Ischemic Brain Edema Formation Research Articles

Impact of endovascular recanalization on quantitative lesion water uptake in ischemic anterior circulation strokes

Studies evaluating the effect of reperfusion on ischemic edema in acute stroke described conflicting results. Net water uptake (NWU) per brain volume is a new quantitative imaging biomarker of space-occupying ischemic edema, which can be measured in computed tomography (CT). We sought to investigate the effects of vessel recanalization on the formation of ischemic brain edema using quantitative NWU. In this multicenter observational study, acute ischemic stroke patients with a large vessel occlusion (LVO) in the anterior circulation were consecutively screened. Patients with vessel recanalization (thrombolysis in cerebral infarction (TICI) 2 b or 3) versus persistent vessel occlusion (no thrombectomy, TICI 0-1) were compared. Lesion-NWU was quantified in multimodal admission CT and follow-up CT (FCT), and ΔNWU was calculated as difference. Of 194 included patients, 150 had successful endovascular recanalization and 44 persistent LVO. In FCT after treatment, the mean (standard deviation) ΔNWU was 15.8% (5.7) in patients with persistent LVO and 9.8% (5.8) with vessel recanalization (p < 0.001). In multivariate regression analysis, vessel recanalization was independently associated with a lowered ΔNWU by 6.3% compared to LVO (95% confidence interval: 3.7–9.0, p < 0.001). Successful vessel recanalization was associated with a significantly reduced formation of ischemic brain edema. Quantitative NWU may be used to compare the treatment effects in acute stroke.

Central Role of Maladapted Astrocytic Plasticity in Ischemic Brain Edema Formation.

Brain edema formation and the ensuing brain damages are the major cause of high mortality and long term disability following the occurrence of ischemic stroke. In this process, oxygen and glucose deprivation and the resulting reperfusion injury play primary roles. In response to the ischemic insult, the neurovascular unit experiences both intracellular and extracellular edemas, associated with maladapted astrocytic plasticity. The astrocytic plasticity includes both morphological and functional plasticity. The former involves a reactive gliosis and the subsequent glial retraction. It relates to the capacity of astrocytes to buffer changes in extracellular chemical levels, particularly K+ and glutamate, as well as the integrity of the blood-brain barrier (BBB). The latter involves the expression and activity of a series of ion and water transport proteins. These molecules are grouped together around glial fibrillary acidic protein (GFAP) and water channel protein aquaporin 4 (AQP4) to form functional networks, regulate hydromineral balance across cell membranes and maintain the integrity of the BBB. Intense ischemic challenges can disrupt these capacities of astrocytes and result in their maladaptation. The maladapted astrocytic plasticity in ischemic stroke cannot only disrupt the hydromineral homeostasis across astrocyte membrane and the BBB, but also leads to disorders of the whole neurovascular unit. This review focuses on how the maladapted astrocytic plasticity in ischemic stroke plays the central role in the brain edema formation.

Erratum in “Antioxidant Activity-Mediated Neuroprotective Effects of an Antagonist of AT1 Receptors, Candesartan, Against Cerebral Ischemia and Edema in Rats,”

We examined the effects of post-ischemic blockade of angiotensin AT1 receptors by candesartan on cerebral infarction and formation of edema. Male Sprague–Dawley rats were divided into three groups, sham, control ischemic, and candesartan-treated (0.3 mg/kg) ischemic. Transient focal cerebral ischemia was induced by 90-min-long occlusion of the left middle cerebral artery followed by 24-h-long reperfusion. Neurological deficit score was evaluated at the end of the reperfusion period. Thereafter, the animals were randomly selected and used for three projects: (i) Measurement of the infarct volumes, (ii) investigation of ischemic brain edema formation using a wet/dry method, and (iii) assessment of the malondialdehyde (MDA) and reduced glutathione (GSH) concentrations using a HPLC technique. Induction of cerebral ischemia in the control group produced considerable infarctions in the cortex and striatum in conjunction with severely impaired motor functions. Candesartan treatment significantly reduced the infarct volumes and improved the above functions. The water content in the left (lesioned) hemisphere was considerably elevated in the control ischemic group. Candesartan treatment significantly lowered the water content in the ischemic lesioned hemisphere, retained tissue GSH level, and led to a lower MDA production. AT1 receptor blockade by candesartan treatment can noticeably decrease ischemic brain injury and attenuate edema formation, likely via increasing the antioxidant activity.

Antioxidant Activity-Mediated Neuroprotective Effects of an Antagonist of AT1 Receptors, Candesartan, against Cerebral Ischemia and Edema in Rats

We examined the effects of post-ischemic blockade of angiotensin AT1 receptors by candesartan on cerebral infarction and formation of edema. Male Sprague–Dawley rats were divided into three groups, sham, control ischemic, and candesartan-treated (0.3 mg/kg) ischemic. Transient focal cerebral ischemia was induced by 90-min-long occlusion of the left middle cerebral artery followed by 24-h-long reperfusion. Neurological deficit score was evaluated at the end of the reperfusion period. Thereafter, the animals were randomly selected and used for three projects: (i) Measurement of the infarct volumes, (ii) investigation of ischemic brain edema formation using a wet/dry method, and (iii) assessment of the malondialdehyde (MDA) and reduced glutathione (GSH) concentrations using a HPLC technique. Induction of cerebral ischemia in the control group produced considerable infarctions in the cortex and striatum in conjunction with severely impaired motor functions. Candesartan treatment significantly reduced the infarct volumes and improved the above functions. The water content in the left (lesioned) hemisphere was considerably elevated in the control ischemic group. Candesartan treatment significantly lowered the water content in the ischemic lesioned hemisphere, retained tissue GSH level, and led to a lower MDA production. AT1 receptor blockade by candesartan treatment can noticeably decrease ischemic brain injury and attenuate edema formation, likely via increasing the antioxidant activity.

Aquaporin-4 and ischemic brain edema*

Objective To investigate the relationship of aquaporin 4 (AQP 4) and brain edema. Data sources Using the terms of “aquaporin-4, brain edema”, we searched PubMed database to identify studies published from January 1997 to April 2006 in the English languages. Meanwhile, we also searched China National Knowledge Infrastructure (CNKI) for related studies. Study selection The collected data were selected firstly. Studies on AQP 4 and brain edema were chosen and their full-texts were searched for, and those with repetitive or review studies were excluded. Data extraction Totally 146 related studies were collected, 42 of them were involved and the other 104 studies were used for reading reference data. Data synthesis AQP 4 is a selective water permeable integral membrane protein. It is mainly expressed in astrocytes and ependymocyte, and is the important structural basis for water regulation and transportation between glial cells and cerebrospinal fluid or vessels. Phosphorylation is involved in the regulation of AQP 4. AQP 4 participates in the formation of brain edema caused by various factors. Studies on the structure and pathological changes of AQP 4 are still in the initial stage, and the role and mechanism of AQP 4 in the formation of brain edema is very unclear. Conclusion AQP 4 plays a critical regulating role in the formation of ischemic brain edema, but whether it is regulated by drugs lacks reliable evidence.

Secondary ischemia impairing the restoration of ion homeostasis following traumatic brain injury

It is well established that posttraumatic secondary ischemia contributes to poor outcome. Ion dysfunction leading to cytotoxic edema is a primary force in the formation of ischemic brain edema and is a principal component of traumatic brain swelling. Because cell swelling is the result of net ion and water movement, it is crucial to have a thorough understanding of these transient phenomena. The purpose of this study was to characterize the effects of secondary ischemia following traumatic brain injury (TBI) on the ability to restore ion homeostasis. Twenty-four Sprague-Dawley rats were divided into four groups of six animals each. The rats underwent transient forebrain ischemia via bilateral carotid artery occlusion combined with hypotension: 15 minutes of forebrain ischemia (Group 1); 60 minutes of forebrain ischemia (Group 2); impact acceleration/TBI (Group 3); and impact acceleration/TBI followed by 15 minutes of ischemia (Group 4). Ischemia resulted in a rapid accumulation of [K+]e:41.94 +/- 13.65 and 66.33 +/- 6.63 mM, respectively, in Groups 1 and 2, with a concomitant decrease of [Na+]e:64 +/- 18 mM and 72 +/- 11 mM in Groups 1 and 2. Traumatic brain injury resulted in a less severe although identical trend in ion dysfunction ([K+]e 30.42 +/- 11.67 mM and [Na+]e 63 +/- 33 mM). Secondary ischemia resulted in prolonged and sustained ion dysfunction with a concomitant elevation of intracranial pressure (ICP). Analysis of these results indicates that ischemia and TBI are sublethal in isolation; however, when TBI is associated with secondary ischemia, ion dysfunction is sustained and is associated with elevated ICP.

Attenuation of ischemic brain edema and cerebrovascular injury after ischemic preconditioning in the rat.

Ischemic preconditioning (IPC) induces neuroprotection to subsequent severe ischemia, but its effect on the cerebrovasculature has not been studied extensively. This study evaluated the effects of IPC on brain edema formation and endothelial cell damage that follows subsequent permanent focal cerebral ischemia in the rat. Transient (15 minute) middle cerebral artery occlusion (MCAO) was used for IPC. Three days after IPC or a sham operation, permanent MCAO was induced. Twenty-four hours after permanent MCAO, neurologic deficit, infarction volume, and water and ion content were evaluated. Six hours post-ischemia, blood-brain barrier (BBB) permeability was examined using [3H]-inulin. Water, ion contents, and BBB permeability were assessed in three zones (core, intermediate, and outer) depending on their relation to the MCA territory. Heat shock protein 70 (HSP70) was also examined as a potential marker of vascular injury. The model of IPC significantly reduced brain infarction and neurologic deficit. Compared with a sham operation, IPC also significantly attenuated brain edema formation in the intermediate (sham and IPC water contents: 5.99+/-0.65 vs. 4.99+/-0.81 g/g dry weight; P < 0.01) and outer zones (5.02+/-0.48 vs. 4.37+/-0.42 g/g dry weight; P < 0.01) of the ipsilateral hemisphere but not in the core zone. Blood-brain barrier disruption assessed by [3H]-inulin was significantly attenuated in the IPC group and the number of blood vessels that displayed HSP70 immunoreactivity was also reduced. Thus, IPC significantly attenuates ischemic brain edema formation, BBB disruption, and, as assessed by HSP70, vascular injury. Understanding the mechanisms involved in IPC may provide insight into methods for preserving cerebrovascular function during ischemia.

Cerebral ischemia reperfusion-induced vasogenic brain edema formation in rats: effect of an intracellular histamine receptor antagonist.

Resuscitation in pediatric emergency and some neurological interventions may result in ischemia reperfusion-induced cerebral injuries. Histamine is one of the well established mediators of cerebral swelling and H1- and H2-receptor antagonists could prevent the development of ischemic brain edema. In the present study, time-dependent changes in the blood-brain barrier (BBB) permeability were investigated in the cerebral cortex of male Wistar rats 1, 2, 4, 8, and 16 h after the beginning of post-ischemic reperfusion. Cerebral ischemia-reperfusion evoked by the 4-vessel occlusion model resulted in significant (p < 0.05) elevations in BBB permeability for albumin, but not for sodium fluorescein. Pre-treatment with a new intracellular histamine receptor antagonist could not prevent ischemic brain edema formation in that model. We conclude that experimental studies could help us to reveal the therapeutic role of histamine receptor antagonists during ischemic brain edema.

The effect of endothelins on ion transport systems in cultured rat brain capillary endothelial cells.

Brain capillary endothelial cells regulate the movement of ions and water across the blood-brain barrier via specific ion transport systems. Disturbances in these ion transport systems are involved in the formation of ischemic brain edema. This study describes the effects of endothelins (i.e., ET-1 and ET-3) on ion transport systems in cultured rat brain capillary endothelial cells using 86Rb+ and 22Na+ as markers for K+ and Na+, respectively. ET-1 stimulated K+ uptake and efflux with EC50 values of 0.6 nM and 0.5 nM, respectively. The potencies of ET-3 on these responses were considerably lower. Both ET-1 and ET-3 stimulated Na+ uptake through a Na+/H+ exchange system with similar potencies (i.e., EC50 = 0.80 nM and 1.89 nM, respectively). ET-stimulated K+ uptake, K+ efflux, and Na+ uptake activities were all inhibited by BQ123 (selective ETA receptor antagonist). ET-1 stimulated K+ uptake and efflux, in contrast to Na+ uptake, were also reduced by protein kinase C inhibitors and by an intracellular Ca2+ chelator. The results suggest that ETs can affect the activities of ion and water transport at the blood-brain barrier through different signal transduction mechanisms.

Interleukin-1 as a pathogenetic mediator of ischemic brain damage in rats.

It has been suggested that interleukin-1 (IL-1) is a potent inflammatory mediator and that it is synthesized and secreted into the brain parenchyma. The aim of the present study is to evaluate the contribution of IL-1 to brain edema formation after focal brain ischemia. The brain water content was measured to evaluate postischemic brain injury in rats after 60 minutes of middle cerebral artery occlusion and reperfusion. The effects of exogenous application of recombinant human interleukin-1 beta (rhIL-1 beta), anti-interleukin-1 beta neutralizing antibodies (anti-IL-1 beta), and the IL-1 blocker zinc protoporphyrin (ZnPP) on brain water content were observed, and histological technique was used to measure the infarction size and number of inflammatory cells infiltrated into the brain. Transient ischemia induced marked increase of brain water content, necrosis, and neutrophilic infiltration in the cortex perfused by the middle cerebral artery and the dorsal and ventral areas of the caudate putamen. Injection of rhIL-1 beta into the left lateral ventricle immediately after reperfusion markedly enhanced ischemic brain edema formation in these three areas in a dose-dependent manner (88.4 +/- 0.7% and 86.6 +/- 0.4% in the dorsal and ventral parts of the caudate putamen, respectively, in rats treated with 10 ng rhIL-1 beta; P < .01). rhIL-1 beta also increased the size of the brain infarction, and it tended to increase the number of infiltrating neutrophils in ischemic areas and the number of neutrophils adherent to the endothelium. In contrast, administration of anti-IL-1 beta and ZnPP into the left cerebral ventricle attenuated the postischemic increase of brain water content and decreased the size of brain infarction (83.5 +/- 2.0% and 79.9 +/- 2.0% in the dorsal and ventral parts of the caudate putamen, respectively, in rats treated with 10 micrograms anti-IL-1 beta; P < .01). The number of neutrophils that infiltrated into ischemic areas also tended to decrease with anti-IL-1 beta or ZnPP treatment. Application of rhIL-1 beta augmented the increase of brain water content, and application of anti-IL-1 beta depressed the increase of water content. These results tended to correlate with the neutrophilic infiltration into the parenchyma. It thus appears that IL-1 beta may play an important role in ischemic brain damage after reperfusion.

Liposome-entrapped superoxide dismutase reduces ischemia/reperfusion ?oxidative stress? in gerbil brain

Bilateral common carotid artery occlusion (15 min.) followed by two hours of recirculation reduced mitochondrial superoxide dismutase (SOD) and glutathione reductase (GR) activities, and increased susceptibility of mitochondrial membranes to in vitro lipid peroxidation in brain regions (i.e., cortex, striatum and hippocampus) of Mongolian gerbil. Intraperitoneal bolus injection (2 mg/kg b.w.) of liposome-entrapped CuZn superoxide dismutase (1-SOD) increased the endogenous SOD activity in normal brain tissue and, when given at the end of ischemia, counteracted both the ischemic reduction of endogenous SOD and the increased peroxidation of mitochondrial membranes. 1-SOD treatment was ineffective in reducing brain swelling, suggesting that superoxide radicals are not a main participant in the process of (post)ischemic brain edema formation.

Cyclosporin A protects against ischemia-reperfusion injury in the brain

We investigated the protective effect of Cyclosporin A (CsA) against ischemia-reperfusion injury in the brain using a transient focal ischemia model in rats. In CsA-treated rats, ischemic brain edema formation 1 day after reperfusion in the cerebral cortex perfused by the middle cerebral artery (MCA) and infarct size were decreased compared with those in olive oil treated control rats. These results suggest that CsA is beneficial in reducing ischemia-reperfusion injury, possibly by the suppression of immunological reactions.

Possible involvement of interleukin-1 in ischemic brain edema formation

To determine the contribution of interleukin 1 (IL-1) on ischemic brain edema formation, the effect of recombinant human interleukin 1β (rhIL-1β), or zine protoporphyrin (ZnPP) as an IL-1 blocker, on brain edema was studied in rats. The animals were subjected to 60 min of ischemia in a middle cerebral artery occlusion model. Immediately after reperfusion, rhIL-1β at a dose of 10 ng 2 μ1 , or ZnPP at doses of 1 and 10 μ g 2 μ1 were topically applied into lateral cerebroventricle. In rhIL-1β-treated rats, ischemic brain edema formation was significantly increased in the dorsal and ventral areas of the caudate putamen 24 h after reperfusion, compared to that of vehicle-treated control rats. Furthermore, in ZnPP-treated rats, brain edema was decreased in both caudate-putamen areas. This suggests that IL-1 plays an important role in pathogenesis for post-ischemic brain edema.

Interaction between free radicals and excitatory amino acids in the formation of ischemic brain edema in rats.

Both oxygen free radicals and excitatory amino acids have been implicated as important cellular toxins in ischemic brain. Recent in vitro studies suggest that there may be a mutual interaction between these two mediators. We explored the relation between oxygen free radicals and excitatory amino acids in the development of ischemic brain edema in vivo. Male Sprague-Dawley rats were treated with the free radical scavenger dimethylthiourea 1 hour before ischemia or with the excitotoxin antagonist MK-801 30 minutes before ischemia produced by occlusion of the middle cerebral artery. Groups of seven or eight animals were treated with vehicle, low-dose (375 mg/kg) dimethylthiourea, high-dose (750 mg/kg) dimethylthiourea, low-dose (0.5 mg/kg) MK-801, high-dose (2.0 mg/kg) MK-801, or both high-dose dimethylthiourea and low-dose MK-801. After 4 hours of ischemia, brain water content was determined. In eight vehicle-treated controls, mean +/- SEM water content of tissue in the center of the ischemic zone was 83.29 +/- 0.18%. A significant reduction of brain edema was observed in all drug-treated groups: for example, 50.2% (p less than 0.001) in the high-dose dimethylthiourea group, 53.7% (p less than 0.001) in the low-dose MK-801 group, and 66.4% (p less than 0.001) in the combined dimethylthiourea and MK-801 group. Combined treatment with dimethylthiourea and MK-801 provided no significant additive effect over that resulting from treatment with MK-801 alone.(ABSTRACT TRUNCATED AT 250 WORDS)

Neutrophil as a mediator of ischemic edema formation in the brain

We investigated the contribution of neutrophils to brain edema formation using a transient focal ischemia model in rats. Rats were given antineutrophil monoclonal antibody (RP3) intraperitoneally to deplete circulating neutrophils. In RP3-treated rats, ischemic brain edema formation 1 day after reperfusion was significantly decreased compared to that of saline-treated control rats. We speculate that chemical mediators released by infiltrating neutrophils alter vascular permeability and play an important role in post-ischemic brain edema formation.

Blood-brain barrier sodium transport limits development of brain edema during partial ischemia in gerbils.

Sodium derived from the blood is known to accumulate in brain tissue during the early stages of incomplete ischemia. Our present studies were undertaken to determine the relation between blood-brain barrier sodium transport and the development of ischemic brain edema. Incomplete cerebral ischemia was produced in gerbils by ligation of the left common carotid artery under ether anesthesia. Following recovery from the anesthetic, the gerbis were evaluated for the presence of neurologic symptoms and were divided into symptomatic (n = 77) and asymptomatic (n = 94) groups. Tissue water, sodium, and potassium contents, tissue plasma volume, and brain uptake of 22Na were measured in both groups 1.5, 3, 6, 12, and 24 hours after carotid ligation. There was a progressive accumulation of sodium and water in the ipsilateral cerebral cortex of the symptomatic group compared with either the corresponding contralateral cortex of the same gerbils or with the asymptomatic group. Net changes in brain sodium and potassium concentrations appeared to be the main determinants of fluid accumulation. Brain edema was not due to opening of the blood-brain barrier because the unidirectional transport of 22Na remained low and was even reduced by 35-55% in the ischemic cortex. Nevertheless, this sodium transport activity appeared to be rate-limiting in the development of brain edema during the first 3 hours of ischemia because the rate of sodium accumulation in the tissue was the same as the rate of 22Na transport from the blood to the brain. We conclude that blood-brain barrier sodium transport is an important factor in the formation of ischemic brain edema.

Inhibition of ischemic brain edema formation by post-ischemic administration of a prostaglandin oligomer

We studied the efficacy of an oligomeric derivative of prostaglandin E 1 in protecting the rat brain against focal ischemia. The degree of ischemic damage was evaluated from three parameters, namely, the degree of edema formation, reduction of motor performance, and memory disturbance as measured by a passive avoidance test. The pre-ischemic administration of the drug (6 mg/kg i.p.) had some effects, but the differences were not significant. The post-ischemic administration (6 mg/kg i.p.) produced significant improvement in all three parameters. The increase of water content of the ischemic hemisphere was reduced (p<0.05); the total motor score was improved (p<0.01); and the memory disturbance as estimated by the passive avoidance test was reduced (p<0.01). A possible mechanism of protection is discussed.

Ornithine decarboxylase activity and immunohistochemical location in postischemic brain.

Ornithine decarboxylase, rate-limiting in polyamine formation, has been found to be necessary for the development of vasogenic edema after cryogenic cerebral injury and is postulated to be of importance in late ischemic brain edema formation. Ornithine decarboxylase activity and accompanying edema was studied after transient cerebral ischemia in Mongolian gerbils. Bilateral carotid artery occlusion was utilized to produce dense forebrain ischemia. After 4 h of reperfusion a significant elevation in ornithine decarboxylase activity was present (72.5 +/- 24.7 vs 8.5 +/- 2 pmoles/mg protein/h, p less than 0.05). Immunohistochemical localization of ornithine decarboxylase indicated its presence in cortical neurons of ischemic gerbils. This was typically located in the perinuclear cytoplasm and extended into proximal dendrites. Nonischemic animals did not contain ornithine decarboxylase immunoreactivity. These studies show the presence and location of ornithine decarboxylase in cerebral tissue subjected to transient ischemia. The increase in this marker of polyamine activity paralleled previous studies in this model of cerebral edema formation and reperfusion deficit in blood flow and evoked potential, suggesting that ornithine decarboxylase is a marker for and may be associated with those late metabolic events leading to progressive functional deterioration after incomplete cerebral ischemia.

Is Ca 2+-activated potassium efflux involved in the formation of ischemic brain edema?

A possible role of Ca 2+-activated potassium efflux in brain ischemia was studied using a rat focal cortical infarction model. Three days after ischemic insult, tissue contents of water, sodium, potassium and calcium ions were measured. Charybdotoxin, a specific inhibitor of Ca 2+-activated potassium efflux, was found to reduce the formation of ischemic brain edema when a dosage of 0.15 mg/kg was given by i.v. 20–30 min prior to the onset of ischemic insult.

Identification and quantitative analysis of hydroxy-eicosatetraenoic acids in rat brains exposed to regional ischemia.

To clarify possible roles in the pathogenesis of ischemic brain edema, identification and quantitative analysis of hydroxy-eicosatetraenoic acids (HETEs) in rat brains exposed to middle cerebral artery occlusion were carried out using high-performance liquid chromatography. Rat brain sampling was done by in situ freezing 24 and 72 hours after occlusion. Only a small amount of 15-HETE was found in control rat brains. Twenty-four hours after ischemia, 11-HETE appeared, and the amount of 15-HETE tended to increase. Seventy-two hours after ischemia, when brain edema reached its maximum, 5-, 8-, 9-, 11-, 12-, and 15-HETEs were identified, and the amounts of all HETEs except 8- and 12-HETE were significantly increased. The detection of 5-HETE in ischemic rat brain indicates the simultaneous production of leukotrienes in the same brain area. The above results support the view that lipoxygenase products may play significant roles in the formation of ischemic brain edema.