Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0917798 (cerebral ischemia)
 17,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The role of glial cells in neuronal death has become a major research interest. Glial cell activation has been demonstrated to accompany cerebral ischemia. However, there is disagreement whether such gliosis is a cell death or a neuroprotective response. In the present study, we examined alterations in glial cell responses to the reported neuroprotective action of the free radical scavenger, melatonin, against cerebral ischemia. Adult male Wistar rats were given oral injections of either melatonin (26 micromol/rat) or saline just prior to 1 h occlusion of the middle cerebral artery (MCA), then once daily for 11 or 19 consecutive days. At 11 and 19 days after reperfusion of the MCA, randomly selected animals were killed and their brains removed for immunohistochemical assays. Melatonin significantly enhanced survival of glial cells (as revealed by glial cell specific markers, glial fibrillary acidic protein and aquaporin-4 immunostaining) at both time periods postischemia, and the preservation of these glial cells in the ischemic penumbra corresponded with a markedly reduced area of infarction (detected by immunoglobulin G and hematoxylin-eosin staining), as well as increased neuronal survival. The ischemia-induced locomotor deficits were partially ameliorated in melatonin-treated animals. In vitro replications of ischemia by serum deprivation or by exposure to free radical-producing toxins (sodium nitroprusside and 3-nitropropionic acid) revealed that melatonin (10 microg/ml or 100 microM) treatment of pure astrocytic cultures significantly reduced astrocytic cell death. These results suggest a potential strategy directed at enhancing glial cell survival as an alternative protective approach against ischemic damage.
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PMID:Glial cell survival is enhanced during melatonin-induced neuroprotection against cerebral ischemia. 1087 23

Aquaporin-4 (AQP4) is the major water channel in the CNS. Its expression at fluid-tissue barriers (blood-brain and brain-cerebrospinal fluid barriers) throughout the brain and spinal cord suggests a role in water transport under normal and pathological conditions. Phenotype studies of transgenic mice lacking AQP4 have provided evidence for a role of AQP4 in cerebral water balance and neural signal transduction. Primary cultures of astrocytes from AQP4-null mice have greatly reduced osmotic water permeability compared with wild-type astrocytes, indicating that AQP4 is the principal water channel in these cells. AQP4-null mice have reduced brain swelling and improved neurological outcome following water intoxication and focal cerebral ischemia, establishing a role of AQP4 in the development of cytotoxic (cellular) cerebral edema. In contrast, brain swelling and clinical outcome are worse in AQP4-null mice in models of vasogenic (fluid leak) edema caused by freeze-injury and brain tumor, probably due to impaired AQP4-dependent brain water clearance. AQP4-null mice also have markedly reduced acoustic brainstem response potentials and significantly increased seizure threshold in response to chemical convulsants, implicating AQP4 in modulation of neural signal transduction. 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 CNS associated with altered brain water balance.
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PMID:New insights into water transport and edema in the central nervous system from phenotype analysis of aquaporin-4 null mice. 1556 13

Aquaporin-4 (AQP4) is expressed in astrocytes throughout the central nervous system, particularly at the blood-brain and brain-cerebrospinal fluid barriers. Phenotype analysis of transgenic mice lacking AQP4 has provided compelling evidence for involvement of AQP4 in cerebral water balance, astrocyte migration, and neural signal transduction. AQP4-null mice have reduced brain swelling and improved neurological outcome in models of (cellular) cytotoxic cerebral edema including water intoxication, focal cerebral ischemia, and bacterial meningitis. However, brain swelling and clinical outcome are worse in AQP4-null mice in models of vasogenic (fluid leak) edema including cortical freeze-injury, brain tumor, brain abscess and hydrocephalus, probably due to impaired AQP4-dependent brain water clearance. AQP4 deficiency or knock-down slows astrocyte migration in response to a chemotactic stimulus in vitro, and AQP4 deletion impairs glial scar progression following injury in vivo. AQP4-null mice also manifest reduced sound- and light-evoked potentials, and increased threshold and prolonged duration of induced seizures. Impaired K+ reuptake by astrocytes in AQP4 deficiency may account for the neural signal transduction phenotype. Based on these findings, we propose modulation of AQP4 expression or function as a novel therapeutic strategy for a variety of cerebral disorders including stroke, tumor, infection, hydrocephalus, epilepsy, and traumatic brain injury.
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PMID:Three distinct roles of aquaporin-4 in brain function revealed by knockout mice. 1656 96

Astrocytes play a key role for maintenance of brain water homeostasis, but little is known about mechanisms of short-term regulation of astrocyte water permeability. Here, we report that glutamate increases astrocyte water permeability and that the molecular target for this effect is the aquaporin-4 (AQP4) serine 111 residue, which is in a strategic position for control of the water channel gating. The glutamate effect involves activation of group I metabotropic glutamate receptors (mGluR), intracellular calcium release, and activation of calcium/calmodulin-dependent protein kinase II (CaMKII) and nitric oxide synthase (NOS). The physiological impact of our results is underlined by the finding that mGluR activation increases the rate of hypoosmotic tissue swelling in acute rat hippocampal slices. Cerebral ischemia is associated with an excessive release of glutamate, and in postischemic cerebral edema ablation of AQP4 attenuates the degree of damage. Thus, we have identified AQP4 as the molecular target for drugs that may attenuate the development of brain edema.
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PMID:Identification of a molecular target for glutamate regulation of astrocyte water permeability. 1828 43

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 cerebral ischemia-reperfusion injury remains a major medical problem due to the lack of effective treatment. The mechanism of brain injury is still unknown. The defensive and offensive factors, such as platelet-derived growth factor-BB (PDGF-BB), 5-lipoxygenase (5-LO), aquaporin-4 (AQP-4) and insulin-like growth factor-1 (IGF-1) may play important roles. So far, only individual factors were reported. What are the relationships among them in brain ischemia-reperfusion injury remains obscure. The present study is to investigate simultaneously the expression of PDGF-BB, 5-LO, AQP-4 and IGF-1 in middle cerebral artery occlusion/reperfusion (MCAO/R) in rats. We found that 5-LO and IGF-1 reached the peak level at 24h after reperfusion, AQP-4 at 72 h and PDGF-BB at 7 days. With these results we inferred that both defensive factors, such as PDGF-BB, AQP-4 and IGF-1, and offensive factor, like 5-LO, play some roles in the ischemia-reperfusion injury.
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PMID:Longitudinal changes of defensive and offensive factors in focal cerebral ischemia-reperfusion in rats. 1944 8

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

High is the incidence of gastrointestinal dysfunction induced by cerebrovascular disease. However, little is known about the effects of CGRP on gastrointestinal injuries induced by cerebrovascular disease. The purpose of the present study was to investigate the protective effects of calcitonin gene-related peptide (CGRP) on gastric mucosa injury after focal cerebral ischemia reperfusion in rats. Thirty healthy adult male Wistar rats were selected for this experiment and were randomly divided into CGRP-treated, sham-operated, and control groups, respectively. Ten rats were involved in each group. Focal cerebral ischemia reperfusion rat model was established by a 2-hour left middle cerebral artery occlusion (MCAO) using an intraluminal filament, followed by 46h of reperfusion. CGRP (1 microg/ml) at the dose of 3 microg/kg was injected intraperitoneally (i.p.) at the beginning of reperfusion for rats in CGRP-treated group. Saline as vehicle (3 ml/kg body weight), i.p., was administered at the beginning of reperfusion for rats in control group. Sham-operated animals were subjected to an operation without MCAO. Forty-eight hours after operation, the samples were taken out and processed for calculating stomach mucous membrane damage index according to Guth method, detecting pathological changes of gastric mucosa tissue by light microscopy, determining mast cell distribution by toluidine blue staining, and observing the expression of gastrin (Gas), somatostatin (SST), aquaporin-4 (AQP4), and basic fibroblast growth factor (bFGF) by immunohistochemical staining. The results showed that: (1) Gastric mucosa with diffuse edema, splinter hemorrhage and erosion, numerous endothelial cells necrosis, mucosa dissociation, infiltration of inflammatory cells were observed in both control and CGRP-treated animals. CGRP administration could reduce the damage of gastric mucosa. The injury index of gastric mucosa was lower in CGRP-treated group as compared with that in control group (P<0.05). (2) Gas expression in gastric antrum mucosa was lower in CGRP-treated group than that in control group (P<0.01). SST expression in gastric antrum mucosa was higher in CGRP-treated group than that in control group (P<0.01). AQP4 expression in gastric mucosa was lower in CGRP-treated group than that in control group (P<0.05). bFGF expression in gastric mucosa was higher in CGRP-treated group than that in control group (P<0.01). (3) The mast cell degranulation ratio in control group in gastric mucosa was significantly higher than that in CGRP-treated group (P<0.01). It is concluded that CGRP can regulate the secretion of Gas, SST, AQP(4), and bFGF, inhibit mast cell degaranulation and thus alleviate the damage of gastric mucosa induced by cerebral ischemia and reperfusion. CGRP may be one of the good candidates of potential clinical therapy drugs for regulating gastric mucosal protection and maintaining gastric mucosal integrity after cerebral ischemia and reperfusion.
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PMID:The protective effects of calcitonin gene-related peptide on gastric mucosa injury after cerebral ischemia reperfusion in rats. 1990 Apr 92

The purpose of the present study was to examine the protective action and mechanisms of pinocembrin (1) on the neurovascular unit (NVU) in permanent cerebral ischemic rats. Focal cerebral ischemia was induced by occlusion of middle cerebral artery (MCAO) in rats. Compound 1 (3, 10, or 30 mg/kg) was intravenously injected at 0, 8, 16 h after MCAO. At 24 h of occlusion, 1 alleviated neuronal apoptosis, edema of astrocytic end-feet, and the deformation of endothelial cells and capillaries as revealed by the transmission electron microscopy study. To understand the mechanisms of action, the anti-inflammation effect of 1 was examined. Compound 1 reduced the expressions of tumor necrosis factor-alpha, interleukin-1beta, intercellular adhesion molecule-1, vascular cell adhesion molecule-1, inducible NO synthase and aquaporin-4; inhibited the activation of microglias and astrocytes; and downregulated the expression of matrix metalloproteinases (MMPs) in the ischemic brain. The ischemia-induced decreases in mRNA expressions of tight junction constituent proteins, occludin and ZO-1, were also inhibited by 1. These results indicated that 1 can protect the rat brain against ischemia injury by inhibiting the inflammatory cascade, reducing the expression of MMP-9, and preventing the integrity of tight junction. This resulted in the protective action of 1 on the NVU.
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PMID:Pinocembrin protects the neurovascular unit by reducing inflammation and extracellular proteolysis in MCAO rats. 2049 98

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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