PMID:In vitro evidence of the role of hemoglobin during vasospasm on the modifications of the expression of PKCalpha and zeta. 1778 70

Subarachnoid hemorrhage due to the rupture of a cerebral aneurysm is a life-threatening disease. Despite this, the detailed mechanisms underlying the initiation and progression of cerebral aneurysm are unclear. The relation of hypercholesterolemia and apolipoprotein E (ApoE) to cerebral aneurysm formation, has been unclear until now. We used, in the present study, a previously established cerebral aneurysm model of rats and mice whose histological features were closely similar to human cerebral aneurysms. ApoE protein was expressed mainly in the endothelial cells of arterial walls both in control arteries and cerebral aneurysms. The expression of ApoE was reduced during aneurysm formation in the immunohistochemistry. The mRNA expression of ApoE in arterial walls was not different between the controls and cerebral aneurysms. Owing to the deficiency of ApoE, mice presented marked hypercholesterolemia, but there was no difference in cerebral aneurysm formation. In the present study, we clarified that ApoE was not responsible for cerebral aneurysm formation.
Int J Mol Med 2008 Apr
PMID:The efficacy of apolipoprotein E deficiency in cerebral aneurysm formation. 1836 Jun 91

The study aimed to investigate the involvement of cerebral microcirculation turbulence after subarachnoid hemorrhage (SAH). Wistar rats were divided into non-SAH and SAH groups. Autologous arterial hemolysate was injected into rat's cisterna magna to induce SAH. Changes of pial microcirculation within 2 h were observed. It was found that there were no obvious changes of the diameters, flow velocity, and fluid state of microvessels in non-SAH group. With the exception of rare linear-granular flow in A4 arteriole, linear flow was observed in most of the arterioles. There was no blood agglutination in any of the arterioles. After SAH, abnormal cerebral pial microcirculation was found. Spasm of microvessels, decreased blood flow, and agglutination of red blood cells occurred. Five minutes following the induction of SAH, the diameters of the arterioles and venules significantly decreased. The decreased diameters persisted for 2 h after cisternal injection. Decreased flow velocity of venules was found from 5 to 90 min after induction of SAH. Spasm of the basilar artery and increased brain malondialdehyde were also found after SAH. We concluded that cerebral microcirculation turbulence plays an important role in the development of secondary cerebral ischemia following SAH.
Cell Mol Neurobiol 2009 Mar
PMID:Dynamic alterations of cerebral pial microcirculation during experimental subarachnoid hemorrhage. 1882 Oct 9

Cerebral aneurysm is a common disease with a high prevalence and can cause a catastrophic subarachnoid hemorrhage. To elucidate the molecular mechanism of the formation and progression of cerebral aneurysms, gene expression profiling was performed in experimentally induced rat cerebral aneurysms. The intima and media of cerebral arterial walls in rats with or without aneurysm induction were dissected respectively by a laser-microdissection technique. Changes in gene expression in the intima and media of aneurysmal walls were analyzed using Agilent Rat Oligo Microarrays, followed by a specific pathway analysis using GeneSpring software. Of the 41,012 genes examined, 633 were differentially expressed between a normal cerebral artery and a cerebral aneurysm in the intima, with 395 showing increased expression and 238 showing decreased expression. In the media, 1344 were differentially expressed, with 928 showing increased expression and 416 showing decreased expression. Specific pathway analysis revealed that increased gene expression was associated with proteinase, reactive oxygen species, growth factor, chemokine, complement, adhesion molecule and apoptosis in both the intima and the media of aneurysmal walls. Some genes showed an opposite expression pattern between the intima and the media indicating a different role between endothelial cells and vascular smooth muscle cells in cerebral aneurysm formation and progression. These data suggest that cerebral aneurysmal formation and progression are closely related to vascular inflammation, degeneration of extracellular matrix and apoptosis.
Int J Mol Med 2008 Nov
PMID:Gene expression profile of the intima and media of experimentally induced cerebral aneurysms in rats by laser-microdissection and microarray techniques. 1894 79

Cerebral aneurysm (CA) causes catastrophic subarachnoid hemorrhage which is characterized by a high mortality and morbidity rate. CA is a common disease worldwide but to date there is no medical treatment against unruptured CAs. Thus, it is important to study the mechanisms of CA formation. Our previous report demonstrated that chronic inflammatory response in cerebral arterial bifurcation by hemodynamic stress deteriorated arterial walls and formed CA. Therefore, drugs with anti-inflammatory effects might effectively treat CA formation. As renin angiotensin system (RAS) is a major inflammatory cascade and related to various vascular diseases, including aortic aneurysms, the role of angiotensin (Ang) II type 1 receptor might contribute to the progression of CAs. However, in cerebral aneurysmal walls, Ang II type 1 receptor was not up-regulated. In addition, subcutaneously administered Ang II type 1 receptor blocker did not inhibit CA formation, nor inflammation in cerebral aneurysmal walls in rat models at a sub-suppressor dose. These results indicate that RAS might play a less important role in CA formation compared to aortic anuerysms or other vascular diseases. This suggests that there are different mechanisms between the pathogenesis of cereberal and aortic aneurysms.
Int J Mol Med 2009 Sep
PMID:Role of angiotensin II type 1 receptor in cerebral aneurysm formation in rats. 1963 27

Ischemic stroke occurs most often in the territory of the middle cerebral artery (MCA) in humans. Since its description in rats more than two decades ago, the minimally invasive intraluminal suture occlusion of MCA is an increasingly used model of stroke in both rats and mice due to its ease of inducing ischemia and achieving reperfusion under well-controlled conditions. This method can be used under the guidance of laser-Doppler flowmetry to ascertain the magnitude of occlusion or reperfusion and to decrease the rate of subarachnoid hemorrhage. Ninety minutes of transient ischemia in the territory of MCA results in substantial and reproducible ischemic lesions in both the striatum and the cortex, with characteristics of lesion core and penumbra. Thus, this model is applicable to neuroprotective drug studies, including ischemic brain lesion evaluation (either in vivo with magnetic resonance imaging or post-mortem with brain tissue staining) and neurological status (motor deficits simply assessed by a six-point neurological score scale) as outcome parameters.
Methods Mol Biol 2009
PMID:Ischemic stroke in mice and rats. 1976 24

Rho kinase (ROCK) is important in fundamental processes of cell proliferation and survival. Blockade of ROCK promotes stem cell survival in vitro and axonal regeneration in vivo, exhibiting therapeutic potential such as spinal cord injuries and stroke. Here, we used the model of hypoxia/reoxygenation (H/R) injury to explore the possibility whether Fasudil, a ROCK inhibitor in clinical application for subarachnoid hemorrhage and stroke, mobilizes adult neural stem cells in vivo. Most interestingly, Fasudil triggers neurogenesis especially in the subventricular zone after H/R. The increase of Brdu+ cholinergic neurons was observed in striatum and forebrain cortex of Fasudil-treated mice after 30 days. Further observation demonstrates that both levels of granulocyte colony-stimulating factor (G-CSF) and astrocytes expressing G-CSF were elevated in mice treated with Fasudil, as compared to mice injected with saline. In vitro H/R model of cultured astrocytes, Fasudil promoted astrocytes to produce G-CSF in a dose-dependent manner. In addition, antibody neutralization and receptor blocking of the G-CSF pathway clearly demonstrate that Fasudil-induced neurogenesis was mediated partially through astrocyte-derived G-CSF. Our results indicate that Fasudil might represent a promising therapeutic perspective by mobilizating endogenous adult neural stem cells in the CNS.
Mol Cell Neurosci 2010 Feb
PMID:Fasudil, a Rho kinase inhibitor, drives mobilization of adult neural stem cells after hypoxia/reoxygenation injury in mice. 1991 17


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