Cerebrovascular and brain metabolism reviews最新文献

Studies of regional cerebral blood flow (rCBF) are rapidly increasing our understanding of migraine mechanisms. In the early phase of an attack, migraine with aura (previously classic migraine) is associated with posterior focal hypoperfusion in one hemisphere. This spreads forward, usually to involve the posterior one-third to one-half of a hemisphere. Hypoperfusion persists into the headache phase and is associated with partial or complete vasoparalysis. From patient to patient, it varies in severity, ranging from almost normal to well below the usual ischemic threshold. After 1 h to several hours, the formerly hypoperfused areas becomes hyperperfused. The headache begins while rCBF is decreased and relates topographically to the area affected by rCBF changes. There is no association with hyperperfusion, which usually begins long after headache onset and often outlasts headache. In migraine without aura, there are no focal rCBF abnormalities but a dispute as to whether flow is globally increased. For a number of reasons, pain mechanisms, however, are likely to be the same as in migraine with aura, just initiated by something else. Extracranial blood flow is unchanged during migraine attacks but the superficial temporal artery on the side of the headache is dilated and recent transcranial Doppler studies have been interesting although difficult to interpret. These results will stimulate further studies of large arteries. The migrainous aura is probably the clinical manifestation of a cortical spreading depression. The resulting ionic and neurotransmitter changes are by way of local irritation of pial perivascular nerves, the most likely mechanism of migraine headache.

The endothelium of the brain microvasculature is much tighter than that elsewhere in the body. Although brain endothelium appears to possess the same routes for transendothelial transfer as other endothelia, the rarity of some routes leads to an extremely low overall permeability. Cells associated with brain endothelium, particularly astrocytic glial cells, appear to be involved in induction of the low permeability state. Although relatively unaffected by hypoxia and changes in plasma ion concentration, brain endothelial permeability is increased by stretch and shrinkage of endothelial cells, and by inflammatory mediators. Recent evidence suggests that many mediators of increased transendothelial permeability act by raising intracellular free calcium, and causing a contractile event that pulls apart the tight junctions; this also appears to apply to brain endothelium. Comparison of the brain endothelium with the perineurium of peripheral nerve, part of the blood-nerve barrier, suggests that the modulation of brain endothelial permeability seen in pathological situations may give some physiological advantage.

Recent evidence suggests that glutamate-induced neuronal damage may contribute importantly to neuronal death in several neurological diseases, including cerebral hypoxia-ischemia. This review outlines a range of measures that might be used to protect neurons from such excitotoxic damage. The organizing thesis is a speculative consideration of glutamate neurotoxicity as a sequential three-stage process--induction, amplification, and expression--each perhaps specifically amenable to therapeutic interference. Overstimulation of glutamate receptors likely induces the intracellular accumulation of several substances, including Ca2+, Na+, inositol-1,4,5-trisphosphate, and diacylglycerol. Blockade of this induction might be accomplished most easily by antagonizing postsynaptic glutamate receptors, but also might be accomplished by reducing glutamate release from presynaptic terminals, or improving glutamate clearance from synaptic clefts. Following induction, several steps may importantly amplify the resultant rise in intracellular free Ca2+, and promote the spread of excessive excitation to other circuit neurons. Protective strategies operative at this level might include blockade of additional Ca2+ influx, blockade of Ca2+ release from intracellular stores, and interference with the mechanisms coupling glutamate receptor stimulation to lasting enhancements of excitatory synaptic efficacy. Following amplification, toxic levels of intracellular free Ca2+ might trigger destructive cascades bearing direct responsibility for resultant neuronal degeneration--the expression of excitotoxicity. The most important cascades to block may be those related to the activation of catabolic enzymes, and the generation of free radicals. Broad consideration of possible methods for antagonizing glutamate neurotoxicity may be needed to develop therapies with the greatest efficacy, and least adverse consequences for brain function.

Endothelin was predictably found to be one of the endothelium-derived contraction factors (EDCFs) with the aid of advanced protein technology. It is the most potent and long-lasting vasoconstrictor peptide known to date. By analysis of the amino acid sequence, modern gene technology has made it possible to find isopeptides. These isopeptides, namely the endothelin family composed of endothelin-1, -2, and -3, have made and are achieving a breakthrough in every field of physiology and pathology. In the central nervous system, they act not only as a vasoconstrictor but also as a neuropeptide, in particular endothelin-1 and -3. Here we overview the findings obtained over the past 2 years since its discovery, and look to future progress.

Nerve growth factor (NGF) is a protein necessary for the differentiation and maintenance of peripheral sympathetic neurons, certain sensory neurons, and cholinergic neurons of the basal forebrain. NGF is synthesized in target areas of NGF-responsive neurons. This protein binds to specific cell surface receptors on the nerve terminals and is retrogradely transported to the cell bodies of the neurons, during which various physiological functions are expressed. In spite of its physiological importance, the regulatory mechanisms of NGF synthesis are unknown. We approached this problem from an in vitro cellular aspect and in turn applied the knowledge obtained to in vivo studies on the regulation of NGF synthesis. Nonneuronal cells, such as astroglial cells, fibroblast cells, and Schwann cells, synthesize and secrete NGF in cultures. NGF synthesis by these cells is growth dependent, suggesting that the expression of some genes relevant to cell growth is associated with upregulation of NGF synthesis. To elucidate neuronal influences, we tested various neurotransmitters and found that catecholamines and their analogues have stimulatory effects on NGF synthesis of nonneuronal cells. From the results of a structure-activity relationship, alkylcatechol compounds with an alkyl group at position 4 of the catechol ring show a potent stimulatory activity in vitro. Evidence that NGF has a potent protective activity on neuronal degeneration both in the central nervous system (CNS) and peripheral nervous system (PNS) is accumulating. NGF is a macromolecule that cannot pass through the blood-brain barrier, suggesting a limited availability of this protein for therapeutic use in diseases with neuronal degeneration in the CNS. We considered that compounds with a low molecular weight that elicit stimulatory activity on NGF synthesis are much more useful and practical for therapeutic purposes. Therefore, we investigated alkylcatechol compounds and their diacetyl derivatives, and found them to be able to induce NGF synthesis in the rat PNS in vivo. This is the first step in developing an agent capable of inducing NGF synthesis for therapeutic use in the future. The physiological and/or therapeutic significance of NGF induction is discussed.

Positron emission tomography (PET) in human brain tumors presents specific problems, such as tissue inhomogeneity and disruption of the blood-brain barrier (BBB), that are not present or at least not that important in normal brain. In addition, tracer metabolism may be different from normal brain. Mathematical arguments demonstrate that quantitation in inhomogeneous tissue is extremely difficult with tracers undergoing reversible metabolism, whereas irreversible metabolic steps can be quantified more easily. Even for metabolically inert tracers with reversible transport across the BBB, physiological identification of transport rate constants may be ambiguous, since diffusion processes within the tissue cannot be differentiated from slow transport components at the BBB. Mathematical analysis shows that transport is usually underestimated, whereas metabolism is usually overestimated in inhomogeneous tumor tissue. For accurate measurements of blood flow and BBB permeability, use of short measurement times is recommended. Measurements of tumor glucose consumption with [18F]2-fluoro-2-deoxy-D-glucose (FDG) are probably only little affected by tumor heterogeneity. There are, however, major problems caused by variation of the lumped constant, which relates the kinetics of FDG to those of glucose. Most experimental data indicate a considerable increase of the lumped constant in malignant tumors, resulting in overestimation of glucose metabolism if the standard value is used. In spite of these limitations, measurements of glucose metabolism with FDG are useful clinically to evaluate the prognosis of patients with brain tumors and to differentiate between late radiation necrosis and recurrent tumor. New tracers for measurement of protein synthesis, cell proliferation, and uptake of cytostatic drugs are of high clinical interest. As yet, little is known about the contribution of metabolites in brain and plasma to measured tissue activity, and differentiation between transport at the BBB and metabolism may be difficult. Therefore, the basis for accurate quantitation with these new compounds is still incomplete. Clinical reports suggest that some amino acid tracers can be used for localization and grading of brain tumors.

Autoregulation of blood flow denotes the intrinsic ability of an organ or a vascular bed to maintain a constant perfusion in the face of blood pressure changes. Alternatively, autoregulation can be defined in terms of vascular resistance changes or simply arteriolar caliber changes as blood pressure or perfusion pressure varies. While known in almost any vascular bed, autoregulation and its disturbance by disease has attracted particular attention in the cerebrovascular field. The basic mechanism of autoregulation of cerebral blood flow (CBF) is controversial. Most likely, the autoregulatory vessel caliber changes are mediated by an interplay between myogenic and metabolic mechanisms. Influence of perivascular nerves and most recently the vascular endothelium has also been the subject of intense investigation. CBF autoregulation typically operates between mean blood pressures of the order of 60 and 150 mm Hg. These limits are not entirely fixed but can be modulated by sympathetic nervous activity, the vascular renin-angiotensin system, and any factor (notably changes in arterial carbon dioxide tension) that decreases or increases CBF. Disease states of the brain may impair or abolish CBF autoregulation. Thus, autoregulation is lost in severe head injury or acute ischemic stroke, leaving surviving brain tissue unprotected against the potentially harmful effect of blood pressure changes. Likewise, autoregulation may be lost in the surroundings of a space-occupying brain lesion, be it a tumor or a hematoma. In many such disease states, autoregulation may be regained by hyperventilatory hypocapnia. Autoregulation may also be impaired in neonatal brain asphyxia and infections of the central nervous system, but appears to be intact in spreading depression and migraine, despite impairment of chemical and metabolic control of CBF. In chronic hypertension, the limits of autoregulation are shifted toward high blood pressure. Acute hypertensive encephalopathy, on the other hand, is thought to be due to autoregulatory failure at very high pressure. In long-term diabetes mellitus there may be chronic impairment of CBF autoregulation, probably due to diabetic microangiopathy.

The development of delayed cerebral ischaemia and hence neurological deficit remains a serious problem following subarachnoid haemorrhage. Over recent years, attention has focussed on the use of the dihydropyridine class of calcium channel blocking agents ("calcium antagonists"), in particular nimodipine, as drug therapy in the prophylaxis and treatment of this condition. The theoretical basis for this is briefly discussed and then the clinical experience of the use of calcium antagonists following subarachnoid haemorrhage reviewed. In particular, attention is focussed on the randomised controlled trials that have eventually been able to show that such treatment is beneficial, both in terms of reduction of ischaemic deficit attributable to cerebral "vasospasm" and in clinical outcome, when given prophylactically, although not apparently therapeutically once deficit has developed. The evidence of the mode of action of calcium antagonists in this situation is discussed, again with particular reference to clinical data obtained in situ in the course of such trials. Although the mechanism of action remains unclear, it appears likely that it is at least in part due to the selective cerebral vasodilation induced by these compounds. The necessity for large well-controlled, prospective, randomised clinical trials in the assessment of therapeutic efficacy is stressed.

It has been appreciated for many years that the recovery of brain protein synthesis activity following a transient ischemic insult lags considerably behind the normalization of brain energy metabolism. More recently, selective increases or decreases in the synthesis of specific proteins have been documented to occur during postischemic recirculation, the best characterized of such changes being the induction of proteins characteristic of the "heat shock" or "stress" response. This review will summarize these developments in the study of changes in gene expression following ischemia, with an emphasis on regional differences in the vulnerability of overall translational activity as well in the expression of stress proteins and their mRNAs. The neuronal localization of the 70 kDa heat shock protein, hsp70, after ischemia is contrasted with its largely glial and vascular induction following a hyperthermic stress. The lasting depression of protein synthesis and sustained expression of hsp70 mRNA in vulnerable hippocampal CA1 neurons appear to be mechanistically related and may constitute markers for cellular pathophysiology leading to neuronal cell loss. Elucidating the mechanisms responsible for cell-specific regulation of stress proteins and other gene products may eventually contribute to a more precise understanding of the evolution of brain injury at the molecular level following diverse insults.

An excitotoxic action of glutamate and aspartate contributes to the pathological outcome after transient global cerebral ischaemia, focal ischaemia, neonatal hypoxia/ischaemia, and secondary ischaemia following brain trauma. This provides a therapeutic approach utilising drugs acting on (i) glutamate release, (ii) postsynaptic glutamate receptors, and (iii) the secondary events following receptor activation (including the arachidonic acid cascade). Both NMDA and non-NMDA receptors are involved in the excitotoxic effects of glutamate and aspartate. The availability of competitive and noncompetitive antagonists acting at the NMDA receptor has permitted the demonstration of cerebroprotective effects of these compounds in animal models of global, focal, neonatal, and secondary cerebral ischaemia. Protection is seen with antagonist administration prior to and after the onset of ischaemia. The postischaemic therapeutic time window is not fully defined for the different models but is in the range of 0-20 min for incomplete global ischaemia and 1-3 h for focal ischaemia. The clinical usefulness of this approach remains to be established.