Effect of aminophylline on postischemic edema and brain damage in cats

We attempted to ameliorate postischemic edema and brain tissue injury in cats by administering aminophylline to reduce the reactive hyperemia that supposedly aggravates both these sequelae. Forty-one cats were subjected to 1 hour of middle cerebral artery occlusion and were killed after 3 hours, 3 days, or 14 days of recirculation; one half of the cats received 0.916 ml/kg of a 25 mg/ml solution of aminophylline by infusion at a constant rate via the femoral vein starting 10 minutes before release of the occlusion and continuing for 5 minutes after initiation of recirculation; the other half received saline. Regional cerebral blood flow was monitored by the hydrogen clearance method and water content was evaluated by specific gravity measurements after 3 hours of recirculation; the status of the blood-brain barrier was assessed with Evans blue tracer. Morphologic observations were carried out in cats killed after 3 or 14 days of recirculation. Aminophylline-treated cats killed after 3 hours of recirculation showed significantly reduced hyperemia and edema and no leakage of Evans blue, which was present in all untreated cats killed after 3 hours or 3 days of recirculation. Morphologic observations revealed conspicuously more severe ischemic brain tissue damage in the untreated than in the aminophylline-treated cats after 3 and 14 days of recirculation. Our studies indicate the beneficial effect of administration of aminophylline in the amelioration of postischemic edema and brain tissue injury, which is presumably achieved by reduction of reactive hyperemia.     

乌司他丁对创伤性脑水肿合并海水淹溺性肺水肿大鼠的治疗作用

目的 探讨乌司他丁对创伤性脑水肿(TBE)合并海水淹溺性肺水肿(PE-SWD)大鼠的治疗作用. 方法 32只SD大鼠按照随机数字表法分为对照组(8只)和治疗组(24只).脑侧方液压打击伤+气管内灌注海水建立大鼠TBE合并PE-SWD动物模型.伤后治疗组腹腔注射不同剂量(2500、50 000、100 000 U/kg)乌司他丁溶液1 mL,对照组腹腔注射1 mL生理盐水,伤后24 h观察脑、肺组织含水量变化,血清、脑组织、肺组织白细胞介素-1β(IL-1β)和肿瘤坏死因子-α(TNF-α)含量的变化以及脑、肺组织病理学变化. 结果 乌司他丁治疗后.TBE合并PE-SWD大鼠脑、肺组织含水量及血清、脑组织、肺组织IL-1β和TNF-α含量均明显降低,差异有统计学意义(P<0.05);脑、肺组织病理学改变有明显减轻. 结论 乌司他丁可以减轻TBE及PE-SWD.其机制与抗炎作用有关.     

Biomechanics of brain edema in acute cerebral ischemia in cats

We studied whether the biomechanical properties of brain play an important role in the development of early ischemic brain edema in cats with middle cerebral artery occlusion. Brain tissue pressure, tissue compliance, and tissue resistance were measured from the gray matter in the core and the periphery of the middle cerebral artery territory for 6 hours after occlusion. Regional cerebral blood flow and water content were also measured from the same areas. Ventricular fluid pressure was recorded. Tissue pressure rose gradually in the core, where flow was 6 ml/100 g/min, over 4 hours and then stabilized. The pressure gradient measured between edematous tissue and ventricular fluid was 5.3 mm Hg. Tissue resistance increased 1 hour after occlusion when water content increased to 10 mg/g. Later, when water content increased by 40 mg/g, tissue resistance decreased and tissue compliance increased significantly. In the periphery, where flow was 17.6 ml/100 g/min, tissue pressure rose slightly while tissue compliance and tissue resistance did not change within 6 hours. Our data indicate that as ischemic injury progresses, edema fluid accumulates in highly compliant brain parenchyma, then migrates through highly conductive tissue into the cerebrospinal fluid spaces, driven by the hydrostatic pressure gradient between the edematous tissue and the cerebrospinal fluid.     

Influence of preischemic hyperglycemia on osmolality and early postischemic edema in the rat brain.

Preischemic hyperglycemia, which raises tissue lactate content during ischemia, is known to aggravate ischemic brain damage. To explore the possibility that the enhanced lactic acidosis gives rise to osmotic damage, we studied the influence of a varied preischemic plasma glucose concentration on the early postischemic edema. Brain edema was measured by the specific-gravity technique. Brain and plasma osmolality were measured with a vapor pressure osmometer. We examined different brain regions in hyperglycemic and moderately hypoglycemic rats subjected to 15 min of forebrain ischemia, followed by recirculation for 5, 15, and 30 min. The decrease in specific gravity was compared with the increase in osmolality, to study whether the edema formation in the different groups correlated to the increase in tissue osmolality. We found edema formation to be most pronounced in frontoparietal cortex. In this structure and in hippocampus, statistically significant decreases of specific gravity were seen at all recirculation times studied. In caudoputamen, significant edema was seen only in the groups with 5 and 15 min of recirculation. Contrary to expectations, no difference was found between hyperglycemic and hyperglycemic animals. Tissue osmolality increased during ischemia in both the low and high glucose groups, but to a higher level in the latter (hypoglycemia 311 +/- 1 mmol kg-1, hyperglycemia 328 +/- 10 mmol kg-1; mean +/- SD, p less than 0.05). In the hyperglycemic group, brain osmolality remained elevated for the first 15 min of recirculation.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of calcium antagonists on postischemic protein biosynthesis in gerbil brain.

BACKGROUND AND PURPOSE: Prolonged inhibition of protein synthesis precedes delayed neuronal death in the CA1 sector of the hippocampus after transient cerebral ischemia. Organic calcium antagonists have been recommended for alleviation of ischemic neuronal damage. The present study was undertaken to investigate whether these drugs improve the recovery of protein biosynthesis after interruption of cerebral blood flow. METHODS: Cerebral protein synthesis was measured biochemically and autoradiographically in gerbils submitted to 5 minutes of bilateral occlusion of the common carotid arteries followed by 2 hours or 2 days of recirculation. Flunarizine (25 mg/kg) or nimodipine (1.5 mg/kg) were applied intraperitoneally shortly after ischemia. RESULTS: Treatment with either calcium antagonist did not markedly influence postischemic recovery of protein synthesis in the resistant regions of the brain and did not prevent the persisting inhibition in the vulnerable stratum pyramidale of the CA1 sector of the hippocampus. CONCLUSIONS: The postischemic application of the organic calcium antagonists nimodipine and flunarizine does not promote postischemic recovery of protein synthesis. The beneficial effects of these drugs must, therefore, be based on other mechanisms.     

海水淹溺性肺水肿对大鼠创伤性脑水肿的影响

目的探讨海水淹溺性肺水肿对创伤性脑水肿的影响。方法将72只大鼠随机均分为9组：①侧方液压打击致单纯颅脑创伤1h组：⑦单纯颅脑创伤6h组：③颅脑创伤合并淡水淹溺1h组；④颅脑创伤合并淡水淹溺6h组；⑤颅脑创伤合并海水淹溺1h组；⑥颅脑创伤合并海水淹溺6h组；⑦单纯颅脑创伤6h电镜组；⑧颅脑创伤合并淡水淹溺6h电镜组；⑨颅脑创伤合并海水淹溺6h电镜组。检测①～⑥组大鼠伤区脑组织含水量及Na^＋、K^＋、Ca^2＋含量，并行病理学检查；⑦～⑨组行伤区脑组织电镜检查。结果与单纯颅脑创伤组和淡水淹溺组相比．颅脑创伤合并海水淹溺组脑组织含水量和脑组织中Na^＋、Ca^2＋的含量显著性增加，K^＋含量则显著性降低．颅脑创伤后的病理及超微结构改变加重。结论海水淹溺性肺水肿可加重创伤性脑水肿与继发性脑损伤。     

Effect of MCI-186 on brain edema in rats

We induced brain edema in 72 rats by injecting 5 microliters of 3.0% wt:vol polyvinyl acetate into the left internal carotid artery, producing permanent embolization in the left cerebral hemisphere, which developed ipsilateral brain edema reproducibly. Edema was assessed 24 hours after embolization by determining the brain water content and the sodium and potassium concentrations. In this model, the free radical scavenger MCI-186 at 1.0 and 3.0 mg/kg i.v. prevented brain edema in a dose-dependent manner. At 3.0 mg/kg i.v., MCI-186 significantly reduced water content by 1.5% and improved the sodium-potassium balance to within the normal range in the embolized left hemisphere. Dexamethasone at 1.0 mg/kg i.v. did but at 3.0 mg/kg i.v. did not significantly inhibit the development of brain edema. Indomethacin at 4.0 mg/kg i.p. had no effect on brain edema. We suggest that the cyclooxygenase metabolites of arachidonic acid liberated from neuronal cell membrane phospholipids are not likely to be involved in the pathogenesis of permanent brain edema induced by polyvinyl acetate. Our results suggest that MCI-186 attenuates brain edema by suppressing the production of lipoxygenase metabolites, including free radicals or lipid peroxides, and that it may prove valuable for the treatment of brain edema associated with cerebral ischemia.     

Strong attenuation of ischemic and postischemic brain edema in rats by a novel free radical scavenger

Regional changes in the amount of free fatty acids, polyphosphoinositides, and water content in the cerebral cortex were examined using a middle cerebral artery occlusion model of rats. The amount of various free fatty acids increased as polyphosphoinositides decreased during 3 and 6 hours of ischemia in the occluded middle cerebral artery territory. After 3 hours of reperfusion following 3 hours of ischemia, free fatty acids partially recovered while polyphosphoinositides did not. Water content increased significantly after 3 and 6 hours of ischemia, and a further increase was found after 3 hours of reperfusion following 3 hours of ischemia. The change of polyenoic fatty acids in this occluded middle cerebral artery territory was much smaller than that in the case of decapitation ischemia, although the amounts of polyphosphoinositides and monoenoic and saturated fatty acids showed almost identical changes in both cases, probably because polyenoic fatty acids may be washed out and/or peroxidatively consumed in the middle cerebral artery occlusion model due to its residual blood flow. Changes in the area surrounding the occluded middle cerebral artery territory were similar to the above results, although less dramatic. However, there was no change in free fatty acids, polyphosphoinositides, and water content in the contralateral cortex. A novel free radical scavenger (MCI-186), which prevents both nonenzymatic peroxidation and lipoxygenase activity in vitro, markedly attenuated the ischemic and postischemic brain swelling. These results suggest that free radical mechanisms may be involved in ischemic and postischemic brain edema.     

The effect of intracerebral ouabain administration on the composition of edema fluid isolated from cats with cold-induced brain edema

Brain edema fluid was collected from cats with a freezing lesion in the left parietal cortex by the insertion into the brain of needles containing nylon wicks and connected to polyethylene tubes. The edema fluid samples which accumulated in the polyethylene tubes were regularly analyzed for Na+ and K+ content, colloid osmotic pressure, lactate dehydrogenase and creatine phosphokinase activity, and 99mTc-albumin radioactivity; the albumin tracer being introduced intravenously at the time of cold-injury. One series of cats received an intracerebral injection of ouabain solution, the control series an intracerebral injection of saline, at 100 min after the cold-injury. The ouabain injection was followed by an increase of K+ content, LDH and CPK activities but a decrease of Na+ concentration in the edema fluid, attributable to a concentration of solutes in the edema fluid as presumably water and Na+ were shifted into the cells and hence the extracellular space was reduced.     

高压氧治疗外伤性顽固性脑水肿

目的探讨高压氧治疗外伤性顽固性脑水肿的疗效。方法将100例该病患者随机分成A、B两组。A组53例,在常规治疗情况下加用高压氧治疗(0.2MPa,吸纯氧40min×2次,其间吸空气10min)。B组47例,为常规治疗组,在使用甘露醇、速尿的基础上加用甘油及七叶皂苷等药物治疗。结果高压氧治疗外伤性顽固性脑水肿疗效明显优于常规药物治疗。结论对临床众多的外伤性顽固性脑水肿患者来说,高压氧治疗是目前疗效最好的方法。     

Effect of carrageenin-induced pedal edema on rat brain prostaglandins

Carrageenin-induced pedal inflammation in rats, was found to significantly enhance brain levels of prostaglandin (PG) E₂ and PGF_2α. PG levels increased after 30 min of induction of the inflammation, peaked at 1 h, and attained normal levels by 4 h. Bilateral adrenalectomy had little effect on carrageenin-induced increase in rat brain PGs. The pattern of elevation of central PGs and the time course of carrageenin inflammation were at variance, the latter peaking between 3 and 4 h. The findings lend credence to the postulate that inflammatory hyperalgesia involves participation of central pain circuits, and that fever accompanying inflammation is caused by the central release of PGs. The central nociceptive and hyperthermic actions of PGs are well documented. However, the increase in central PG levels may well be caused by stress induced by the peripheral inflammation, since the pattern of elevation in either case is qualitatively similar.     

Effect of uridine 5'-diphosphate on cryogenic brain edema in rabbits

This study was undertaken to examine the effect of uridine 5'-diphosphate, administered intravenously or intraperitoneally, on cold injury-induced brain edema in rabbits. Bolus injection or continuous intravenous infusion of uridine 5'-diphosphate 26 hours after a lesion was established had adverse effects, such as increased intracranial pressure and lowered systolic arterial blood pressure and cerebral perfusion pressure for approximately 10-29 minutes, but these parameters did not change appreciably from 29 minutes to 3 hours after administration. Intraperitoneally administered uridine 5'-diphosphate did not affect these parameters appreciably during 3 hours. Thus, the intravenous administration of uridine 5'-diphosphate is harmful under neurosurgical conditions. In contrast, 10 mg/kg/day i.p. uridine 5'-diphosphate pretreatment and posttreatment, beginning 24 hours before and continuing until 24 hours after the insult, significantly reduced neurologic abnormalities, Evans blue extravasation, water content in the injured gray matter, and intracranial pressure without affecting water content in the white matter. Intravenous dexamethasone pretreatment and posttreatment in this setting significantly reduced only neurologic abnormalities. However, there were no significant differences between intraperitoneal uridine 5'-diphosphate and intravenous dexamethasone effects on cold-injured brain.     

Seizure-induced transient brain edema in the medial temporal lobe]

We reported a patient with sudden onset seizure resulting in prolonged amnesia. MRI revealed a T2 high signal lesion with swelling in the right medial temporal lobe. Because the MRI lesion remained to be the same in size for two months, biopsy specimens were obtained under informed consent to rule out the brain tumor. Based on histological findings showing brain edema without specific abnormal findings (malignancy, inflammation etc), we concluded that the temporal lesion was the edema induced by the seizure attack. In Japan, many papers on non-herpetic acute limbic encephalitis (NHALE) have recently been published. In their reports, seizures were frequently observed as a preceding symptom; moreover, clinical courses and MRI findings are similar to those of seizure-induced brain edema. The secondary brain edema induced by the seizure must be considered in patients with NHALE and other CNS disorders, especially if the patient has a history of the recent seizure.     

Effect of a combination of pentoxifylline and nimodipine on lipid peroxidation in postischemic rat brain

The authors studied the effects of a combination of pentoxifylline and nimodipine on cerebral lipid peroxidation in postischemic rat brain. Pentoxifylline (40 mg/kg) and nimodipine (3 mg/kg) were administered per os 30 min before 5 min of ischemia (four-vessel occlusion model of transient ischemia). The extent of peroxidation in brain tissue (cerebral cortex, hippocampus, striatum) was then estimated by assay of thiobarbituric acid reactive substances (TBARS). The concentration of TBARS was significantly lower in the cerebral cortex and hippocampus of the group treated with the combination of drugs than in untreated ischemic rats. However, this concentration was not significantly different from that found in the cerebral cortex and hippocampus of other groups premedicated with nimodipine or pentoxifylline alone. The tested drugs had no effect on TBARS in the striatum. The hypothesis that the combination of drugs would have a synergistic effect on postischemic lipid peroxidation was therefore not confirmed.     

Long-term observations on calcium accumulation in postischemic gerbil brain

We studied delayed postischemic calcium accumulation and neuronal damage in the gerbil brain, using 45Ca autoradiography as a marker for detection of injured tissue and light microscopy. Transient cerebral ischemia was induced for 15 min. Sham-operated gerbils showed no abnormal calcium accumulation and neuronal damage throughout the brain. At 2 and 7 days following 15 min of ischemia, marked calcium accumulation and mild to severe neuronal damage were found in the selectively vulnerable areas such as neocortex, striatum, hippocampus and thalamus, and brainstem such as medial geniculate body, substantia nigra and inferior colliculus. After 1-2 months of recirculation, the calcium accumulation was not recognized in the brainstem. But, the accumulation was still detectable in the striatum, the hippocampus and the thalamus. Morphological study showed that marked proliferation of glia cells was rapid in the inferior colliculus and was relatively slow in the striatum and the hippocampus, although these structures were severely damaged after ischemia. The result suggests that the speed of restoration of injured tissue and the mechanisms for the damage after cerebral ischemia may be different between the selectively vulnerable areas and the brainstem. Furthermore, they suggest that 45Ca autoradiographic technique may provide a useful approach for diagnosis of the restoration of injured tissue at chronic stage following cerebral ischemia.     

Effect of a superoxide dismutase derivative on cold-induced brain edema

Although the involvement of reactive oxygen species has been suggested in the pathogenesis of brain edema, direct evidence supporting this concept is lacking. To elucidate a critical role of oxygen radicals, effect of a superoxide dismutase (SOD) derivative that circulated bound to albumin with a half-life of 6 h on the occurrence of cold-induced brain edema was studied in the rat. When animals were challenged with brain injury by applying a liquid-nitrogen-cold probe to one side of the cerebral hemisphere over the bony skull for 20 s, the vascular permeability of the underlying tissue increased significantly and unilateral brain edema occurred as determined by the accumulation of intravenously injected Evan's blue and the increase in brain weight. Intravenous administration of the SOD derivative markedly suppressed the increase in vascular permeability and the occurrence of brain edema, particularly at their early stages. These and other results suggest that superoxide anion and/or its metabolite(s) might play a critical role in the pathogenesis of traumatic brain injury.