Regional cerebral ischemia in the gerbil: measurement of regional cerebral blood flow by quantitative autoradiography

Alterations in the regional CBF after occlusion of the posterior communicating, middle cerebral, or common carotid artery were investigated in the gerbil with a quantitative autoradiographic technique using [14C]iodoantipyrine. Occlusion of the posterior communicating artery produced severe ischemia in the ipsilateral hippocampus, thalamus, and dorsal mesencephalon. Occlusion of the middle cerebral artery produced severe ischemia in the ipsilateral rostral and central cerebral cortex and lateral caudate-putamen. Occlusion of the common carotid artery produced ipsilateral hemispheric ischemia of variable degrees. The distribution and degree of cerebral ischemia produced by occlusion of one of these arteries correlated closely to the arterial territory and the extent of collateral blood supply. Since the areas affected after occlusion of the posterior communicating or middle cerebral artery differ, those models will be useful for the comparative investigation of the ischemia-related cerebral pathophysiology associated with different sites of primary lesion.     

Effect of propentofylline on cerebral blood flow in a gerbil focal cerebral ischemia

BACKGROUND AND PURPOSE: Neuroprotection and improvement of cerebral blood flow are two basic principles of pharmacological intervention in acute stroke. Propentofylline, an adenosine uptake and phosphodiesterase inhibitor, has been shown to be neuroprotective in various models of cerebral ischemia. However, its effect on cerebral circulation in ischemic conditions is not yet fully elucidated. Present experiments were designed to investigate the effect of propentofylline on regional cerebral blood flow (rCBF) in the gerbil permanent focal cerebral ischemia model. METHODS: Focal cerebral ischemia in gerbils was produced by clipping one common carotid artery and contralateral external carotid artery. rCBF was measured in both parietal cortices concurrently by the hydrogen clearance. RESULTS: Propentofylline at 10 mg/kg administered intraperitoneally 30 min after induction of cerebral ischemia significantly increased rCBF in ischemic regions (increase of 94.6%). Effects were dose dependent. Higher dosage (30 mg/kg) induced reductions of ischemic rCBF, which were associated with significant decreases of mean arterial blood pressure. Lower dosage (5 mg/kg) was without significant effect. CONCLUSIONS: Results suggest that propentofylline at suitable dosage improves rCBF in ischemic brain areas. Taking into account neuroprotective potentials of propentofylline, results offer additional rationale for clinical trials investigating efficacy of propentofylline in treatment of acute stroke.     

Crossed cerebellar diaschisis in patients with cerebral ischemia assessed by SPECT and 123I-HIPDM

Crossed cerebellar diaschisis (CCD) was investigated in a series of 59 patients (34 completed strokes and 25 reversible ischemic attacks, RIAs) using single photon emission computerized tomography (SPECT) with 123I-HIPDM as a cerebral blood flow (CBF) indicator. CCD was present in 17 (50%) of the patients with completed stroke and in 6 (24%) of the patients with RIAs. CCD was significantly correlated to the clinical severity (p less than 0.001) and to the extension of the supratentorial lesion (p less than 0.05). However, CCD was also recorded in 3 out of 16 patients with normal neurological examination and CT scan, suggesting that a 'functional' hemispheric disturbance may be sufficient to produce a remote effect on the contralateral cerebellar hemisphere. Time elapsed between the clinical onset and SPECT study was not critical, since CCD was recorded in the acute as well as in chronic studies. Follow-up SPECT studies showed that CCD disappeared in 5 out of 18 patients after a successful extra-intracranial bypass, while a spontaneous recovery was observed in only one of 16 nonsurgical patients.     

Acetazolamide effect on cerebellar blood flow in crossed cerebral-cerebellar diaschisis

We studied the effect of acetazolamide on cerebellar blood flow in 11 stroke patients with large, unilateral cerebral hemispheric infarcts and no evidence of cerebellar infarction, but with cerebrocerebellar diaschisis of cerebral blood flow. Blood flow was determined with xenon-133 inhalation and dynamic single-photon emission computed tomography at rest and 20 minutes after the intravenous injection of 1.0 g acetazolamide. After acetazolamide, the mean +/- SD increases in blood flow in the affected and contralateral cerebellar hemispheres were 11.1 +/- 3.7 and 12.0 +/- 5.3 ml/100 g/min, respectively; the difference between hemispheres was not significant. The absolute increase in cerebellar flow in these 11 patients was of the same magnitude as that in 12 healthy controls. We conclude that cerebellar vasoreactivity is intact in stroke patients with crossed cerebrocerebellar diaschisis of cerebral blood flow. Our results lend further support to the concept that reduced cerebellar blood flow is secondary to functional deactivation. Our patients were studied 2 weeks to 5 years after their stroke, indicating that this phenomenon may be persistent.     

Local glucose utilization in acute focal cerebral ischemia: local dysmetabolism and diaschisis.

By means of an autoradiographic technique employing 14C-2-deoxyglucose, abnormalities of local brain glucose utilization were studied 90 minutes following occlusion of the left middle cerebral and common carotid arteries in a series of pentobarbital-anesthetized cats. Sham-insulted control animals exhibited a normal pattern of regional glucose utilization. In animals with vascular occlusion, a zone of greatly suppressed glucose utilization occupied the caudate nucleus of the ischemic hemisphere, with variable extension, and was surrounded by a narrow rim of increased local brain glucose utilization, suggesting the occurrence of enhanced anaerobic glycolysis in the latter zones. The cerebral cortex, which was less constantly affected, showed alternating regions of increased and decreased glucose utilization. Quantitation of local brain glucose utilization values from the contralateral nonischemic hemisphere revealed a mild suppression of cortical glucose utilization relative to the control animals. This may be the metabolic equivalent of diaschisis.     

Autoradiographic analysis on second-messenger systems and local cerebral blood flow in ischemic gerbil brain

Alterations of the second-messenger systems, adenylate cyclase (AC) and protein kinase C (PKC), and local cerebral blood flow (lCBF) were evaluated during experimental cerebral ischemia in gerbils employing a quantitative autoradiographic method, which permitted these three parameters to be measured in the same brain. Ischemia was induced by occlusion of the right common carotid artery for 6 h. Animals attaining more than 5 in their ischemic scores were utilized for further experiments. At the end of ischemia, lCBF was measured by the [14C]iodoantipyrine method. The AC and PKC activities were estimated by the autoradiographic technique developed in our laboratory using [3H]forskolin (FK) and [3H]phorbol-12,13-dibutyrate (PDBu), respectively. The lCBF fell below 10 ml/100 g/min in most cerebral regions on the ligated side. The greatest reduction in FK binding was noted in the olfactory tubercle, caudate-putamen, and globus pallidus, followed by the hippocampus and cerebral cortices. The FK binding tended to be low at lCBF less than 20 ml/100 g/min in the cerebral cortices. However, the PDBu binding was relatively well preserved in each cerebral structure, and no significant correlation between lCBF and PDBu binding was noted in the cerebral cortices. The AC system may thus be vulnerable to ischemic insult over extensive brain regions, while the PKC system may be relatively resistant to ischemia.     

Cerebral crossed diaschisis caused by cerebellar lesion: role of the cerebellum in mental functions

In 3 patients with a stroke limited to the posterior fossa, regional cerebral blood Flows were measured by the 133 Xe inhalation method (the first two cases) or by the SPECT with HMPAO method (the third case). The first patient had a median and paramedian hematoma of the left cerebellar hemisphere and the left dorsolateral portion of the pons. Remote cerebral hypoperfusion, measured 3 months later, was observed in both frontal premotor regions (but more marked in the right hemisphere) and in a circumscribed area of the right temporal region. The second patient had a right-sided ischaemic lesion of the anterior cerebellar lobe and the mesencephalic tectum. Contralateral parietal and rolandic hypoperfusion, measured 7 weeks after the stroke, was observed. The third patient had on old infarct of the right cerebellar hemisphere. The SPECT, measured 17 years later, showed a left fronto-parieto-temporal hypoperfusion and the absence of perfusion in the right cerebellar hemisphere. Preliminary data of neuropsychological assessment in our patients disclosed impairment in visuo-spatial and constructive organization, memory and learning compatible with the published findings in some patients and animals with predominantly cerebellar damage. These interesting findings should be confirmed in a large number of patients with age, sex, and sociocultural matched controls. In the absence of supratentorial insult, and during the hemodynamical stable phase, crossed cerebello-cerebral diaschisis is suggested in our 3 patients. Although it is too early to draw definite conclusions, our findings may: (1) confirm the functional interconnections between the cerebellum and the cerebrum in man and (2) provide functional basis for the behavioral function impairment reported in patients with cerebellar insult. Further rCBF, metabolism, and pathologic studies on this subject are required to elucidate this issue.     

A decrease in regional cerebral blood volume and hematocrit in crossed cerebellar diaschisis.

BACKGROUND AND PURPOSE: The pathophysiology of crossed cerebellar diaschisis (CCD) remains to be elucidated. In CCD, the metabolic suppression resulting from deafferentation may cause vasoconstriction, which may result in a decrease in cerebral blood volume (CBV) and may differentially affect the flows of red blood cells and of plasma. The purpose of this study was to investigate whether CCD decreases the total CBV (cerebral red blood cell volume [CRCV] plus cerebral plasma volume [CPV]) and, if so, whether CCD differentially affects the CRCV and CPV, resulting in a change in hematocrit. METHODS: We used positron emission tomography to study 7 patients with a unilateral supratentorial infarct and CCD. The distributions of CRCV and CPV were assessed by using 15O-labeled carbon monoxide and 62Cu-labeled human serum albumin-dithiosemicarbazone tracers, respectively. The CRCV, CPV, and calculated hematocrit values were compared between the cerebellar hemispheres. RESULTS: In the cerebellar cortex contralateral to the supratentorial infarct, the values of CRCV, CPV, and total CBV were significantly decreased compared with those in the ipsilateral cerebellar cortex. The CRCV was decreased to a greater degree than the CPV, and the value of the hematocrit was decreased in the contralateral cerebellar cortex. CONCLUSIONS: CCD may decrease the total CBV, which may reflect vasoconstriction caused by decreased metabolism due to deafferentation. In addition, the more pronounced decrease in CRCV than in CPV may result in a decrease in hematocrit in CCD.     

Crossed cerebellar diaschisis in ischemic stroke: a study of regional cerebral blood flow by 133Xe inhalation and single photon emission computerized tomography

Seventy measurements of CBF were performed in 12 stroke patients by 133Xe inhalation and a rapidly rotating single photon emission computerized tomograph. CBF was measured every other day during the acute phase and at 2- and 6-month follow-up visits. A persistent contralateral cerebellar blood flow depression was evident in five patients with severe hemispheric low flow areas, which correlated with large, hypodense lesions on the computerized tomographic scan. In a sixth patient with a small, deep infarct, a transient crossed cerebellar low flow was observed, while the clinical symptoms persisted. It is concluded from this serial study that crossed cerebellar diaschisis is a common finding in completed stroke. It is probably caused by disconnection of the corticopontine pathways, a disconnection that tends to persist. The phenomenon is in fact less variable than the stroke-related CBF changes in the infarcted hemisphere, in which a period of relative hyperemia is frequently seen.     

Effect of nitro- -arginine on cerebral blood flow and monoamine metabolism during ischemia/reperfusion in the mongolian gerbil

Inhibition of nitric oxide synthase with nitro- -arginine (i.p., 40 mg/kg body weight) in contrast to -arginine (300 mg/kg body weight) delayed the initial recovery of cerebral blood flow (CBF) and altered dopamine (DA) metabolism in brain ischemia/reperfusion of Mongolian gerbils. Similar changes but more severe were observed with pargyline (monoamine oxidase inhibitor). Data suggest nitric oxide involvement in postischemic CBF recovery and modulation of DA metabolism due to nitro- -arginine-induced CBF reduction.     

Effect of supratentorial space-occupying lesions on regional intracranial pressure and local cerebral blood flow: an experimental study in baboons

Cortical blood flow and epidural intracranial pressure have been measured in the two supratentorial compartments of the intracranial space in experimental baboons during the acute expansion of a parieto-occipital epidural balloon. Differential pressures between the two halves of the supratentorial space have been found, and these have been associated with evidence that flow has fallen more quickly in the hemisphere most compressed. The evidence points to a more rapid exhaustion of the autoregulatory capacity in the hemisphere subjected to greater compression, a fall in perfusion pressure to below critical autoregulatory levels occurring slightly before that in the opposite hemisphere, and the establishment of a differential flow pattern for a short time during a critical phase of compression. The displacements induced by inflation of the parieto-occipital balloon have been described.     

Alzheimer disease: caused by primary deficiency of the cerebral blood flow.

Alzheimer's disease (AD) is associated with considerably decreased cerebral blood flow (CBF) thought to be secondary, since dead neurons do not need oxygen and glucose. This view, however, needs to be critically re-examined. The role of CBF in AD was submitted to a thorough analysis, raising the question: "Is there really a lack of demand in the presence of undisturbed blood supply?" CBF decline is present in AD while the number of affected CNS systems is still quite small. The step-by-step evolution of AD mirrors a brain that progressively becomes ischemic. Areas related to memory function (hippocampus, temporal lobe cortex and vicinity) are bound to suffer first because of their particularly vulnerable blood supply. This is the scenario of a disorder caused by primary and not by secondary CBF deficiency--a deficiency perhaps attributable to the upright gait of homo sapiens. This new approach also opens new avenues for treatment and prevention, which will be briefly discussed.     

Cerebral and cerebellar blood flow autoregulations in acutely induced cerebral ischemia in spontaneously hypertensive rats--transtentorial remote effect

Autoregulation of cerebral (CBF) and cerebellar blood flow (CeBF) was studied before, during and after acutely induced cerebral ischemia in spontaneously hypertensive rats. Cerebral ischemia of the supratentorial portion was induced for one hour by bilateral carotid artery ligation (BCL). The animals were artificially ventilated and the blood flow was measured with a hydrogen clearance technique. To test the autoregulation, the blood pressure was stepwise lowered by bleeding and maintained at a new level, i.e. 15% or 30% lower than the baseline values before, during and after cerebral ischemia. At the preischemic state, CBF and CeBF were 52.1 +/- 6.2 and 58.9 +/- 4.6 ml/100 g/min (mean +/- SEM), of which autoregulations were normally preserved. Following BCL, CBF was markedly decreased to about 10% of control value while CeBF was minimally reduced to 46.9 +/- 8.6 ml/100 g/min (80%). At the ischemic state, CBF became almost zero flow during hypotension. CeBF was also reduced to 74% and further to 58% of the resting value by 15% and 30% decrease in the blood pressure, respectively, indicating impaired CeBF autoregulation. At the 30 min post-ischemic state, CBF was recovered to 48.0 +/- 4.9 and CeBF to 53.9 +/- 5.4 ml/100 g/min. Autoregulation of CBF was still abolished, whereas CeBF was kept constant by 15% fall of blood pressure and slightly reduced to 84% by 30% hypotension, indicating almost recovery of CeBF autoregulation.(ABSTRACT TRUNCATED AT 250 WORDS)     

Improvement in local cerebral blood flow measurement in gerbil brains by prevention of postmortem diffusion of [14C]iodoantipyrine.

Postmortem diffusion of [14C]iodoantipyrine, which distorts the image of cerebral blood flow, can occur in at least three steps; from decapitation until the brain is frozen, while frozen sections on coverslips are thawed, and when dried sections are applied to x-ray film. In the present study, the first two steps were modified to reduce the time during which brain tissue was wet. When the brains of gerbils were taken out of the skulls and immersed in chilled isopentane (-45 degrees C), 90-95 s elapsed between decapitation until the brain tissues were frozen. However, immersion of whole heads in liquid nitrogen after decapitation decreased the time to 25 s. The autoradiograms had better contrast after the freezing procedure with liquid nitrogen than after that with chilled isopentane. The drying time of the thawed sections was markedly reduced by blowing hot air across the sections on a hot plate, and this resulted in clearer images on autoradiograms. In most of the tissues with values of cerebral blood flow over 100 ml 100 g-1 min-1 as measured using the conventional drying method, the corresponding values were higher if the modified method was used. In contrast, in tissues with values less than 100 ml 100 g-1 min-1, the corresponding values were lower. Moreover, the differences between flows in adjacent small brain structures were less clear if the sections were dried by the conventional method. Reducing the time during which postmortem brains or sections are wet can help prevent [14C]iodoantipyrine diffusion artifacts.     

Contralateral flow reduction in unilateral stroke: evidence for transhemispheric diaschisis

Using clinical presentation, angiography, computed tomography, and nuclear magnetic resonance imaging, 7 patients were identified who had strictly unilateral hemispheric infarction and unilateral cerebrovascular disease. In 6, cerebral blood flow measured by fluorine-18-fluoromethane inhalation and positron emission tomography was reduced in the contralateral hemisphere (p less than 0.05). Multiple regression analysis demonstrated a high correlation between contralateral flow reduction and the degree of flow impairment in the infarcted area (r = 0.941, p = 0.0014) but not with age, risk factor profile, blood pressure, PCO2, hematocrit, or duration of stroke. We conclude that transhemispheric diaschisis best explains the contralateral flow reduction seen in supratentorial ischemic stroke.     

Cerebral blood flow. A predictor of recovery from ischemia in the gerbil.

Cerebral ischemia was induced in gerbils by bilateral carotid ligation for periods of 10 to 40 minutes. Cerebral blood flow (CBF) was measured by hydrogen clearance. Following ischemia, ultimate clinical and electroencephalogram recovery could be predicted in every case within the first five minutes by recovery could be predicted in every case within the first five minutes by recovery of CBF to at least 100% of the control level. In animals without EEC recovery, the postischemic CBF was always less than 80% of control and progressively declined to zero. Residual flow during ischemia appeared to minimize the likelihood of brain death. The determination of ultimate brain death appeared to coincide with a major circulatory abnormality that is probably microvascular.     

Sequential cerebral blood flow changes in short-term cerebral ischemia in gerbils

Using quantitative autoradiography, we studied sequential changes in regional cerebral blood flow during and after 2 minutes of bilateral common carotid artery occlusions in 18 gerbils. Occlusion (n = 4) led to severe ischemia in the forebrain (regional cerebral blood flow less than 5% of control [n = 4]) and midbrain (regional cerebral blood flow less than 10% of control), but was morphologically nonlethal. Reperfusion of the brain was complete, and regional cerebral blood flow was not different from control 1 minute after ischemia (n = 4), but hypoperfusion (regional cerebral blood flow 30-50% of control) occurred at 5 minutes (n = 3) and was pronounced at 1 hour (n = 4); at this stage blood flow was inhomogeneous. Hypoperfusion had disappeared at 4 hours (n = 3). Our results indicate that the well-documented sequence of cerebral blood flow changes (i.e., ischemia, initial recovery of blood flow, and delayed hypoperfusion) takes place even after nonlethal cerebral ischemia.