Cerebrovascular and brain metabolism reviews最新文献

In focal ischaemia, the penumbra defines regions with blood flow below that needed to sustain electrical activity, but above that required to maintain cellular ionic gradients, and that lead in time to infarction. Among other terms used to describe regions surrounding the ischaemic core, "penumbra" is the only one based on a precise functional state of partially ischaemic tissue. The precarious balance between energy supply and demand that characterizes the penumbra and the proximity of the ischaemic core are the basis of a number of important features: (a) It is a time-limited condition, with a tendency to evolve towards infarction and to propagate to adjacent viable tissue; (b) "misery perfusion" is associated with increased oxygen extraction, acidosis, and high glucose utilization, but residual ATP; (c) recurrent spreading depression contributes to the deterioration of the penumbra, at least in animal models of stroke; (d) there is no sustained increase of extracellular glutamate; and (e) improvement of local perfusion and reduction of energy demand remain the most rational approaches to rescue the penumbra. By defining a window of opportunity for therapeutic intervention in stroke, the concept of ischaemic penumbra has enormously stimulated research in this field and led to a better understanding of the pathophysiology of cerebral ischaemia, with direct practical application for the surgical management of cerebrovascular disorders such as aneurysms.

Information about the presence of the endothelin system in the cerebrovascular bed and its physiological or pathophysiological role(s) in the control of the cerebral circulation has dramatically increased in recent years. Endothelin-1 can be produced in the cerebrovascular bed from circulating big endothelin or by endogenous endothelin mRNA expression. Endothelins bind to specific ETA and ETB receptors in cerebral vessels. Activation of these receptors triggers intracellular signal transduction mechanisms mediating tone maintenance as well as long-term vascular changes. Endothelins are potent constrictors of cerebral arteries isolated from different species, including humans. In vivo the reductions in vessel diameter or blood flow due to the direct vasoconstrictive effects of endothelin-1 are modulated or even changed in some cases to opposite vasodilatative effects because of the release of dilatative substances. The ability of locally applied endothelin-1 to reduce blood flow to pathologically low levels has been used to develop animal models of focal cerebral ischemia. Endothelin-1 is thought to play a role in the pathophysiology of nonhemorrhagic cerebral infarct and in cerebral vasospasm after subarachnoid hemorrhage.

This article focuses on the key concept that a basal production of nitric oxide (NO) is required as a background for biological modulation, although an excess can be cytotoxic. Studies of ischaemia and neurodegeneration have tended to emphasise detrimental effects of excess NO, but this review contrasts the emerging importance of diminished NO or interference with its action in vasospasm following subarachnoid haemorrhage (SAH) in ageing and in atherosclerosis. Clinical intervention in cerebral ischaemia will require specificity of action, since NO appears to be protective or detrimental depending on the time, source, and distribution of its production. It may be possible to utilise targeted action on the different forms of NO synthase or the specific redox forms of NO in different tissue areas.

Cerebrovascular reserve (CVR) can be assessed by measuring the hemodynamic response to a physiological stress such as alteration of blood pressure, increase in tissue acidosis, lowered oxygen supply, increase in metabolic demand, or occlusion of an artery. Failure of the cerebrovascular system to maintain function or normative values of several interrelated hemodynamic variables--cerebral blood flow (CBF), oxygen extraction fraction (OEF), cerebral blood volume (CBV), and cerebral metabolic rate of oxygen (CMRO2),--in response to a stress implies a compromise of the normally robust compensatory mechanisms. The conclusions that are possible from this information depend on the type of stress induced and the technology used to measure the response. Technologies that permit a rapid test-retest format coupled with a physiological stress provide the most direct information about the hemodynamics of cerebrovascular territories. Patients whose cerebral vasculature becomes compromised by any of a broad range of disorders and who, thus, are at increased risk for stroke now can be readily identified based upon evidence of exhausted CVR. Strategies for treating hemodynamically driven disorders also can now be designed based upon such patient-specific CVR information. It is hoped that integration of CVR into the standard clinical assessment of patients with occlusive vascular disorders (OVD) will lead to treatments that focus not only on the previously understood embolic causes of stroke, but also on the often interrelated hemodynamic factors.

Recent developments in the field of magnetic resonance imaging (MRI) have opened up new opportunities in the investigation of disease. This review seeks to illustrate how some of these advances have made MRI a powerful tool with which to study the pathology and physiology of cerebral ischaemia. Emphasis will be placed on new techniques at the disposal of the MR investigator. These include techniques to monitor alterations in cerebral blood flow and volume; diffusion-weighted imaging to investigate the acute pathology of cerebral ischaemia; and techniques sensitive to alteration in tissue blood oxygenation levels that provide a wholly noninvasive means of assessing cerebral haemodynamics, including hyperaemia and CO2 reactivity. Particular reference to the ability of such techniques to identify ischaemic tissue prior to irreversible damage will be made, and the implication for pharmaceutical research and potential therapy will be discussed. A detailed technical description of nuclear MR theory is avoided, and we have concentrated on the application of MRI to interrogate the pathophysiology of cerebral ischaemia.

Following subarachnoid hemorrhage (SAH) from an intracranial aneurysm, ischemic deficits related to cerebral vasospasm still account for significant morbidity and mortality. Operative decisions and timing must be based on the presence of vasospasm and other complications of the hemorrhagic period. Transcranial Doppler sonography provides a noninvasive method for evaluating the status of the intracranial arteries following SAH. The method can, with good reproducibility, identify the patient likely to suffer symptomatic vasospasm, outline the progress of the disease, and serve as a guide to therapy. There are inherent errors produced by the anatomy of the intracranial tree and by peculiarities of the disease. Proximal vasospasm, distal vasospasm, defective autoregulation, and distal infarction with hyperperfusion add confusion to the velocity equation. In experienced hands, however, the method correlates well with the angiographic image of the vessels studied.

This review examines and evaluates the double-indicator technique for utilization in quantitative measurements of the transport of substances across the human blood-brain barrier (BBB). The classic double-indicator method and its limitations are described along with a new approach for correction of capillary heterogeneity and tracer backflux. This approach considers the total course of the venous outflow curves and involves a short-time experiment model that incorporates calculations of parameters for transport from the blood into the brain and from the brain back to the blood, for the uptake of neurons and glia cells, and for the tracer distribution volume. A modification of the double-indicator technique with intravenous instead of intracarotid bolus injection is discussed along with advantages and limitations of this technique. The application of the method is described and examples are given for D-glucose as well as for some large neutral amino acids and flow tracers. On the basis of the model, it is demonstrated that after crossing the BBB, D-glucose distributes in the brain interstitial fluid volume, and already at the peak of the glucose outflow curves, the apparent extraction is significantly influenced by backflux from the brain. For large neutral amino acids, the permeability from the interstitial fluid space back to the blood is approximately 10 times higher than the permeability from the blood into the brain. Such a difference in permeabilities across the BBB can almost entirely be ascribed to the effect of a nonlinear transport system combined with a relatively small brain amino acid metabolism. This high and rapid backflux causes methodological problems when estimating blood-to-brain transfer of amino acids with traditional in vivo methods. The method is also evaluated for high-permeable substances. Water and the two flow tracers ethyl cysteinate dimer and hexamethylpropyleneamine oxime and the obtained values for brain extraction and distribution volume compare well with those obtained by other methods. Finally, ethical aspects and the future role and possibilities of the double-indicator technique are discussed and related to other methods for determination of BBB permeabilities in the living human brain.

The original observation that inhibitors of nitric oxide (NO) synthesis can antagonize glutamate toxicity in cell culture has led to extensive investigation of the role of NO in the pathophysiology of cerebral ischemic injury in vivo. However, studies of the efficacy of NO synthase inhibitors in models of focal cerebral ischemia have generated widely disparate findings, ranging from dramatic neuroprotection to exacerbation of ischemic damage. This review summarizes these studies and proposes that their apparently contradictory findings can be reconciled by viewing the results as a continuum of response that reflects the many and diverse physiological actions of NO. Thus, differences in experimental design between studies can alter the balance between these NO-controlled processes and result in the transformation of an overt neuroprotective effect of NO synthesis inhibition into one of exacerbation of ischemic injury. Thus, this review also identifies some of the most important physiological and pathophysiological functions of NO (and the consequences of their inhibition by NO synthase inhibitors) that may interact to determine outcome after a focal cerebral ischemic insult. A clearer appreciation of the potential therapeutic utility of both NO synthesis inhibitors and NO donors will emerge only when the complexity of their effects on mechanisms that interact to determine the extent of ischemic damage in vivo are more fully defined and understood.

The development of selective, systemically active alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA)/kainate antagonists over the last 4 years has enabled the role of this excitatory amino acid receptor subtype to be scrutinised in the different models of ischaemia. The animal models of cerebral ischaemia can be subdivided into two major categories: focal ischaemia, in which the resulting infarct resembles the clinical condition of stroke; and models of severe forebrain ischaemia, in which there is delayed neuronal degeneration of hippocampal CA1 neurones. The neuropathology in the latter models resembles the clinical condition seen following a cardiac arrest, for example. It is well established that N-methyl-D-aspartate (NMDA) antagonists such as MK-801, 3-(2-carboxypiperazine-4-yl)-propenyl-1-phosphonate (CPPene), DL-(E)-2-amino-4-methyl-5-phosphono-3-pentanoic acid (CGP 37849), and N-(1-naphthyl)-N'-(3-ethylphenyl)-N'-methylguanidine hydrochloride (CNS 1102) are neuroprotective in animal models of focal ischaemia. However, in models of severe forebrain ischaemia NMDA antagonists produced only partial protection. The discovery of 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(F)quinoxaline (NBQX) as a systemically active AMPA receptor antagonist enabled the role of this receptor subtype in ischaemia to be investigated. NBQX was shown to be neuroprotective against delayed neuronal degeneration of hippocampal CA1 neurones in animal models of severe forebrain ischaemia. Recent studies have demonstrated that NBQX administration can be delayed by up to 12 h and amelioration of delayed neuronal degeneration of hippocampal CA1 neurones can still be seen. NBQX has also been shown to be neuroprotective in animal models of permanent and temporary middle cerebral artery occlusion. 1-(Aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine (GYKI 52466), a systemically active noncompetitive AMPA/kainate antagonist, was neuroprotective against focal ischaemia but was unable to attenuate hippocampal CA1 neuronal degeneration. Whilst the newer compounds such as (3SR,4aRS,6RS,8aRS)-6-[2-(1H-tetrazol-5-yl )-ethyl]-1,2,3,4,4a,5,6,7,8a-decahydroisoquinoline-3-carboxylic acid (LY 215490) and 6-(1-imidazolyl)-7-nitroquinoxaline-2,3(1H,4H)-dione (YM900) have been demonstrated to be neuroprotective in focal ischaemia models, there is still a lack of information with regard to their efficacy in models of severe forebrain ischaemia. It appears from initial studies that AMPA/kainate antagonists have a better behavioural profile than NMDA antagonists in terms of a lack of phychostimulant and phychotomimetic effects. However, these antagonists have their own problems in that they cause severe depression of glucose utilisation in the central nervous system at neuroprotective doses.(ABSTRACT TRUNCATED AT 400 WORDS)

The effect of thrombolytic therapy is well-documented in acute myocardial infarction. In acute cerebral infarction, thrombolytic therapy has been evaluated in small series of patients. The point of thrombolytic therapy is to avoid or reduce ischemic damage of neuronal tissue by rapid arterial recanalization. In thrombolytic therapy of cerebral vascular occlusion, the pathophysiology of reperfusion needs further investigation and documentation. This review describes studies of thrombolysis in embolic stroke using animals embolized by intracarotid injections of blood clots. Vascular occlusion was demonstrated by angiography and measurement of cerebral blood flow. Thrombolytic therapy with recombinant tissue-type plasminogen activator was initiated after varying periods of time. Reperfusion, cellular function, and brain damage were examined by angiography and by clinical and pathoanatomical examination. Based mainly on results from our own investigations, the following theses concerning ischemic stroke were made: (a) Cerebral infarction caused by arterial occlusion is due to delayed, incomplete, or no reperfusion. Spasms, or hemodynamic mechanisms, seem to be of only minor importance. (b) Early thrombolytic therapy in animal models increases the degree of reperfusion and reduces brain damage, clinical deficits, and mortality. (c) Early arterial reperfusion reduces cerebral infarction and related edema. With early reperfusion, the extent of brain damage correlates to the length of the delay from onset of ischemia. (d) Cerebral stunning is caused by arterial occlusion followed by very early spontaneous or induced reperfusion, as neurons temporarily lose their functional capabilities without dying. (e) Multiple embolic microclots in experimental stroke result in more brain damage than a single macroclot, and with clots the extent of brain damage is dependent on the structural composition and volume of emboli. (f) The ability to recanalization in experimental embolic stroke is related to the amount of red cells in the emboli and inversely related to the volume of emboli and to the fibrin content and density of the clots. (g) Infarct-limiting effects in experimental stroke can be obtained by ischemic neuroprotectants or by hypothermia, either alone or with thrombolytic therapy, which then reduces brain damage further.