Dimethylthiourea Reduces Ischemic Brain Edema without Affecting Cerebral Blood Flow

Martz, D; Beer, Mary E.; Betz, A. Lorris

doi:10.1038/jcbfm.1990.64

Cited by 60 publications

(18 citation statements)

References 27 publications

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“…The increase in BBB [ 3 H]AIB permeability after intracerebral infusion of lysed RBCs is also greater than that which occurs in focal cerebral ischemia, in which increases of 70% to 100% occur 24 hours after middle cerebral artery occlusion in the rat. 14,36 Similarly, we found that BBB inulin permeability is increased by a factor of 3 at 6 hours after middle cerebral artery occlusion, compared with an 11-fold increase induced by lysed RBCs reported in this study. 37 Because the adverse effect of an ICH seems to result from a "toxic" effect of blood components on the brain, the question arises as to whether clot removal is the best therapeutic strategy, because it would result in the removal of all the toxic components.…”

Section: Discussionsupporting

confidence: 52%

Mechanisms of Edema Formation After Intracerebral Hemorrhage

Hua

Bhasin

et al. 2001

Stroke

178

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Background and Purpose-Red blood cell (RBC) lysis contributes to brain edema formation after intracerebral hemorrhage (ICH), and RBC hemolysate (oxyhemoglobin) has been implicated to be a spasminogen in subarachnoid hemorrhage. Whether cerebral ischemia contributes to brain edema formation after ICH remains unclear, however. The aims of this study were to test whether extravasation of RBCs induces cerebral ischemia and/or blood-brain barrier disruption in a rat ICH model characterized by perihematomal brain edema. Methods-In this study, 87 pentobarbital-anesthetized Sprague-Dawley rats were used. In each animal, saline, packed RBCs, or lysed RBCs were injected into the right caudate nucleus. Sham injections served as controls. Regional cerebral blood flow, brain water and ion contents, blood-brain barrier integrity, and plasma volume were measured. Results-Intraparenchymal infusion of lysed RBCs caused severe brain edema by the first day but did not induce ischemic cerebral blood flows. In contrast, blood-brain barrier permeability increased during the first day after infusion of lysed RBCs (a 3-fold increase) and 3 days after infusion of packed RBCs (a 4-fold increase). Conclusions-These results suggest that ischemia is not present at 24 or 72 hours after hematoma induction by injection of intact or lysed RBCs. RBC constituents that appear after delayed lysis, however, increase blood-brain barrier permeability, which contributes to edema formation. (Stroke. 2001;32:2932-2938.)

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Section: Discussionsupporting

confidence: 52%

Mechanisms of Edema Formation After Intracerebral Hemorrhage

Hua

Bhasin

et al. 2001

Stroke

178

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“…942 In a previous study using ketamine/xylazine-anesthetized rats, cerebral blood flow was found to average 17 ml/100 g/min in the center zone, 26 ml/100 g/min in the intermediate zone, and 44 ml/100 g/min in the outer zone after 4 hours of ischemia. 9 The rats were divided into six groups: eight were treated with vehicle, seven with 375 mg/kg DMTU, eight with 750 mg/kg DMTU, eight with 0.5 mg/kg MK-801, seven with 2.0 mg/kg MK-801, and eight with both 750 mg/kg DMTU and 0.5 mg/kg MK-801. Since our previous experimental results showed that the water content of the nonischemic hemisphere was identical to that in sham-operated control rats, 9 ' 11 in the present study the sham-operated control group was omitted.…”

Section: Methodsmentioning

confidence: 99%

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

Betz

1991

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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 nig/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<0.001) in the high-dose dimethylthiourea group, 53.7% (p<0.001) in the low-dose MK-801 group, and 66.4% (/?<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. These results indicate that pretreatment with either dimethylthiourea or MK-801 can reduce brain edema during the early stages of cerebral ischemia and further suggest that excitatory amino acids and oxygen free radicals may damage the brain by a common pathway. Supported by a grant-in-aid from the American Heart Association of Michigan.Address for correspondence: A. Lorris Betz, MD, PhD, D3227 Medical Professional Building, University of Michigan, Ann Arbor, MI 48109-0718.Received December 28, 1990; accepted March 18, 1991. have shown that excitatory amino acid receptor antagonists have a protective effect on brain following cerebral ischemia. -28One putative source of oxygen free radicals during cerebral ischemia is the arachidonic acid cascade. 29 " 31 Since the activation of excitatory neurotransmitter receptors leads to the release of arachidonic acid, 32 excitatory amino acids could theoretically cause the generation of oxygen free radicals by this mechanism during cerebral ischemia. In support of this hypothesis, oxygen free radical quenchers or lipid peroxidation inhibitors were recently shown to reduce excitatory amino acid-induced neuronal injury in vitro. 33- 34 Other recent reports suggest that oxygen free radicals can themselves cause excitatory amino acid release. PellegriniGiampietro et al 35 reported that oxygen free radicals generated from xanthine-xanthine oxidase stimulated the release of excitatory amino acids from rat hippocampal slices. Furthermore, in an in vitro ischemic model, oxygen free radical quenchers prevented the release of excitatory amino acids. jury mechanisms dur...

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“…Three samples (ipsi-or contralateral) were taken from the remaining tissue using 5-and 7-mm cork borers (Dickinson and Betz, 1992;Martz et al, 1990). The core region was taken from the cortex and striatum underlying the MCA immediately distal to the region of occlusion (Fig.…”

Section: Measurement Of Brain Water and Ion Concentrationmentioning

confidence: 99%

Attenuation of Ischemic Brain EDEMA and Cerebrovascular Injury after Ischemic Preconditioning in the Rat

Masada

Hua

et al. 2001

J Cereb Blood Flow Metab

112

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Summary: 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 [ 3 H]-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 [ 3 H]-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. Key Words: Brain ischemia-Ischemic preconditioning-Brain edema-Blood-brain barrier-HSP70.

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Dimethylthiourea Reduces Ischemic Brain Edema without Affecting Cerebral Blood Flow

Cited by 60 publications

References 27 publications

Mechanisms of Edema Formation After Intracerebral Hemorrhage

Mechanisms of Edema Formation After Intracerebral Hemorrhage

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

Attenuation of Ischemic Brain EDEMA and Cerebrovascular Injury after Ischemic Preconditioning in the Rat

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