thiourea and Brain-Edema

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)

Topics: Amino Acids; Animals; Brain; Brain Edema; Brain Ischemia; Dizocilpine Maleate; Drug Interactions; Free Radicals; Male; Neurotoxins; Oxygen; Potassium; Rats; Rats, Inbred Strains; Sodium; Thiourea

Oxygen free radicals have been implicated as mediators of tissue damage in ischemic brain. We previously demonstrated that the hydroxyl radical scavenger 1,3-dimethyl-2-thiourea (DMTU) reduces infarct size after middle cerebral artery occlusion (MCAO) in rats. The present study was undertaken to determine whether this protection results from a preservation of the CBF. Adult male Sprague-Dawley rats were treated with DMTU (750 mg/kg i.p.) or saline vehicle 1 h before right MCAO. One-half 4, or 24 h after MCAO, animals were killed and samples were taken from the central, intermediate, and outer zones of the MCA distribution of each cortical mantle. Separate groups of animals were used to analyze these samples for water content (wet and dry weight), CBF [( 14C]butanol), or blood-brain barrier permeability [( 3H]alpha-aminoisobutyric acid). CBF was reduced in a graded fashion in the ischemic cortex: 0.169 +/- 0.020, 0.261 +/- 0.017, and 0.435 +/- 0.023 ml/g/min (mean +/- SEM, n = 8) after 4 h in the central, intermediate, and outer zones, respectively. Brain edema was present in a similar pattern, while blood-brain barrier permeability remained normal. Treatment with DMTU significantly reduced brain edema in the central and intermediate zones at both 4 and 24 h. However, CBF in the DMTU-treated animals was identical to that of the vehicle-treated animals. These results suggest that hydroxyl radicals play a role in the development of ischemic brain edema, but the mechanism does not appear to involve a direct effect on CBF.

Topics: Animals; Blood-Brain Barrier; Brain Edema; Brain Ischemia; Capillary Permeability; Cerebrovascular Circulation; Male; Rats; Rats, Inbred Strains; Thiourea

The effects of dimethyl sulfoxide (DMSO) and dimethylthiourea (DMTU) and deferoxamine (DFO) were investigated in cats during a standard cortical freezing method for the production of vasogenic brain oedema. Hydroxyl radical scavenging activity was studied by electron spin resonance assay using DMPO as the trap. The hydroxyl radical spin adduct was extinguished by DFO and a large dose of DMTU. Evans blue dye extravasation was reduced in DFO and DMSO treated groups as well. DFO appears to be an effective agent for the prevention of cold induced oedema. DMSO and DMTU are direct hydroxyl radical scavengers. These studies suggest that scavenging the hydroxyl radicals has a beneficial effect in the treatment of traumatic brain oedema.

Topics: Animals; Body Water; Brain; Brain Edema; Brain Injuries; Cats; Deferoxamine; Dimethyl Sulfoxide; Free Radical Scavengers; Freezing; Thiourea

Oxygen-free radicals have been implicated as causative factors in ischaemic and traumatic processes. Oxygen-free radical scavengers can be used potentially to treat brain oedema. We investigated the effects of superoxide dismutase and dimethylthiourea on brain oedema. Vasogenic brain oedema was produced in 44 cats by a cortical freezing lesion. Animals were separated into three groups: (1) cold-induced oedema with sacrifice at 6, 24 and 48 h; (2) cold-induced oedema with sacrifice at 6, 24 and 48 h: subgroup A was pretreated with 10,000 u./kg polyethylene glycol and superoxide dismutase; subgroup B received a bolus injection of free superoxide dismutase (4 mg/kg) and then 1 mg/kg/min for 20 min; (3) cold-induced oedema with sacrifice at 6 and 24 h: this group was pretreated with 500 mg/kg dimethylthiourea. Brain water content was measured by the specific gravity method. Detection of superoxide radicals was carried out by the direct cortical application of nitroblue tetrazolium. Free and polyethylene glycol-superoxide dismutase did not prevent the development of brain oedema, but superoxide radicals were detected in the cold lesion. Dimethylthiourea prevented the development of brain oedema in the white matter adjacent to the lesion at 6 h but not at 24 h. These findings indicate that oxygen-free radicals are generated by the brain following cold injury and the demonstration of these radicals offers an important clue in the genesis of traumatic brain oedema.

Topics: Animals; Brain Edema; Cats; Female; Free Radicals; Male; Oxygen; Superoxide Dismutase; Thiourea

The contribution of toxic O2 metabolites to cerebral ischemia reperfusion injury has not been determined. We found that gerbils subjected to temporary unilateral carotid artery occlusion (ischemia) consistently developed neurologic deficits during ischemia with severities that correlated with increasing degrees of brain edema and brain H2O2 levels after reperfusion. In contrast, gerbils treated just before reperfusion (after ischemia) with dimethylthiourea (DMTU), but not urea, had decreased brain edema and brain H2O2 levels. In addition, gerbils fed a tungsten-rich diet for 4, 5, or 6 wk developed progressive decreases in brain xanthine oxidase (XO) and brain XO + xanthine dehydrogenase (XD) activities, brain edema, and brain H2O2 levels after temporary unilateral carotid artery occlusion and reperfusion. In contrast to tungsten-treated gerbils, allopurinol-treated gerbils did not have statistically significant decreases in brain XO or XO + XD levels, and reduced brain edema and brain H2O2 levels occurred only in gerbils developing mild but not severe neurologic deficits during ischemia. Finally, gerbils treated with DMTU or tungsten all survived, while greater than 60% of gerbils treated with urea, allopurinol, or saline died by 48 h after temporary unilateral carotid artery occlusion and reperfusion. Our findings indicate that H2O2 from XO contributes to reperfusion-induced edema in brains subjected to temporary ischemia.

Topics: Allopurinol; Animals; Brain; Brain Chemistry; Brain Edema; Brain Ischemia; Female; Gerbillinae; Hydrogen Peroxide; Male; Nervous System Diseases; Thiourea; Tungsten; Urea; Xanthine Oxidase

Topics: Animals; Brain Edema; Cats; Dogs; Metiamide; Radiation Injuries, Experimental; Thiourea; Yttrium Radioisotopes