Cerebrovascular and brain metabolism reviews最新文献

The brain is a highly differentiated organ, exhibiting a variety of local metabolic and hemodynamic responses to ischemia. Several analytical strategies are useful in characterizing these abnormalities: these include the direct assay of tissue metabolites; topographic methods for depicting regional patterns of NADH, ATP, glucose, lactate, and pH; in vivo spectroscopic methods for analyzing mitochondrial redox state over time; autoradiographic approaches to quantitation of local glucose utilization, blood flow, protein synthesis, and pH; and the noninvasive methods of positron emission tomography and NMR spectroscopy, which are applicable as well to human studies. In focal ischemia, "core" regions of severe blood-flow reductions progress to irreversible injury, while the adjacent "penumbral" zone appears to represent an unstable region threatened with possible injury yet potentially amenable to therapeutic intervention. Glucose utilization in focal ischemia is remarkable for its local heterogeneity and, in the postischemic state, tends to be predictive of local tissue injury. The selective vulnerability of particular brain regions to injury following global ischemia has now been extensively correlated with alterations of local metabolism and hemodynamics. Hyperglycemia is generally deleterious to neuronal survival in ischemia--an effect mediated via tissue lactacidosis. Small differences in brain temperature also profoundly influence ischemic outcome. Areas remote from an ischemic focus may also show metabolic and functional abnormalities--so-called "diaschisis," which may be transneuronally and/or humorally mediated. Multiple neurotransmitters are released during ischemia and interact to influence tissue injury. Regional postischemic hypoperfusion may also influence outcome.

A growing body of evidence supports the hypothesis that platelet-activating factor (PAF) may be a key mediator in neuroinjury. PAF, originally isolated from stimulated basophils, can be produced by a variety of cells, such as polymorphonuclear leukocytes (PMNLs), platelets, monocytes, macrophages, and endothelial cells and has been suggested as a mediator of inflammation, platelet and neutrophil activation, plasma extravasation, and anaphylactic shock. Enhanced phospholipid metabolism in the ischemic penumbral zone has been reported and provides opportunity for production of PAF. A possible involvement of this lipid mediator in processes associated with cerebral ischemia and neurotrauma has been suggested by an increasing number of reports. PAF exerts cytotoxic effects on neuronal cells, causes vasoconstriction, and increases the blood-brain barrier permeability. Beneficial effects of PAF antagonists have been shown in various models of cerebral ischemia: pre- as well as postischemic application of the PAF antagonist resulted in reduction of edema and improved neurological outcome and improved cerebral microcirculation. These effects were correlated with improved neuronal survival and reduced accumulation of PMNLs, supporting a link and positive feedback between PAF and PMNLs in these processes. Since PAF appears to be uniquely involved in various pathophysiological events, it may function as a key mediator in ischemic and traumatic neuroinjury. The current review summarizes the current understanding of the function and biochemistry of PAF with respect to CNS physiology and pathology.

Almost 30 years have passed since the first measurement of regional cerebral blood flow in humans by 133Xe clearance. A review of the methodology is presented for the two-dimensional intracarotid method and the related inhalation and IV injection techniques. Emphasis is placed on the mathematical models employed and the blood flow indices derived from them. Similarities and differences between methods are described, and the contribution of each to clinical research is summarized.

An accumulation of experimental data suggests that N-methyl-D-aspartate (NMDA) receptor antagonists will prevent ischemic neuronal injury following transient global ischemia and reduce infarct volumes following focal ischemic insults. The excitotoxic hypothesis states that the excitatory amino acid neurotransmitter L-glutamate has neurotoxic properties that can be attenuated by antagonism of the NMDA receptor. In vitro work has shown that a variety of NMDA antagonists will prevent the death of neurons grown in culture and subsequently exposed to either brief periods of hypoxia or glutamate exposure. In vivo it has been shown that glutamate is released following ischemia, that the NMDA receptors remain functional both during and following ischemia, and that the concentration of NMDA receptors is highest in those regions that are most sensitive to ischemic neuronal injury. Once stimulated, these receptors mediate a lethal influx of calcium. Experiments with global ischemia have reported a cytoprotective effect by either prior removal of glutamate afferents or pretreatment with either competitive or noncompetitive receptor antagonists. Some of these data have been challenged and one suggestion that has been made is that the observed pharmacoprotection may be the result of coincidental drug-induced hypothermia. Numerous studies using a variety of models of focal ischemia have shown that the volume of a cortical infarct can be reduced with NMDA antagonists given either before or after an ischemic insult. These data are more consistent than those achieved for models of global ischemia and have led to proposals for clinical trials. Novel compounds that antagonize the NMDA receptor are now the subject of phase I clinical studies that are envisaged as a prelude to randomized acute stroke trials. The hypothesis that blockade of excitatory amino acid receptors will prevent neuronal death presages a new era in acute stroke treatment.

Cerebral ischemia is a complex injury process that occurs when the nutrient blood supply to cerebral structures is reduced below critical levels. The causes of cerebral ischemia are protean, but the underlying pathophysiologic mechanism that leads to injury is a mismatch between the supply of nutrients to a given cell (or population of cells) and the demand of the cell(s) for those essential nutrients. Extensive research is ongoing in our attempt to find a treatment strategy and/or pharmacologic agent that might protect cerebral structures when exposed to ischemia. To date, few strategies or agents have proven themselves truly "protective." In this communication, the complexities of the cerebral ischemia injury process will be reviewed, the principles of cerebral protection (both practical and theoretical) will be outlined, and the merits of barbiturate anesthesia with regard to planned temporary cerebral ischemia will be discussed.

The nervous system is particularly susceptible to the harmful effects of alcohol. These include Wernicke-Korsakoff syndrome, which is related to thiamine deficiency secondary to chronic alcohol abuse. Other neurotoxic effects of alcohol with cognitive impairments include delirium tremens, alcoholic seizures or "rum fits," and alcoholic neuropathies. It has become recognized in recent years that alcohol and its metabolites directly damage the nervous system even in the absence of nutritional deficiencies. Cerebral blood flow (CBF) measurements provide a noninvasive indirect monitor of cerebral metabolic activity. It has been shown conclusively that CBF measured by the 133Xe inhalation method is decreased in chronic alcoholism, correlating well with the amount of alcohol consumed. With abstinence, CBF returns toward normal levels provided the neurotoxic effects of chronic alcoholism are of recent onset. Clinical and pathological studies show significant loss of brain volume with ventricular dilatation after alcohol abuse even among young "social" drinkers. This toxic effect of alcohol is accompanied by varying degrees of cognitive impairments ranging from slight memory loss to frank dementia. Both the decrease in brain volume and the cognitive impairments, which occur with or without nutritional deficiency, are to a large extent reversible with abstinence and nutritional supplementation. Alcohol appears to accelerate age-related declines in CBF while nutritional deficiencies enhance the neurotoxic effects of alcohol. Measurements of local CBF (LCBF) and partition coefficients (L lambda) in deep cerebral structures, including the hypothalamus, thalamus, forebrain nuclei, and limbic system, can be achieved utilizing three-dimensional methods after inhalation of stable xenon as a contrast medium combined with serial computed tomographic imaging of the brain. Among chronic alcoholics, there are significant and diffuse reductions in cortical and subcortical gray matter CBF that are especially remarkable in hypothalamus and substantia innominata, which includes the nucleus basalis of Meynert, a major source of cholinergic input to neocortex and hippocampus. Reductions in LCBF are measurable in cognitively impaired patients with and without Wernicke-Korsakoff syndrome. Reductions of CBF include white matter and are more severe in patients with Wernicke-Korsakoff syndrome. Both types of encephalopathy improve with treatment, but recovery is usually more rapid and complete if nutritional deficiency is absent. Alcohol also appears to be a risk factor for stroke, possibly by depleting neuronal reserves and unfavorably influencing cardiovascular risks.

Cerebral blood flow is inversely related to in vitro whole blood viscosity, the major determinant of which is haematocrit. Haemodilution increases cerebral blood flow in polycythaemic patients and in subjects with high normal haematocrit. There is now increasing evidence that this relationship reflects a homeostatic and physiological regulation of oxygen-carrying capacity. A high normal haematocrit proves to be a weak risk factor for stroke whilst stroke risk is clearly related to the target haematocrit in patients treated for polycythaemia rubra vera. Whilst venesection remains accepted prophylactic treatment against stroke and other vaso-occlusive events in the latter case, no large scale trial has formally assessed the role of haematocrit reduction in patients with early manifestations of cerebrovascular disease like transient ischaemic attacks or in the early stages of multi-infarct dementia. There are theoretical reasons why a high haematocrit might have adverse effects on the cerebral circulation in the presence of vessel occlusion. Thus, flow and therefore oxygen delivery would become constrained by high viscosity (haematocrit) in the maximally dilated ischaemic vascular bed, and secondary thrombosis would be encouraged by low flow rates, and increased cell-cell interaction. These arguments have led to two large multicentre clinical trials of haemodilution in acute stroke victims. Neither has revealed any clinical benefit in the treated group. The reasons for the failure of the trials are discussed. It is envisaged that haemodilution, as well as retaining a clinical role in the prevention of stroke in patients with polycythaemia, may be used as an adjunct to other therapy for the immediate sequelae of cerebral ischaemia.

Positron emission tomography (PET) enables the study of neuropharmacological variables, such as regional receptor densities, alterations in receptor occupancy from endogenous neurotransmitters and exogenous drugs, and receptor plasticity in living human subjects. The purpose of this paper is to review the procedures currently used to study brain pharmacology based on the use of radioactive tracers and PET, and to identify open issues in this field. In particular, the article reviews methodology for tracer validation, including essential biochemistry and kinetic modeling, as well as present clinical applications of tracers used to study dopamine, opioid, benzodiazepine, and cholinergic receptors.

In this review, we assess the role of nuclear magnetic resonance (NMR) spectroscopy as a noninvasive method of studying metabolism in cerebral ischaemia. Phosphorus-31 NMR provides a monitor of intracellular pH and energy metabolites, including ATP, phosphocreatine, and inorganic phosphate, while other nuclei, including 1H, 13C, 19F, and 23Na can give additional information about several aspects of brain metabolism and physiology. For example, 1H NMR not only provides excellent images, but may also be used to monitor a range of metabolites, including lactate and several amino acids. Comparisons are made with the large body of information that is available from more traditional methods of studying metabolism. Emphasis is placed on the correlation of NMR data with parallel measurements of regional blood flow, tissue oxygenation, oedema, electrical activity, and tissue damage. Technical aspects of NMR are discussed where appropriate; for example, in relation to the range of metabolites that are accessible to study, the spatial resolution that is available for studies of focal lesions, problems arising from tissue heterogeneity, and quantification of metabolite levels. Applications in animal models and in humans are discussed; these primarily involve the 31P nucleus, but for the future it appears that 1H NMR studies offer particular promise.

Although free radicals have been suggested to contribute to ischemic brain damage for more than 10 years, it is not until quite recently that convincing evidence has been presented for their involvement in both sustained and transient ischemia. The hypothesis is examined against current knowledge of free radical chemistry, as it applies to biological systems, and of cellular iron metabolism. It is emphasized that those advents have changed our outlook on free radical-induced tissue damage. First, it has been realized that damage to DNA and proteins may be an earlier event than lipid peroxidation, perhaps also a more important one. Second, evidence now exists that the triggering event in free radical-induced damage is a disturbance of cellular iron metabolism, notably delocalization of protein-bound iron, and its chelation by compounds that trigger site-specific free radical damage. Third, methods have been developed that allow the demonstration of partially induced oxygen species in tissues, and scavengers have become available that can curb free radical reactions. As a result of these events, it has been possible to demonstrate formation of free radicals in oxygen toxicity, trauma, and ischemia, and their participation in the cell damage that is incurred in these conditions, particularly in causing vascular pathology and edema. It is suggested that in ischemia, free radical damage becomes pathogenetically important when the ischemia is of long duration, when conditions favor continued delivery of some oxygen to the ischemic tissue, and particularly when such partially oxygen-deprived tissue is reoxygenated.