Cannabis Use and Cerebrovascular Disease
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Cannabis is the most commonly abused illicit drug and is often considered innocuous. However, cases of acute onset neurologic dysfunction occurring in relation to cannabis use have been described and corresponding cerebral imaging studies have documented focal ischemic changes and vessel abnormalities.This article reviews all reported cases of presumed cannabis related cerebral ischemic events in the medical literature, as well as pertinent human and animal experimental studies on the cardiovascular and cerebrovascular effects of cannabis.Cannabis use seems to have been causally related to several instances of cerebral ischemia and infarction. Proposed etiologic mechanisms have included cerebral vasospasm, cardioembolization, and systemic hypotension with impaired cerebral autoregulation, but most of the available data points to a vasospastic process. The exact relation of cannabis to cerebrovascular disease remains to be determined.Keywords:
Effects of cannabis
Cerebral Vasospasm
The continuous release of nitric oxide (NO) is required to maintain basal cerebrovascular tone. Oxyhemoglobin, a putative spasmogen, rapidly binds NO, implicating loss of NO in the pathogenesis of cerebral vasospasm after subarachnoid hemorrhage (SAH). If vasospasm is mediated by depletion of NO in the vessel wall, it should be reversible by replacement with NO. To investigate this hypothesis, the authors placed blood clots around the right middle cerebral artery (RMCA) of four cynomolgus monkeys; four unoperated animals served as controls. Arteriography was performed before and 7 days after surgery to assess the presence and degree of vasospasm, which was quantified in the anteroposterior (AP) projection by computerized image analysis. On Day 7, cortical cerebral blood flow (CBF) in the distribution of the right MCA was measured during four to six runs in the right internal carotid artery (ICA) of brief infusions of saline followed by NO solution. Arteriography was performed immediately after completing the final NO infusion in three of the four animals with vasospasm. Right MCA blood flow velocities were obtained using transcranial Doppler before, during, and after NO infusion in two vasospastic animals. After ICA NO infusion, arteriographic vasospasm resolved (mean percent of preoperative AP area, 55.9%); that is, the AP areas of the proximal portion of the right MCA returned to their preoperative values (mean 91.4%; range 88%-96%). Compared to ICA saline, during ICA NO infusion CBF increased 7% in control animals and 19% in vasospastic animals (p < 0.002) without significant changes in other physiological parameters. During NO infusion, peak systolic right MCA CBF velocity decreased (130 to 109 cm/sec and 116 to 76 cm/sec) in two vasospastic animals. The effects of ICA NO on CBF and CBF velocity disappeared shortly after terminating NO infusion. Intracarotid infusion of NO in a primate model of vasospasm 1) increases CBF, 2) decreases cerebral vascular resistance, 3) reverses arteriographic vasospasm, and 4) decreases CBF velocity in the vasospastic artery without producing systemic hypotension. These findings indicate the potential for the development of targeted therapy to reverse cerebral vasospasm after SAH.
Cerebral Vasospasm
Transcranial Doppler
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Delayed release of hemoglobin from the subarachnoid clot in the vicinity of conductive arteries leads to cerebral vasospasm after SAH. The mechanism of vasospasm however remains unclear. The one thousand times higher affinity of ferrous heme for nitric oxide, a potent vasodilator of cerebral vessels, than to oxygen, has led to the concept that hemoglobin scavenges nitric oxide and produces delayed cerebral vasospasm after SAH. For several years we have investigated the pathological mechanism(s) behind this event using in vivo experiments. We summarize experimental data and discuss the clinical value of the observations for the development of a new treatment for vasospasm after SAH.
Cerebral Vasospasm
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BACKGROUND: Cerebral vasospasm is delayed-onset cerebral arterial narrowing in response to blood clots left in the subarachnoid space after spontaneous aneurysmal subarachnoid hemorrhage (SAH). Ideally, studies on the pathogenesis and treatment of cerebral vasospasm in humans should be conducted using human cerebral arteries. Because in vivo experiments using human vessels are not possible, and postmortem pathological examination of human arteries in vasospasm provides only a limited amount of information, a number of animal models of vasospasm have been developed. METHODS: The literature was searched to find all references to in vivo animal models of SAH and vasospasm. An online search of the medical database MEDLINE was initially performed using the key words "cerebral," "vasospasm," "subarachnoid," "hemorrhage," "animal," and "model." References were checked to determine the first description of each in vivo animal model. RESULTS: Fifty-seven models of SAH and vasospasm were identified. These models used one of three techniques to simulate SAH: 1) an artery was punctured allowing blood to escape and collect around the artery and its neighbors; 2) an artery was surgically exposed, and autologous blood obtained from another site was placed around the artery; or 3) blood from another site was injected into the subarachnoid space and was allowed to collect around arteries. Each technique has advantages and disadvantages. The majority of animal models of SAH and vasospasm use intracranial arteries; however, extracranial arteries have also been used recently in vasospasm experiments. These studies seem easier and less costly to perform, but concerns exist regarding the physiological dissimilarity between systemic and cerebral arteries. CONCLUSION: The model of SAH and vasospasm used most frequently is the canine "two-hemorrhage" model, in which two injections of blood into the dog's basal cistern performed 48 hours apart result in greater arterial vasoconstriction than that effected by a single injection of blood. On the basis of its ability to accurately predict what occurs in human SAH, the best model of vasospasm seems to be the primate model in which a blood clot is surgically placed around the large cerebral vessels at the base of the monkey's brain.
Cerebral Vasospasm
Subarachnoid space
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Cerebral vasospasm is the most common and most dangerous complication of subarachnoid hemorrhage (SAH). If it can not be diagnosed and treated early, it will result in delayed cerebral ischemia and delayed ischemic neurological deficits, and seriously affect the outcomes of patients. SAH can cause oxidative stress and inflammation, causing vasospasm, and leading to brain tissue damage. Numerous studies have shown that the concentrations and activities of numerous metabolites will change in these pathological physiological processes. Identification of the changes of location, time and trend of these markers has important clinical significance for investigating the mechanism of cerebral vasospasm after SAH and seeking better therapeutic targets. This article reviews the molecular markers of cerebral vasospasm after SAH.
Key words:
Subarachnoid Hemorrhage; Vasospasm, Intracranial; Biological Markers
Cerebral Vasospasm
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Cerebral Vasospasm
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Objective: A multitude of subarachnoid hemorrhage (SAH) models have been described but only several of them are still in use. All models to a different degree helped in understanding of pathophysiology of cerebral vasospasm after SAH. Their advantages and drawbacks have been reviewed in this paper. Since 2000, when the last review on cerebral vasospasm in animal models was written, new animal models of SAH were introduced and our knowledge about pathophysiology of CVS improved. The aim of present review was to update the information about well established and newly implemented models of vasospasm after SAH. Materials and methods: The MEDLINE searches were carried out using keywords that included 'subarachnoid hemorrhage', 'animal', 'model', as well as names of animal species such as 'rats', 'dogs', 'mice', 'rabbits', 'pigs' or animal groups, e.g. 'non-human primates'. Owing to a limited volume, only models of SAH in vivo were included in our review. Results: We identified 53 original models of SAH in considered groups of animals. For the past several years, use of rats and mice became increasingly common in vasospasm studies due to advancements of imaging techniques, new approaches in vessel morphometry and reduced costs related to small animals. However, dog model of SAH is still considered superior for vasospasm studies as the ability of murine models to model human vasospasm is disputed. Conclusion: Testing new concepts of vasospasm etiology will require re-evaluation of in vivo models of CVS. The updated knowledge about their advantages and limitations is necessary for effective design in future studies of cerebral vasospasm after SAH.
Cerebral Vasospasm
Animal model
Pathophysiology
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Animal studies
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✓ The effect of phenoxybenzamine (PBZ) on cerebral vasospasm of the basilar artery induced by the injection of 2 ml of blood into the cisterna magna of dogs was assessed in chronic experiments. The presence of vasospasm was documented arteriographically. In one group of animals, 12 mg/kg of PBZ was given intravenously 2 hours before the intracisternal injection of blood to ascertain whether this drug would prevent the development of vasospasm for 24 hours. In another group of animals a 10 −2M solution of PBZ was given intracisternally 15 minutes after vasospasm was produced, and again 24 hours afterward, to determine if the drug would reverse an existing spasm. These drug-treated animals were compared with controls which were treated with saline alone. The results indicate that the drug treatment was not statistically superior to saline in any of the groups studied. The finding that saline injected into the cisterna magna reversed the cerebral vasospasm illustrates the importance of this procedure in evaluating effectiveness of drugs and confirms the original observation that washing the cerebrospinal fluid with saline can terminate an experimentally induced vasospasm. Moreover, the fact that intracisternal injections of saline were more effective when given soon after the establishment of vasospasm than when injected 24 hours afterward supports the conclusion of others that the pathogenesis of cerebral vasospasm changes with time. The results also indicate that the presence of cerebral vasospasm in some animals did not prevent the return of normal behavior.
Cisterna magna
Cerebral Vasospasm
Phenoxybenzamine
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The removal of subarachnoid clot has been thought to be effective for prevention of cerebral vasospasm. However, it is suggested that the incidence of cerebral vasospasm is not high in the cases where ruptured cerebral aneurysms are obliterated using Guglielmi detachable coils (GDC) without clot removal. The effect of subarachnoid clot removal on the occurrence of cerebral vasospasm and the different incidence of cerebral vasospasm between clipping cases and in GDC cases are reviewed.Surgical clot removal in experimental model indicated marked preventive effect on cerebral vasospasm. However, the clinical trials of clot removal during early aneurysm surgery had failed to show satisfactory preventive effect for vasospasm, and the cumulative incidence of symptomatic vasospasm in these trials was 29%. As fibrinolytic drug, intrathecal administration of tissue plasminogen activator showed sufficient elimination of subarachnoid clot and prevention of cerebral vasospasm in the experimental studies and in the clinical case trials and nonrandomized case-control trials. However, the multi-center, randomized case-control trial showed no statistically significant effect on symptomatic cerebral vasospasm. On the other hand, the cumulative incidence of cerebral vasospasm in GDC cases was 20%. The comparative studies of the incidence of vasospasm between GDC cases and in clipping cases also showed less incidence of symptomatic vasospasm and a more favorable outcome in GDC cases. From the results of studies reviewed, the incidence of cerebral vasospasm seems less in GDC cases than in clipping cases. It should be clarified why clipping could not be dominant in the prevention of cerebral vasospasm compared to GDC.
Cerebral Vasospasm
Clipping (morphology)
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