The effects of etomidate in the cat middle cerebral artery occlusion model of brain ischaemia: An experimental study

The effects of etomidate on focal cerebral ischaemia following transorbital occlusion of the cat middle cerebral artery were investigated. Etomidate had no effect on CBF before or after onset of ischaemia by comparison with controls, but caused a greater fall in CBF in cats with high preocclusion or initial ischaemic CBF than in those in which CBF was lower. There were more sustained rises in Kp on SG. The established flow threshold for water accumulation was lost; more gyri with CBF above and fewer gyri with CBF below the flow threshold accumulated water. The relationship between mean occlusion CBF and in vitro GABA uptake was lost; uptakes from MC were lower and from SG and EG higher than expected. In the ischaemic penumbra there was a trend towards reduction in CBF, disruption of ion homeostasis and cerebral oedema formation, whilst in areas of lower flow there was some recovery of GABA uptake and less cerebral oedema following administration of etomidate.     

Hemorrhagic infarct induced by arterial hypertension in cat brain following middle cerebral artery occlusion

The purpose of this experiment was to determine whether an acute rise in brain perfusion pressure causes hemorrhagic transformation of an infarct without a reopening of the occluded artery. We raised the blood pressure of 22 cats by aortic obstruction 5-24 hours after transorbital middle cerebral artery clipping; hemorrhagic infarcts were induced in 11. Mean arterial blood pressure increased by 57.2 +/- 16.9 mm Hg (mean +/- SD) in the 11 cats with hemorrhagic infarcts and by 40.4 +/- 16.9 mm Hg in the 11 remaining cats with pale brain infarcts (p less than 0.05). Induction of hypertension increased regional cerebral blood flow in the ischemic cortical gray matter more in three cats with hemorrhagic infarcts than in seven with pale infarcts. Our results demonstrate that hemorrhagic transformation of an infarct can be induced by a rapid increase in perfusion pressure to brain tissue already exposed to focal ischemia. We also suggest that the restoration of blood flow through leptomeningeal collaterals plays an important role in the pathogenesis of hemorrhagic infarction in cases without reopening of occluded arteries.     

Local cerebral glucose utilization in chronic middle cerebral artery occlusion in the cat

This study examines the correlation between local CMRglc (LCMRglc) alterations and clinicopathological changes in a chronic middle cerebral artery (MCA) occlusion model in the cat. The left MCA was occluded for a period of 2 h. The animals were grouped into mild, moderate, and severe ischemia based on the depression of the EEG 30 min after the MCA occlusion. Following release of the clip, the animals were allowed to recover for a week during which time daily neurological examinations were performed. On the seventh day [14C]2-deoxyglucose was injected for the determination of LCMRglc. Alternative blocks were processed for histological evaluation in which both neuronal and phagocytic changes were graded into four categories (0 = normal to 3 = severe). LCMRglc (mumol/100 g/min) in the ischemic hemisphere (all histological grades) was significantly lower than the metabolic rate in comparable regions of the sham MCA occlusion group. Regions with significant phagocytosis (grade 2 and 3) invariably exhibited activated glucose metabolism (57.4 +/- 8.4 and 105.9 +/- 6.8 mumol/100 g/min, respectively), which was significantly higher than in regions without phagocytosis (30.4 +/- 0.8 mumol/100 g/min). There was a significant gradient of metabolism in the central, peripheral, and boundary zone and the non-MCA territory in the animals with severe ischemic lesions. LCMRglc in the central MCA territory was well correlated with the EEG amplitude changes (r = 0.82, p less than 0.05) and the morphological score (r = -0.89, p less than 0.05). The metabolic rate was significantly depressed in both the ipsilateral and the contralateral central MCA territories in comparison with the sham occlusion animals. The depression in LCMRglc in the contralateral hemisphere correlated well with the concomitant depression in the contralateral EEG amplitude. These studies demonstrate that local heterogeneous metabolic alterations and contralateral cortical diaschisis exist chronically following temporary MCA occlusion and that the increases in local cerebral glucose metabolism seen in chronic stroke may be due to phagocytotic activity.     

Expression of myelencephalon-specific protease in transient middle cerebral artery occlusion model of rat brain

Myelencephalon-specific protease (MSP) is one of the serine proteases and is expressed in the central nervous system of rats. Its function and alternation in brain injury have not yet been clarified. In this study, we investigated the expression of MSP after transient middle cerebral artery occlusion (MCAO) using in situ hybridization and immunohistochemistry. In situ localization of MSP mRNA demonstrated a higher level in the corpus callosum and around the ischemic area from 12 h to 14 days after MCA reperfusion, with the peak of expression coming 3 days after reperfusion in both regions. Immunohistochemically, the expression of protein was found 1 day after reperfusion in the same brain region that was observed for mRNA. The peak was 7 days after reperfusion in both regions. Micro-autoradiography, immunostaining and double immunohistochemical labeling revealed the expression of MSP to be located mainly in the oligodendrocytes. The present results indicate that MSP may be related to the turnover of the myelin-associated proteins and the extracellular matrix proteins after transient MCAO. The activation of MSP may play a role in remodeling processes such as neurite outgrowth and remyelination.     

Thrombotic occlusion of the middle cerebral artery.

BACKGROUND AND PURPOSE: Epidemiological study of middle cerebral artery occlusion is important because the indication for extracranial-intracranial arterial bypass remains in dispute. To help clarify this issue, we investigated the prognosis of thrombotic middle cerebral artery occlusion in Japanese patients. METHODS: We studied 40 patients with thrombotic middle cerebral artery occlusion who were selected on the basis of clinical features, computed tomographic findings, and angiographic findings. Patients with causes of embolism (i.e., cardiomyopathy, valvular heart disease, cardiac arrhythmia, and carotid ulceration) were excluded. The 40 patients were classified into three groups according to the site of middle cerebral artery occlusion: there were 13 patients with occlusion of the proximal portion of the M1 segment, 13 with distal M1 segment occlusion, and 14 with occlusion of the M2 segment. RESULTS: Good collateral circulation was associated with improved outcomes both clinically and by computed tomography in patients with occlusion of the proximal and distal portions of the M1 segment but not in those with M2 occlusion. CONCLUSIONS: It is reasonable to assume that not only collateral circulation but also the site of occlusion plays an important role in the outcome of middle cerebral artery occlusion. Our finding that good collateral circulation improves the outcome for thrombotic occlusion of the proximal and distal M1 segments supports the possible benefits of such surgery.     

Nerve cell changes in the experimental occlusion of the middle cerebral artery

Summary Morphological and histochemical changes occurring in nerve cells after experimental occlusion of the left middle cerebral artery have been studied. Material consisted of fifty-four dogs with ligation of that artery and ten controls with either only retraction of the cortex or ligation of the anterior or posterior cerebral arteries. Techniques employed were cresyl violet, PAS, Sudan black B and Gomori methods for alkaline and acid phosphatases.In twenty-two animals which survived 39 h to fourteen days, the distribution of chronic lesions and their histological type have been examined, infarcts being nearly always localized within the Sylvian region and the striated nuclei. Thirty-two other dogs had survivals inferior to or of 24 h and in these acute experiments nerve cell changes were carefully studied. Histologically, it was possible to detect three types of acute nerve cell change: (1) shrinkage and (2) hydropic change, the first appearing after 3 h, the second after 6 h, both with focal localization, thus easily distinguishable from similar bilateral artefactual images as the common chromophilic cells; (3) ischemic cell change, encountered for the first time after 6 h and having its peak at 24 h, whereas (1) and (2) became less frequent at this survival period.PAS and Sudan black B stained the three types of acutely damaged nerve cells faintly but were strongly positive in the chromophilic ones. Alkaline and acid phosphatase activities were absent both from changed and chromophilic neurones. However, nerve fibers existing throughout acutely lesioned areas as well as around chronic infarcts had strong acid phosphatase positivity and showed morphological changes such as interruptions, varicosities and terminal swellings. Owing to the rapid appearance of that increased activity, the A. considered it directly due to the ischemia of the nerve fibers.Zusammenfassung Die in Nervenzellen nach experimentellem Verschluß der A. cerebri media auftretenden morphlogischen und histochemischen Veränderungen wurden studiert. Das Untersuchungsmaterial bestand aus 54 Hunden mit Unterindung der A. cerebri media und 10 Kontrolltieren entweder mit Rindenentfernung oder Unterbindung der A. cerebri anterior oder posterior. Kresylviolett, PAS, Sudanschward B-Färbung sowie die Gomori-Methode auf alkalische und saure Phosphatase wurden angewendet.Bei 22 Tieren mit einer Überlebenszeit von 39 Std bis zu 14 Tagen wurde die Verteilung chronischer Läsionen sowie ihr histologisches Bild untersucht. Infarkte waren fast immer in der Sylvischen Region sowie im Striatum lokalisiert. 32 Hunde hatten Überlebenszeiten von weniger oder bis zu 24 Std. Die Nervenzellveränderungen dieser akuten Experimente wurden sorgfältig untersucht. Histologische konnten drei Arten von akuten Nervenzellveränderungen festgestellt werden:1. Schrumpfung, frühestens nach 3 Std; 2. Wasserveränderungen nach 6 std, wobei beide deutliche Herdlokalisation zeigten, und daher leicht von ähnlichen bilateralen Artefakten — wie den üblichen chromohilen Zellen — zu unterscheiden waren; 3. ischämische Zellveränderungen, wobei 1. und 2. zu diesem Überlebenszeitpunkt abnehmen.Mit PAS und sudanschwarz B werden diese drei Arten von akut geschädigten Nervenzellen schwach gefärbt, die Chromohilen hingegen reagieren stark positiv. Alkalische und saure Phosphataseaktivität konnte weder in den veränderten noch in den chromohilen Nervenzellen festgestellt werden. Jedoch zeigten Nervenfasern in akut geschädigten Arealen als auch um chronische Infarkte stark positive saure Phosphataseaktivität und ließen morphologische Veränderungen, wie Unterbrechungen, Unterbrechungen, Schwellungen und Endauftreibungen erkennen. Der Autor vermutet, daß die rasch auftretende Aktivitätssteigerung in direkter Beziehung zu der Ischämie der Nervenfasern steht.With 3 Figures in the Text     

Focal cerebral ischaemia induced by middle cerebral artery occlusion and the neuroprotective effect of ketoprofen in rats

Cerebral ischaemia is eventualy observed during neurosurgical procedures and in several clinical entities that may cause severe neurological deficits and even death. Because it is a severe and complex problem, several studies have been done aiming to elucidate the mechanisms of the ischemic phenomenon and aiming to abolish or to diminish its effects, using drugs that protect the neurons from ischaemia-induced damage. Several neurotransmitters play a role in cerebral ischaemia with emphasis to glutamate by its high concentration in the central nervous system. The purpose of this study was to evaluate the effect of focal cerebral ischaemia in the rat through the dosage of the glutamate and morphological findings, and to evaluate a possible protective effect of the ketoprofen to ischemic neurons. Thirty-six rats Wistar were divided into four groups. The first was a control group, the second a sham group and the animals of the third and fourth groups were submitted to induced cerebral ischaemia through selective obstruction of the midlle cerebral artery during 15, 30 and 45 minutes. Animals of the fourth group were previously treated with ketoprofen 15 minutes before the ischaemia. The ischaemia was evaluated through the histopathological examination and through dosage of the extracellular glutamate in vitro. The histopathological examination showed that there was no difference between the animals of the control and of the sham groups. In the animals submitted to ischemia histopathological alterations appeared at 30 minutes and become more intense at 45 minutes of ischaemia. The main findings were interstitial edema, chromatinic disorganization, vacuolization and nuclear desintegration. The animals treated with ketoprofen showed similar alterations, but they were less intense. Decrease in the dosage of glutamate in the parietal cortex of the animals submitted to ischaemia started at 30 minutes and became more intense at 45 minutes of ischaemia and was similar for animals previously treated or not with ketoprofen, indicating that this drug seems not to interfere with the metabolism of the glutamate at the synapses. The morphological findings in the parietal cortex of the animals submitted to ischaemia, previously treated or not with ketoprofen, suggest that this drug has a neuroprotective effect.     

A model of proximal middle cerebral artery occlusion in rat

A highly reproducible model of middle cerebral artery (MCA) occlusion in rat is described. Reproducibility relates to MCA occlusion at its most proximal portion and the surgical approach through a widened foramen ovale, thus avoiding craniotomy and brain retraction. Spontaneous ventilation is maintained, avoiding intubation. Collateral circulation to cortex is preserved, permitting optimal metabolic and pharmacologic studies of the ischemic regions destined for infarction.     

大鼠局灶脑缺血后钙调神经磷酸酶活性和含量变化

目的 研究大脑中动脉闭塞后钙调神经磷酸酶（Calcineurin,CaN)的活性和含量变化规律。探讨CaN在脑缺血中的作用。方法 制备大鼠大脑中动脉永久性闭塞模型。分别测定缺血后不同时间点病灶侧大脑皮质和海马CA1区CaN的活性和含量。结果 皮质组织在缺血6h及其后各时间点CaN 的含量下降，其活性于缺血后4h,6h和12h短暂性增强。海马CA1区CaN的含量于缺血后24h开始降低且不恢复；CaN的活性在缺血后2h,4h和6h减弱。12h始恢复至正常水平。可见，CaN的活性与含量分离。结论 局灶脑缺血后CaN独特的时间变化规律显示其参与介导缺血性神经元损伤。可能具有毒性作用。     

Prognosis in middle cerebral artery occlusion

The natural history of MCA occlusion has become increasingly important since the surgical option of EC/IC bypass surgery has been available. The clinical course of 24 patients with angiographically-demonstrated occlusion of the MCA artery was reviewed. Eight patients presented with a major disabling stroke and five of these died during the acute phase of this ischemic event. The remaining 19 patients were followed for a mean of 54.2 months. There were five deaths in follow-up and two of these were due to subsequent strokes. Fourteen patients manifested a benign course: one of these had a further minor stroke and four had TIAs. Altogether, 3 strokes occurred during the follow-up period (2 fatal, 1 minor) and all were in the territory of the artery known to be occluded. Of those patients who survived their presenting ischemic event, 12 (63%) remained completely functional in terms of activities of daily living. MCA occlusion does not necessarily carry a poor prognosis with medial therapy alone and the role of bypass surgery hopefully will be clarified by the ongoing clinically randomized trial.     

Detrimental effects of 17beta-oestradiol after permanent middle cerebral artery occlusion.

Oestrogen is a complex hormone whose role as a neuroprotectant in experimental stroke has been published in numerous studies. However, although some clinical studies report a reduction in stroke incidence by oestrogen replacement therapy in postmenopausal women, others have found increased mortality and morbidity after stroke. Diathermy occlusion of the proximal middle cerebral artery (MCAO), one of the most reproducible rodent stroke models, has consequently been employed to investigate physiologic and supraphysiologic doses of 17beta-oestradiol on ischaemic brain damage. Lister Hooded rats were ovariectomised (OVX) and a 21-day release pellet (placebo, 0.025 or 0.25 mg 17beta-oestradiol) implanted in the neck. At 2 weeks after OVX, animals underwent MCAO and were perfusion fixed 24 hours later. Neuronal perikaryal damage was assessed from haematoxylin and eosin-stained sections and in adjacent sections, axonal pathology was assessed with amyloid precursor protein and Neurofilament 200 (NF-200) immunohistochemistry. 17beta-Oestradiol induced a dose-dependent increase in neuronal perikaryal damage, 0.025 and 0.25 mg 17beta-oestradiol increased damage by 20% (P<0.05) and 27.5% (P<0.01) compared with placebo. 17beta-Oestradiol did not influence axonal pathology compared with placebo. Our results suggest that 17beta-oestradiol treatment can exacerbate brain damage in experimental stroke. Thus, further investigation into the role of oestrogen and the mechanisms which mediate its effects in stroke is required.     

Chronic effects of an aminosteroid on microdialytically measured parameters after experimental middle cerebral artery occlusion in the rat.

The effects of the neuroprotective aminosteroid U74006F (tirilazad mesylate, Freedox) were monitored microdialytically in rat cortex during three 4h periods beginning immediately, 25h and 49h after permanent middle cerebral artery occlusion. Either U74006F or vehicle only was administered 15 min, 2h, 6h, 12h and 24h after operation. The dialysate was analysed for on-line pH, ascorbic acid, uric acid, glucose and lactate. The efficacy of post-ischaemic treatment was shown by: a) lesion volume 53h after operation was significantly smaller in U74006F-treated animals; b) microdialytic findings were very similar to those found previously with pre-ischaemic drug application (reduction in release of ascorbic acid, uric acid and lactate, increased pH); c) an effect of U74006F on lactate release could still be seen on days 2 and 3; and d) increases in uric acid on days 2 and 3, possibly reflecting delayed cell death, were smaller in aminosteroid treated animals.     

Traumatic middle cerebral artery occlusion from boxing.

A case of a traumatic middle cerebral artery occlusion resulting from a boxing injury is presented. A 22-year-old man, an amateur boxer, was admitted because of difficulty in speaking, that had appeared a day after a sparring fight. A computed tomographic scan showed low-density areas in the left globus pallidus and corona radiata. A carotid angiogram indicated complete occlusion of the left middle cerebral artery at its origin and an irregularity and narrowing of the left internal carotid artery in its supraclinoid portion. The patient was discharged 4 weeks after the admission with some persistent expressive dysphasia that diminished during the next month. The clinical features and mechanisms of the traumatic middle cerebral artery occlusion are discussed.     

Characterization of microglial reaction after middle cerebral artery occlusion in rat brain

We have studied the microglial reaction that accompanies cortical infarction induced by middle cerebral artery occlusion (MCAO). Lectin histochemistry with the B₄-isolectin from Griffonia simplicifoliaas well as immunocytochemistry with a panel of monoclonal antibodies directed against major histocompatibility complex (MHC) and lymphocytic antigens were performed. Principal attention was focused on neocortical and thalamic regions, representative of primary and secondary ischemic damage, respectively. With the lectin procedure, activated microglial cells were abundant in the neocortex 24 hours after MCAO. In contrast, microglial activation in the thalamus was not apparent until day 2 after MCAO. On day 5, MHC class II antigen was expressed by reactive microglia in fiber tracts traversing the striatum, but was absent from activated microglia in the primary cortical infarction area. MHC class I and lymphocytic antigens were expressed differentially on microglia with class I antigens appearing early and lymphocytic antigens appearing late in the time course after focal ischemia. The findings are compatible with previous studies during global ischemia and confirm the early activation and the progressive nature of immunomolecule expression on activated microglia after an ischemic insult. In addition to neocortical and thalamic sites, our results showed an early microglial activation to be present also in forebrain regions outside of the middle cerebral artery (MCA) territory, such as the contralateral cortex and hippocampus. A unilateral microglial reaction was also detectable after long-term survival (≥4 weeks) in the pyramidal tracts, as well as in the corticospinal tracts at cervical but not lumbar spinal cord levels. Ischemia-induced neuronal damage, as evaluated by Nissl staining, was found only in cortical and thalamic regions. We conclude that the demonstration of reactive microglia indicates not only imminent ischemic neuronal damage within MCA territory but can also delineate extra-focal disturbances, possibly reflecting subtle and transitory changes in neuronal activity. © 1993 Wiley-Liss, Inc.     

The significance of brain temperature in focal cerebral ischemia: histopathological consequences of middle cerebral artery occlusion in the rat.

The purpose of this study was to determine the effect of selective modulation of brain temperature in the experimental settings of permanent and reversible middle cerebral artery (MCA) occlusion in Sprague-Dawley rats. Three models of proximal MCA occlusion were used, in which the effect of brain-temperature modulations could be studied. These included (a) permanent MCA occlusion with an initial 30-min period of hypotension (30 or 36 degrees C x 4 h), (b) permanent MCA occlusion alone (30, 36, or 39 degrees C x 2 h), and (c) 2 h of reversible MCA occlusion (30, 36, or 39 degrees C x 2 h). In the transient MCA occlusion series, intra- and postischemic cortical blood flow was assessed using a laser-Doppler flowmeter placed over the dorsolateral cortex. After a 3-day survival, all rats were perfusion fixed for histopathological analysis and the determination of infarct volume. In animals with permanent MCA occlusion plus hypotension, no significant difference in infarct volume was demonstrated between the 30 and 36 degrees C groups. In rats with permanent MCA occlusion without hypotension, significant differences in infarct volume were again not demonstrable, but an interaction between infarct area and temperature class was shown by repeated-measures analysis, indicating that hypothermia altered the topographic pattern of the cortical infarct. With 2 h of reversible MCA occlusion, there was a statistically significant reduction in infarct volume in the 30 degrees C group compared to 39 degrees C rats. Although intra- and postischemic CBF were not significantly different among the three temperature groups, the cortical infarct volume was positively correlated with postischemic CBF. The postischemic CBF, in turn, was positively correlated to the intraischemic brain temperature and was negatively correlated to CBF during the ischemic period. These findings demonstrate that moderate manipulations of brain temperature have a greater influence on the resulting cortical infarction in the setting of transient focal ischemia than in the context of permanent vascular occlusion.