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)

Edema formation can be observed using magnetic resonance imaging (MRI) in patients with stroke. Recent studies have shown that aquaporin-4 (AQP4), a water channel, is induced early after stroke and potentially participates in the development of brain edema. We studied whether induction of AQP4 correlated with edema formation in a rat pup filament stroke model using high field (11.7-Tesla) MRI followed by immunohistochemical investigation of AQP4 protein expression. At 24 h, we observed increased T2 values and decreased apparent diffusion coefficients (ADC) within injured cortical and striatal regions that reflected the edema formation. Coincident with these MR changes were significant increases in AQP4 expression on astrocytic end-feet in the border regions of injured tissues. Striatal imaging findings were still present at 72 h with a slow normalization of AQP4 expression in the border regions. At 28 d, AQP4 expression normalized in the border while in this region ADC values increased. We show that induction of AQP4 is increased during the period of active edema formation in the border region without regional correlation with edema. Finally, induction of AQP4 on astrocyte end-feet could participate in tissue preservation after ischemia in the immature rat brain.
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PMID:Temporal and regional evolution of aquaporin-4 expression and magnetic resonance imaging in a rat pup model of neonatal stroke. 1762 64

Stroke is the third leading cause of death and the leading cause of adult disability in the industrialized nations. One of the consequences of stroke is blood-brain barrier (BBB) leakage and subsequent edema, which is one of the causes of mortality in this pathology. Aquaporin-4 (AQP4) is the most abundant water channel in the brain. Studies in AQP4 knock-out mice have shown a prominent role of this water channel in edema development and resolution after ischemia. Here we have studied changes in AQP4 mRNA and protein expression in response to vascular endothelial growth factor (VEGF), a potent angiogenic factor. VEGF administration highly upregulated AQP4 mRNA and protein in the ventral midbrain. Perfusion of the animals with FITC-albumin prior to sacrifice demonstrated localization of AQP4 protein in close proximity to the VEGF-induced new blood vessels. Expression levels of AQP4 mRNA were maximum 7 days after VEGF injection whereas our previous report showed that BBB leakage is resolved at this time point. Therefore, we speculate a positive role of AQP4 in edema resolution, which may partially explain the previously reported beneficial effects of delayed VEGF administration in ischemic rats. Our results provide new insights into the molecular changes in the edematous brain and may help in future therapeutical directions.
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PMID:Intracerebral VEGF injection highly upregulates AQP4 mRNA and protein in the perivascular space and glia limitans externa. 1802 90

Cerebral edema contributes significantly to morbidity and mortality after brain injury and stroke. Aquaporin-4 (AQP4), a water channel expressed in astrocytes, plays a key role in brain water homeostasis. Genetic variants in other aquaporin family members have been associated with disease phenotypes. However, in human AQP4, only one non-synonymous single-nucleotide polymorphism (nsSNP) has been reported, with no characterization of protein function or disease phenotype. We analyzed DNA from an ethnically diverse cohort of 188 individuals to identify novel AQP4 variants. AQP4 variants were constructed by site-directed mutagenesis and expressed in cells. Water permeability assays in the cells were used to measure protein function. We identified 24 variants in AQP4 including four novel nsSNPs (I128T, D184E, I205L and M224T). We did not observe the previously documented M278T in our sample. The nsSNPs found were rare ( approximately 1-2% allele frequency) and heterozygous. Computational analysis predicted reduced function mutations. Protein expression and membrane localization were similar for reference AQP4 and the five AQP4 mutants. Cellular assays confirmed that four variant AQP4 channels reduced normalized water permeability to between 26 and 48% of the reference (P < 0.001), while the M278T mutation increased normalized water permeability (P < 0.001). We identified multiple novel AQP4 SNPs and showed that four nsSNPs reduced water permeability. The previously reported M278T mutation resulted in gain of function. Our experiments provide insight into the function of the AQP4 protein. These nsSNPs may have clinical implications for patients with cerebral edema and related disorders.
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PMID:Novel variants in human Aquaporin-4 reduce cellular water permeability. 1851 55

Aquaporin-4 (AQP4) has been shown to be important in the evolution of stroke-associated cerebral edema. However, the role of AQP4 in stroke-associated cerebral edema as it pertains to sex has not been previously studied. The perivascular pool of AQP4 is important in the influx and efflux of water during focal cerebral ischemia. We used mice with targeted disruption of the gene encoding alpha-syntrophin (alpha-Syn(-/-)) that lack the perivascular AQP4 pool but retain the endothelial pool of this protein. Infarct volume at 72 h after transient focal ischemia (90 mins) in isoflurane-anesthetized mice was attenuated in both sexes with alpha-Syn deletion as compared with their wild-type (WT) counterparts. There were no sex differences in hemispheric water content in WT and alpha-Syn(-/-) mice or regional AQP4 expression in WT mice. In neither sex did alpha-Syn deletion lead to alterations in end-ischemic regional cerebral blood flow (rCBF). These data suggest that after experimental stroke: (1) there is no difference in stroke-associated cerebral edema based on sex, (2) AQP4 does not involve in sex-based differences in stroke volume, and (3) perivascular pool of AQP4 has no significant role in end-ischemic rCBF.
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PMID:Lack of sex-linked differences in cerebral edema and aquaporin-4 expression after experimental stroke. 1864 81

The rapid and irreversible brain injury produced by anoxia when stroke occurs is well known. Cumulative evidence suggests that the activation of neuronal ATP-sensitive potassium (KATP) channels may have inherent protective effects during cerebral hypoxia, yet little information regarding the therapeutic effects of KATP channel openers is available. We hypothesized that pretreatment with a KATP channel opener might protect against brain injury induced by cerebral hypoxia. In this study, adult Wistar rats were treated with iptakalim, a new KATP channel opener, which is selective for SUR2 type KATP channels, by intragastric administration at doses of 2, 4, or 8 mg/kg/day for 7 days before being exposed to simulated high altitude equivalent to 8000 m in a decompression chamber for 8 h leading to hypoxic brain injury. By light and electron microscopic images, we observed that hypobaric hypoxia-induced brain injury could be prevented by pretreatment with iptakalim. It was also observed that the permeability of the blood-brain barrier, water content, Na+ and Ca2+ concentration, and activities of Na+,K+-ATPase, Ca2+-ATPase and Mg2+-ATPase in rat cerebral cortex were increased and the gene expression of the occludin or aquaporin-4 was down- or upregulated respectively, which could also be prevented by the pretreatment with iptakalim at doses of 2, 4, or 8 mg/kg in a dose-dependent manner. Furthermore, we found that in an oxygen-and-glucose-deprived model in ECV304 cells and rat cortical astrocytes, pretreatment with iptakalim significantly increased survived cell rates and decreased lactate dehydrogenate release, which were significantly antagonized by glibenclamide, a K(ATP) channel blocker. We conclude that iptakalim is a promising drug that may protect against brain injury induced by acute hypobaric hypoxia through multiple pathways associated with SUR2-type K(ATP) channels, suggesting a new therapeutic strategy for stroke treatment.
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PMID:Iptakalim protects against hypoxic brain injury through multiple pathways associated with ATP-sensitive potassium channels. 1895 57

Cerebral edema plays a central role in the pathophysiology of many diseases of the central nervous system (CNS) including ischemia, trauma, tumors, inflammation, and metabolic disturbances. The formation of cerebral edema results in an increase in tissue water content and brain swelling which, if unchecked, can lead to elevated intracranial pressure (ICP), reduced cerebral blood flow, and ultimately cerebral herniation and death. Despite the clinical significance of cerebral edema, the mechanism of brain water transport and edema formation remain poorly understood. As a result, current therapeutic tools for managing cerebral edema have changed little in the past 90 years. "Malignant ischemic stroke" is characterized by high mortality (80%) and represents a major clinical problem in cerebrovascular disease. Widespread ischemic injury in these patients causes progressive cerebral edema, increased ICP, and rapid clinical decline. In response to these observations, a series of recent studies have begun to target cerebral edema in the management of large ischemic strokes. During cerebral edema formation, the glial water channel aquaporin-4 (AQP4) has been show to facilitate astrocyte swelling ("cytotoxic swelling"). AQP4 has also been seen to be responsible for the reabsorption of extracellular edema fluid ("vasogenic edema"). In the present review, the role of AQP4 in the development of cerebral edema is discussed with emphasis on its contribution to ischemic edema. We also examine the potential of AQP4 as a therapeutic target in edema associated with stroke.
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PMID:Role of aquaporin-4 in cerebral edema and stroke. 1909 76

Brain oedema is a major clinical problem produced by CNS diseases (e.g. stroke, brain tumour, brain abscess) and systemic diseases that secondarily affect the CNS (e.g. hyponatraemia, liver failure). The swollen brain is compressed against the surrounding dura and skull, which causes the intracranial pressure to rise, leading to brain ischaemia, herniation, and ultimately death. A water channel protein, aquaporin-4 (AQP4), is found in astrocyte foot processes (blood-brain border), the glia limitans (subarachnoid cerebrospinal fluid-brain border) and ependyma (ventricular cerebrospinal fluid-brain border). Experiments using mice lacking AQP4 or alpha syntrophin (which secondarily downregulate AQP4) showed that AQP4 facilitates oedema formation in diseases causing cytotoxic (cell swelling) oedema such as cerebral ischaemia, hyponatraemia and meningitis. In contrast, AQP4 facilitates oedema elimination in diseases causing vasogenic (vessel leak) oedema and therefore AQP4 deletion aggravates brain oedema produced by brain tumour and brain abscess. AQP4 is also important in spinal cord oedema. AQP4 deletion was associated with less cord oedema and improved outcome after compression spinal cord injury in mice. Here we consider the possible routes of oedema formation and elimination in the injured cord and speculate about the role of AQP4. Finally we discuss the role of AQP4 in neuromyelitis optica (NMO), an inflammatory demyelinating disease that produces oedema in the spinal cord and optic nerves. NMO patients have circulating AQP4 IgG autoantibody, which is now used for diagnosing NMO. We speculate how NMO-IgG might produce CNS inflammation, demyelination and oedema. Since AQP4 plays a key role in the pathogenesis of CNS oedema, we conclude that AQP4 inhibitors and activators may reduce CNS oedema in many diseases.
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PMID:Aquaporin-4 in brain and spinal cord oedema. 1968 55

Aquaporin-4 (AQP4) plays a role in the generation of post-ischemic edema. Pharmacological modulation of AQP4 function may thus provide a novel therapeutic strategy for the treatment of stroke, tumor-associated edema, epilepsy, traumatic brain injury, and other disorders of the central nervous system (CNS) associated with altered brain water balance. Edaravone, a free radical scavenger, is used for the treatment of acute ischemic stroke (AIS) in Japan. In this study, edaravone significantly reduced the infarct area and improved the neurological deficit scores at 24h after reperfusion in a rat transient focal ischemia model. Furthermore, edaravone markedly reduced AQP4 immunoreactivity and protein levels in the cerebral infarct area. In light of observations that edaravone specifically inhibited AQP4 in a rat transient focal ischemia model, we propose that edaravone might reduce cerebral edema through the inhibition of AQP4 expression following cerebral infarction.
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PMID:Edaravone attenuates cerebral ischemic injury by suppressing aquaporin-4. 1973 35

The endothelial-specific expression of plasmalemmal vesicle associated protein-1 (PV-1) is typical of fenestrated endothelium observed in pulmonary capillaries and some endocrine organs. In the central nervous system (CNS) it is expressed during development but disappears concomitant with maturation of the blood-CNS barrier [1]. Consistent with observations made in models of stroke, Alzheimer's disease, and tumorigenesis, we show PV-1 expression in the spinal cord specifically upregulated by pathologically-activated endothelial cells (ECs) in response to traumatic spinal cord injury (SCI). Adult female C57Bl/6 mice received a moderate T9/10 contusive SCI. PV-1 assessed by qRT-PCR and immunohistochemistry 3 hours to 14 days post-injury showed expression as early as 1 day post-SCI, with levels decreasing by 14 days. This expression was associated with microvessels in the injury epicenter and penumbral zone, with the time course and distribution correlated with progressing peripheral inflammatory cell infiltration. PV-1-immunoreactive ECs were angiogenic as demonstrated by intravascular binding of Griffonia simplicifolia isolectin B4 (IB4). ECs expressing high levels of PV-1 were anatomically and physiologically abnormal with altered/absent immunostaining for occludin and zonula occludens-1 (ZO-1), and decreased expression of glial fibrillary acidic protein (GFAP) and aquaporin-4 (AQP4). Glucose transporter type I (Glut-1) expression decreased in affected, PV-1 positive microvessels with little colocalization of PV-1 and Glut-1 apparent by 7 days post-SCI. These data suggest that upregulation of microvascular expression of PV-1 post-SCI may promote major components of secondary injury including extravasation of cellular and acellular mediators of inflammation and may accelerate loss of neuropil and decline in the functional and anatomical integrity of the neurovascular unit (NVU).
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PMID:Spinal microvascular expression of PV-1 is associated with inflammation, perivascular astrocyte loss, and diminished EC glucose transport potential in acute SCI. 2059 May 23

Female gender, which is abolished following ovariectomy and reproductive senescence, is associated with improved outcome following cerebral stroke. Estrogen replacement partially restores this benefit of the female gender but the effect of progesterone in hormone-deficient animals is currently unknown. We evaluated various outcomes following middle cerebral artery occlusion (MCAO) in ovariectomised female mice, with a physiologically relevant restoration of progesterone levels. Ovariectomised female mice had significantly elevated plasma (P=<0.05) and brain progesterone levels (P=<0.01) following implantation of a 21-day release pellet (50mg) compared with mice that received placebo implants 7 days prior to undergoing 60 min MCAO. Assessment of well-being (body weight recovery) and neurological score at 24h and 48h post-MCAO indicated that MCAO significantly worsened outcome compared with sham-operated mice but progesterone had no effect. MCAO resulted in a substantial lesion formation and a significant increase (P<0.05) in ipsilateral brain water content, both of which were not affected by progesterone treatment. Furthermore, there was no significant alteration in ipsilateral Aquaporin-4 (AQP4) expression following MCAO or progesterone treatment. The present study indicates that sustained physiologically relevant levels of progesterone prior to cerebral ischemia neither benefited nor worsened outcomes in previously ovariectomised female mice.
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PMID:Sustained levels of progesterone prior to the onset of cerebral ischemia are not beneficial to female mice. 2085 Apr 17


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