Cerebrovascular and brain metabolism reviews最新文献

Reduction of cerebral blood flow below a critical threshold for a protracted time interval results in irreversible metabolic events culminating in cell death. The development of agents capable of extending the tolerable ischemic interval is of great importance as such agents may allow time for therapeutic measures to be accomplished which could restore cerebral perfusion. This issue is of particular pertinence in the treatment of complex cerebrovascular diseases when local (or global) cerebral blood flow must be interrupted during vascular reconstruction. Thiopental achieved great popularity once protective properties were demonstrated experimentally. Unfortunately, serious cardiovascular depression associated with high-dose barbiturates as well as prolonged duration of action may decrease collateral flow and limit their utility. Etomidate is a nonbarbiturate carboxylated imidazole which is capable of similar cerebral metabolic suppression without significant cardiac side effects. Accumulating experimental evidence supports the protective properties of this drug and suggests that it may be valuable clinically for this purpose. Significant adrenal suppression is a major toxic effect that must be treated if large doses or protracted administration is planned.

Hemorrhagic infarction and cerebral hematoma are feared events that may follow cerebral ischemia. Newly developed thrombolytic agents may be effective stroke therapy, but may also promote hemorrhagic complications after ischemic stroke. It is therefore critically important to understand the true incidence of hemorrhagic transformation after ischemic stroke, and to identify if possible the mechanisms underlying the phenomenon. In recent years, studies using serial computed tomography to identify hemorrhage have shown that transformation occurs in 15 to 43% of patients presenting with ischemia. Experimental and clinical evidence support the notion that hemorrhage results from augmented collateral circulation into the ischemic zone, perhaps in concert with hypertension. Recanalization and distal migration of the thrombus are not factors that are associated with transformation. Pharmacologic recanalization using thrombolytic drugs are not likely to be associated with hemorrhage if reperfusion is accomplished very soon after the onset of neurologic symptoms.

The cytokine interleukin-1 (IL-1) is synthesised within the brain and acts as a mediator of host defence responses to disease and injury. Several of these central actions of IL-1 are inhibited by an endogenous calcium and phospholipid binding protein, lipocortin-1. Synthesis of IL-1 and lipocortin-1 in the brain is markedly increased by neuronal damage, and inhibition of the actions of endogenous IL-1 by central injection of IL-1 receptor antagonist in the rat significantly inhibits ischaemic and excitotoxic brain damage. Lipocortin-1 appears to act as an endogenous neuroprotective agent that markedly attenuates ischaemic and excitotoxic damage. In contrast, inhibition of the actions of lipocortin-1 by injection of neutralising antiserum exacerbates both forms of neurodegeneration. The mechanisms underlying these effects of IL-1 and lipocortin-1 are largely unknown, but are probably independent of changes in body temperature. Actions of these molecules on corticotrophin releasing factor, arachidonic acid, excitatory amino acids, and nitric oxide, and the possible involvement of these factors in brain damage are discussed.

Until recent years, little has been known about the parasympathetic innervation of cerebral vessels, in contrast to the sympathetic innervation. Recent histochemical and biochemical studies on cerebrovascular parasympathetic nerves have revealed their sources and pathways. Histochemical studies have demonstrated nerve fibers containing choline acetyltransferase, a reliable marker for cholinergic nerves, and vasoactive intestinal polypeptide (VIP) in the cerebral vessels. By combining histochemistry with a retrograde tracer technique and selective denervations, the cerebrovascular parasympathetic innervation has been mapped in the rat, cat, and monkey. Acetylcholine (ACh) has been measured biochemically in the pial arteries of several species. A high-affinity uptake, local synthesis, and tetrodotoxin-sensitive release of ACh have been demonstrated in the pial vessels. Pharmacological studies on isolated pial arteries have revealed ACh- and VIP-induced relaxation through the stimulation of muscarinic and VIPergic receptors, respectively. The action of ACh requires an intact endothelial function. An increase in cerebral blood flow upon stimulation of pre- or postganglionic fibers of the sphenopalatine ganglion has been demonstrated in some animals, and can be mimicked by local administration of ACh and VIP in vivo. This indicates a role of the parasympathetic nerves in tone regulation of the cerebral vessels. The pathophysiological conditions during which these nerves become activated are currently being revealed.

Functional consequences of pharmacological and toxicological manipulations of the dopaminergic systems were evaluated by means of the 2-[14C]deoxyglucose (DG) method for measuring local rates of cerebral glucose utilization. Administration of dopamine agonist drugs modifies glucose metabolism in selected brain areas. Several factors, such as the compound used, the dose, length, and modality of the treatment, and the interval of time between the end of the treatment and the measurement of glucose utilization, contribute to define the topography and intensity of the changes. The differences refer to distinct activation of subtypes of dopamine receptors, to secondary involvement of other neurotransmitter receptor systems, and to modification of the receptor sensitivity occurring during the treatment. Other variables that interfere with the motivated behavior induced by psychostimulants may also affect the metabolic pattern. A few changes in glucose utilization are, however, common to most dopamine agonist drugs. High doses, which induce stereotypic behavior, produce metabolic changes in the extrapyramidal system. Low doses of psychostimulants, which elicit locomotion and exploratory behavior and produce reinforcement, increase glucose metabolism in the limbic system, particularly in the nucleus accumbens. Metabolic mapping in monkeys bearing 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced lesions of the dopaminergic areas in the brainstem contributed to define the key role of the striatopallidal pathway in the production and maintenance of the motor abnormalities that characterize parkinsonism. Metabolic patterns associated with unilateral 6-hydroxydopamine lesion of the nigrostriatal neurons in the rat are modified by dopamine agonist drugs. Specific changes are produced by selective D1 or D2 agonists. In rats bearing unilateral 6-hydroxydopamine lesion, the DG method also revealed functional effects produced by the interaction between D1 and N-methyl-D-aspartate receptors.

Ischemic brain injury is induced in a complex and multifactorial pathogenic cascade; but the fundamental mechanism is the imbalance between energy demand and supply in ischemic brain tissue. Nizofenone is a potent neuroprotective drug which ameliorates this imbalance and also various pathophysiologic events during ischemia, such as ATP depletion, lactate accumulation, glutamate release, free fatty acid liberation, edema, and neuronal degeneration; in particular, ischemia-induced excessive glutamate release has been completely blocked by this drug. This drug has also radical-scavenging action, comparable to vitamin E, and inhibits oxygen radical-induced lipid peroxidation. The potent cerebroprotective effect of nizofenone has been demonstrated in various experimental models of cerebral hypoxia, ischemia (focal and global), ischemia-reperfusion, and infarction. The clinical efficacy of nizofenone has been proved by pioneering double-blind studies in acute subarachnoid hemorrhage patients. Nizofenone is clinically used for preventing the delayed ischemic neurologic deficits due to late vasospasm following subarachnoid hemorrhage. In this report, the property of the cerebroprotective effect and the clinical efficacy of nizofenone is reviewed.

Experimentally, focal and global cerebral ischemia are markedly affected by small changes in brain temperature. Mild hypothermia greatly ameliorates and mild hyperthermia markedly exacerbates ischemic-induced neuronal injury. Mild hypothermia not only protects against neuronal injury but also improves clinical outcome. This effect depends on the temperature of the brain both during and after the ischemic episode. Clinical and laboratory evidence concerning the value of hypothermia and the danger of hyperthermia in acute ischemia are presented. Potential mechanisms of action of hypo- and hyperthermia in ischemic injury are also addressed. The need to treat fever in acute cerebral ischemia, even if evidence is only empiric, and the intriguing possibility of using mild hypothermia to treat acute cerebral infarction are discussed.

Penfield's observations in the 1930s provided the first systematic evidence of changes in regional cerebral blood flow (rCBF) associated with focal seizures. Further studies in humans and animals confirmed increases in cerebral blood flow and metabolism during generalised seizures, but the interictal, ictal, and postictal changes in focal epilepsy have begun to be elucidated in the last decade with the advent of in vivo imaging techniques such as positron emission tomography (PET) and single photon emission computed tomography (SPECT) and, in the case of animal studies, of autoradiography. Most studies have been of temporal lobe epilepsy. Interictally, the characteristic finding has been reduced blood flow and/or metabolism in the affected temporal lobe, or more extensively in the ipsilateral hemisphere. The few studies to date of ictal or postictal changes have been of rCBF using SPECT. They show hyperperfusion of the whole temporal lobe ictally, hyperperfusion of the hippocampus, combined with hypoperfusion of lateral structures in the immediate postictal period. Later in the postictal period, hypoperfusion alone is seen. Studies of focal seizures in animals have shown hyperperfusion and hypermetabolism at the site of the focus often with widespread depression of both parameters in the ipsilateral neocortex. Limited studies of coupling between blood flow and metabolism in humans have suggested that flow during seizures is adequate for metabolic demand, although some animal studies have suggested localised areas of uncoupling. The results of modern in vivo imaging of ictal and postictal changes in blood flow and metabolism have correlated well with Penfield's observations, and these changes are now being used to help localise epileptic foci, allowing wider use of the surgical treatment he pioneered.

Blood flow velocity in the basal intracranial arteries can be reliably recorded using transcranial Doppler (TCD) ultrasonography. The utility of Doppler ultrasound in detecting stenosis of arteries has therefore been extended to include the intracranial basal arteries. This has been useful in detecting intracranial stenosis from a variety of causes including atherosclerosis and vasospasm induced by subarachnoid hemorrhage. Changes in cerebral hemodynamics during significantly increased intracranial pressure have also been detected, and have been useful in warning of compromise of the cerebral circulation in head injury. The assessment of the final hemodynamic effects of occlusive disease on the middle cerebral artery can be studied using the CO2 reactivity test. This offers additional diagnostic information in these patients. The direct detection of intracranial microemboli using TCD is also now possible and this has implications in the management of patients with stroke and transient ischemic attacks. Continuous monitoring of the middle cerebral artery velocity has been useful in indicating relative blood flow changes through this artery under certain specific circumstances. By providing continuous information on relative blood flow changes, the dynamics of the cerebral circulation can be studied in more detail. This has allowed the assessment of cerebral autoregulation, as well as blood flow changes, due to changes in cortical activity induced by visual stimulation. Further research on the dynamics of the human cerebral circulation will be possible using this technology.