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

Even though oxygen is necessary for aerobic life, it can also participate in potentially toxic reactions involving oxygen free radicals and transition metals such as Fe that damage membranes, proteins, and nucleic acids. Oxygen free radical reactions and oxidative damage are in most cases held in check by antioxidant defense mechanisms, but where an excessive amount of oxygen free radicals are produced or defense mechanisms are impaired, oxidative damage may occur and this appears to be important in contributing to several pathological conditions including aging, carcinogenesis, and stroke. Several newer methods, such as in vivo spin-trapping, have become available to monitor oxygen free radical flux and quantitate oxidative damage. Using a combination of these newer methods collectively focused on one model, recent results show that oxidative damage plays a key role in brain injury that occurs in stroke. Subtle changes, such as oxidative damage-induced loss of glutamine synthetase activity, may be a key event in stroke-induced brain injury. Oxygen free radicals may play a key role in carcinogenesis by mediating formation of base adducts, such as 8-hydroxyguanine, which can now be quantitated to very low levels. Evidence is presented that a new class of free radical blocking agents, nitrone spin-traps, may help not only to clarify if free radical events are involved, but may help prevent the development of injury in certain pathological conditions.
 ...
PMID:Role of oxygen free radicals in carcinogenesis and brain ischemia. 218 75

The methionine analogue methionine sulfoximine was administered to 10 rats 24 hours before occlusion of the proximal left middle cerebral artery. Three days later the rats were decapitated and the brain infarct volumes were compared with those in 10 control rats that received saline before middle cerebral artery occlusion. The mean volume of the infarct in the cerebral cortex was reduced by 33% in the group treated with methionine sulfoximine (p less than 0.01). This protective effect may be mediated by a presynaptic mechanism; methionine sulfoximine profoundly inhibits brain glutamine synthetase, thereby interrupting the astrocyte-neuron glutamate shuttle and impairing neuronal glutamate release. Methionine sulfoximine also increases brain glycogen stores, and this increased energy reserve may benefit penumbral tissue during the peri-infarct period. Further study of the mechanisms by which methionine sulfoximine decreases infarct volume could lead to new therapeutic approaches for stroke.
Stroke 1990 Feb
PMID:Methionine sulfoximine reduces cortical infarct size in rats after middle cerebral artery occlusion. 230 10

Intracerebral hemorrhage (ICH) is a devastating stroke sub-type with high mortality and morbidity. ICH frequently occurs in subcortical white matter generating hematomas that contain high heme iron levels. In this study, we examined the consequences of iron-induced oxidation (1-100 microM Fe2+ for 30 min. or 50 microM Fe2+ for 1-120 min.) on the activities of two oxidatively sensitive enzymes, creatine kinase (CK) and glutamine synthetase (GS), and on an oxidative stress marker, protein carbonyl formation, in porcine cerebral cortical white and gray matter. In vitro iron oxidation produced time and concentration dependent decreases in both CK [maximum decreases of 49.3+/-1.2% and 44.3+/-4.1% (average +/- SEM, N=3) for white and gray matter, respectively] and GS activities (maximum decreases of 16.9+/-1.7% and 13.2+/-1.0% for white and gray matter, respectively) and increases in protein carbonyl formation. Interestingly, protein carbonyl concentrations were significantly greater (p<0.05) in white vs. gray matter at 100 microM iron (30 min.) and 50 microM iron (120 min.). Additionally, CK and GS activities were lower for white versus gray matter at several time points and iron concentrations. It is our hypothesis that iron induced oxidative stress contributes to the pathogenesis of perihematomal brain injury following ICH.
 ...
PMID:Protein oxidation and enzyme susceptibility in white and gray matter with in vitro oxidative stress: relevance to brain injury from intracerebral hemorrhage. 1087 54

Environmental enrichment (EE) alleviates sensorimotor deficits after brain infarcts but the cellular correlates are not well-known. This study aimed to test the effects of postischemic EE on neocortical cell genesis. A neocortical infarct was caused by distal ligation of the middle cerebral artery in adult spontaneously hypertensive rats, subsequently housed in standard environment or EE. Bromodeoxyuridine (BrdU) was administered during the first postischemic week to label proliferating cells and BrdU incorporation was quantified 4 weeks later in the periinfarct, ipsilateral medial and contralateral cortex. Immunohistochemistry and confocal microscopy were used to analyze co-localization of BrdU with neuronal (calbindin D28k, calretinin, parvalbumin, glutamic acid decarboxylase, tyrosine hydroxylase), astrocytic (glial fibrillary acidic protein, glutamine synthetase, vimentin, nestin), microglia/macrophage (CD11b/Ox-42, CD68/ED-1), oligodendrocyte progenitor/polydendrocyte (NG2, platelet-derived growth factor alpha receptor) or mature oligodendrocyte (myelin basic protein) markers. BrdU positive cells were increased in all analyzed cortical regions in stroke EE rats compared with stroke standard environment rats. Newly born cells in the periinfarct cortex were mostly reactive astroglia. Occasionally, BrdU positive cells in the periinfarct cortex that were negative for glial or microglia/macrophage markers co-expressed markers typical for interneurons but did not express appropriate functional markers. The majority of BrdU positive cells in intact cortical regions, ipsi- and contralaterally, were identified as NG2 positive polydendrocytes. Perineuronally situated newly born cells and polydendrocytes were found to be brain-derived neurotrophic factor immunoreactive. In conclusion, EE enhanced newborn glial scar astroglia and NG2+ polydendrocytes in the postischemic neocortex which might be beneficial for brain repair and poststroke plasticity.
 ...
PMID:Enriched environment after focal cortical ischemia enhances the generation of astroglia and NG2 positive polydendrocytes in adult rat neocortex. 1642 25

In the present study, memantine (MN) an uncompetitive N-methyl-D-aspartate (NMDA) open channel blocker has been investigated for its suitable therapeutic time-window on the basis of its influence on behavioural and biochemical changes in rats subjected to transient focal ischemia. MN (20 mg/kg, ip) was administered at pre, during and post ischemic state and the extent of neuroprotection was compared to ascertain its therapeutic time-window in stroke treatment. Neuroprotective effect was assessed by measuring glutamate, glutamine synthetase, glutathione, Na+K+ATPase, adenosine triphosphate (ATP) and nicotinamide adenine dinucleotide (NAD), lactate and pyruvate levels. Middle cerebral artery occlusion produced neurological deficits, anxiogenic behaviour, histological changes, increased glutamate levels along with depletion of Na+K+ATPase, energy stores such as ATP, NAD, lactate, and antioxidant glutathione. MN significantly restored glutamate, glutamine synthetase, Na+K+ATPase and lactate levels on preischemic administration. In addition, MN reversed the altered neurological and behavioural paradigms significantly and prevented the neurodegeneration on preischemic treatment. However, it failed to exert any effect on energy metabolite (ATP and NAD) levels irrespective of the treatment phase. Based on the present data, it is summarized that the suitable therapeutic time window of MN is preischemic phase in stroke and it possesses only a subjective role in reversing ischemic brain biochemical alterations preferentially in favor of neuronal homeostasis.
 ...
PMID:Pre-ischemic treatment with memantine reversed the neurochemical and behavioural parameters but not energy metabolites in middle cerebral artery occluded rats. 1946 56

The present study focuses on the temporal calcium significance in middle cerebral artery occluded (2 h ischemia)-reperfused (70 h reperfusion) rats treated with nimodipine (NM) through concurrent measurements of excitotoxicity, bioenergetics and neurobehavioural paradigms. Further, the suitable therapeutic time window of calcium channel antagonism in stroke was also ascertained. NM (5 mg/kg, i.p.) was administered at pre (30 min before the induction of ischemia), during (1 h following occlusion of MCA) and post-ischemic (3 h after begin of reperfusion) states. The magnitude of neuroprotection in terms of excitotoxicity (glutamate, glutamine synthetase, Na(+)K(+)ATPase), bioenergetics (ATP, NAD(+)) and neurobehavioural paradigms (neurological score and open field exploratory behaviour) were measured and compared to ensure the therapeutic time-window of NM in stroke. Middle cerebral artery occlusion-reperfusion (MCAO/R) was found to elevate glutamate, glutamine synthetase levels and deplete Na(+)K(+)ATPase activity in the vehicle treated group (IR group). Significant decrease in bioenergetics such as ATP and NAD(+) levels was also observed. Further, IR group demonstrated grievous oxidative stress (increase in lipid peroxidation, protein carbonyl content, nitrite/nitrate levels and decrease in superoxide dismutase and glutathione levels) along with anxiogenic behaviour, neurological deficits and neuronal damage and decreased nuclear to cytoplasm ratio in CA1 hippocampal region. Post-ischemic NM administration reversed the excitotoxicity, neurobehavioural and histopathological alterations significantly, but it restored bioenergetics level in MCAO/R rats only partially. These findings were further confirmed with the combination treatment (CT) of post-ischemic NM and pre-ischemic memantine (MN) administration, since MN showed protective effect in the pre-ischemic administration (Babu and Ramanathan, 2009). The failure of NM to forefend the neurodegeneration on pre- and during-ischemic administration suggests that the initial phase damages in ischemic-reperfusion (IR) might be mediated through other mechanism(s) such as glutamergic overstimulation or reverse operation of glutamate transporters. From the present study, it is concluded that calcium plays a crucial role in post-ischemic status and the suitable therapeutic time window of calcium antagonism is the post-ischemic state.
 ...
PMID:Post-ischemic administration of nimodipine following focal cerebral ischemic-reperfusion injury in rats alleviated excitotoxicity, neurobehavioural alterations and partially the bioenergetics. 2071 50

Interactions between neurons and astrocytes play a critical role in the central nervous system homeostasis. Cyperus rotundus (family: Cyperaceae), a traditional Indian medicinal herb, used as nervine tonic and nootropic in the Ayurvedic system of medicine. The present study was undertaken to investigate the neuroprotective effect of total oligomeric flavonoids (TOFs), prepared from C. rotundus, in rat model of cerebral ischemia and reperfusion. Male Sprague Dawley rats (290-340g) were subjected to middle cerebral artery occlusion (MCAO) for 2h and reperfusion for 70h. Experimental animals were divided into four groups: Group I - sham operated (n=7); Group II - vehicle treated ischemic-reperfusion (IR) (n=9), and Group III and IV - TOFs treated (100 and 200mg/kg body weight, p.o., respectively; n=7 in each group). Vehicle or TOFs were pretreated for four days before the induction of ischemia and continued for next three days after the ischemia i.e. treatment was scheduled totally for a period of 7 days. MCAO surgery was performed on day 4, 1h after TOFs administration. Neuroprotective effect of TOFs was substantiated in terms of neurological deficits, excitotoxicity (glutamate, glutamine synthetase and Na(+)K(+)ATPase levels), oxidative stress (malondialdehyde, super oxide dismutase, and glutathione) and neurobehavioral functions in the experimental animals. TOFs decreased glutamate, glutamine synthetase (GS) and increased Na(+)K(+)ATPase activity in a dose dependent manner when compared to the IR rats. Treatment with TOFs significantly reduced the neurological deficits and reversed the anxiogenic behavior in rats. Further, it also significantly decreased MDA and increased superoxide dismutase (SOD) and glutathione content in brains of experimental rats. Histopathological examination using cresyl violet staining revealed the attenuation of neuronal loss by TOFs in stroke rats. The present study demonstrates the unswerving involvement of TOFs on ischemia-reperfusion triggered biochemical alterations in MCAO/R rats. Hence, TOFs might be an attractive candidate for further studies in the development of new drugs for cerebral stroke treatment.
 ...
PMID:Total oligomeric flavonoids of Cyperus rotundus ameliorates neurological deficits, excitotoxicity and behavioral alterations induced by cerebral ischemic-reperfusion injury in rats. 2127 18

Astrocyte activation is a hallmark of the response to brain ischemia consisting of changes in gene expression and morphology. Heat shock protein 72 (Hsp72) protects from cerebral ischemia, and although several protective mechanisms have been investigated, effects on astrocyte activation have not been studied. To identify potential mechanisms of protection, microarray analysis was used to assess gene expression in the ischemic hemispheres of wild-type (WT) and Hsp72-overexpressing (Hsp72Tg) mice 24 h after middle cerebral artery occlusion or sham surgery. After stroke both genotypes exhibited changes in genes related to apoptosis, inflammation, and stress, with more downregulated genes in Hsp72Tg and more inflammation-related genes increased in WT mice. Genes indicative of astrocyte activation were also upregulated in both genotypes. To measure the extent and time course of astrocyte activation after stroke, detailed histological and morphological analyses were performed in the cortical penumbra. We observed a marked and persistent increase in glial fibrillary acidic protein (GFAP) and a transient increase in vimentin. No change in overall astrocyte number was observed based on glutamine synthetase immunoreactivity. Hsp72Tg and WT mice were compared for density of astrocytes expressing activation markers and astrocytic morphology. In animals with comparable infarct size, overexpression of Hsp72 reduced the density of GFAP- and vimentin-expressing cells, and decreased astrocyte morphological complexity 72 h following stroke. However, by 30 days astrocyte activation was similar between genotypes. These data indicate that early modulation of astrocyte activation provides an additional novel mechanism associated with Hsp72 overexpression in the setting of ischemia.
 ...
PMID:Effects of heat shock protein 72 (Hsp72) on evolution of astrocyte activation following stroke in the mouse. 2294 Apr 31

The astrocytic response to ischemic brain injury is characterized by specific alterations of glial cell morphology and function. Various studies described both beneficial and detrimental aspects of activated astrocytes, suggesting the existence of different subtypes. We investigated this issue using a novel object-based approach to study characteristics of astrogliosis after stroke. Spontaneously hypertensive rats received permanent middle cerebral artery occlusion. After 96 h, brain specimens were removed, fixed and stained for GFAP, glutamine synthetase (GS), S100Beta and Musashi1 (Msh1). Three regions of interest were defined (contralateral hemisphere, ipsilateral remote zone and infarct border zone), and confocal stacks were acquired (n=5 biological with each n=4 technical replicates). The stacks were background-corrected and colocalization between the selected markers and GFAP was determined using an automated thresholding algorithm. The fluorescence and colocalization channels were then converted into 3D-objects using both intensity and volume as filters to ultimately determine the final volumes of marker expression and colocalization, as well as the morphological changes of astrocyte process arborisation. We found that both S100Beta and Msh1 determined the same GFAP-positive astroglial cell population albeit the cellular compartments differed. GFAP stained most of the astrocyte processes and is hence suitable for the analysis of qualitative characteristics of astrogliosis. Due to its peri-nuclear localization, Msh1 is appropriate to estimate the total number of astrocytes even in regions with severe reactive astrogliosis. GS expression in GFAP-positive astrocytes was high in the remote zone and low at the infarct border, indicating the existence of astrocyte subclasses.
 ...
PMID:Object-based analysis of astroglial reaction and astrocyte subtype morphology after ischemic brain injury. 2359 85

Histamine, a neurotransmitter or neuromodulator has been demonstrated to be neuroprotective in cerebral ischemia. However, few reports concern its function on astrocytes during cerebral ischemia. The purpose of this study was to investigate the effects of histamine on astrocytic cell damage and glutamate signaling, especially on glutamine synthetase (GS) expression in primary cultured cortical astrocytes exposed to oxygen-glucose deprivation (OGD) insult. OGD for 6h caused a severe damage of astrocytic mitochondrial function, and decreased GS expression and then increased the extracellular glutamate level. Pretreatment with histamine significantly prevented the cell damage and rescued the expression of GS in a concentration-dependent manner. The protective effect of histamine on astrocytic cell damage could be partly reversed either by H1 receptor antagonist pyrilamine or H2 receptor antagonist cimetidine. However, the regulatory effect of histamine on GS expression was antagonized only by pyrilamine. In addition, bisindolylmaleimide II, a broad-spectrum inhibitor of PKC, reversed the regulatory action of histamine on GS expression. These results indicate that histamine can effectively protect against OGD-induced cell damage in astrocytes through H1 and H2 receptors, and its regulatory effect on astrocytic GS expression may be due to the activation of H1 receptor and PKC pathway. Histamine may be an endogenous protective factor and calls for its further study as a regulator of astrocyte function during ischemic stroke.
...
PMID:Modulation of astrocytic glutamine synthetase expression and cell viability by histamine in cultured cortical astrocytes exposed to OGD insults. 2379 24


1 2 Next >>