Mechanisms Of Cerebral Ischemia Research Articles

Prognostic impact of microembolic signals in arterial sources of embolism

Sir I read with interest the review by Ritter et al. [3] regarding the prevalence and prognostic impact of microembolic signals (MES) in arterial sources of cerebral embolism. I wish to comment on some important issues related to this review. Emboli originating from an atherosclerotic stenotic plaque are considered to play an important etiological role in subsequent cerebral ischemic events [2], and the detection of MES may help in clinical decision-making, especially in patients previously considered to have asymptomatic arterial stenoses. However, this approach is still not widely accepted and appears to be looking at ‘only one side of the picture.’ Cerebral ischemic events secondary to hemodynamic disturbances (hypoperfusion) in patients with significant stenotic lesions constitute an important clinical group, and these patients can be easily evaluated with transcranial Doppler and assessment of cerebral autoregulation (CA). CA is the inherent ability of the cerebral blood vessels to maintain the blood flow over a wide range of systemic blood pressure and various provocative stimuli [6] and can be assessed by testing the vasomotor reactivity (VMR). Flow velocities obtained in real-time by TCD can reflect cerebral blood flow volume (CBFV), and the velocity changes can be proportionate to the changes in CBFV if certain parameters are known and remain constant (e.g., angle of insonation, perfusion territory, and arterial diameter) and the effect of only one stimulus is observed [5]. Evaluation of VMR to various ‘challenges’ and maneuvers may help in the prognostic assessment of patients with significant stenosis in the cervico-cranial cerebral arteries. Silverstrini et al. [4] demonstrated a significantly higher risk of subsequent cerebral ischemic events in patients with asymptomatic carotid stenosis and having impaired VMR, assessed by breath-holding index. VMR can be easily assessed by monitoring the blood flow velocities (by TCD) during voluntary breath-holding in any intracranial artery distal to the stenosis. Elevation of carbon-dioxide levels in blood during breath-holding is a strong vasodilatory stimulus and results in significant augmentation of flow velocities in the intracranial arteries. However, the arteries distal to the segment with significant stenosis tend to maintain maximal vasodilation and may not dilate further in response to hypercapnia, reflected by a blunted response in the blood flow velocities. The response may be further affected, in some cases, due to ‘intracranial steal phenomenon’ known as ‘reversed Robin Hood syndrome’ [1]. I propose that, in addition to the MES monitoring, patients with hemodynamically significant stenosis in the cervical or intracranial cerebral arteries should be evaluated for VMR by TCD. Assessment of VMR in the arterial segments distal to the atherosclerotic segment would reveal, at least to some extent, the ‘other side of the picture’ and help in better understanding of cerebral hemodynamics and the pathogenic mechanisms of cerebral ischemia in these patients. Well-designed prospective studies would, however, be needed to test the feasibility and efficacy of this approach in clinical decision-making.

Neuroprotection by PGE2 receptor EP1 inhibition involves the PTEN/AKT pathway

The prostanoid synthesizing enzyme cyclooxygenase-2 (COX-2) is involved in the mechanisms of cerebral ischemia, an effect mediated by prostaglandin E2 through activation of EP1 receptors. Thus, inhibition of EP1 receptors is neuroprotective in models of ischemic stroke, but the molecular mechanisms of the effect have not been fully elucidated. We used oxygen glucose deprivation (OGD) in hippocampal slices as an injury model to investigate whether the neuroprotection afforded by EP1 receptor inhibition involves the PI3K/AKT survival pathway. EP1 receptor inhibition with SC51089 or SC51322 reduced the hippocampal damage produced by ODG by 28 ± 2% and 32 ± 3%, respectively ( p < 0.05). OGD induced a transient reduction of AKT activity that was partly counteracted by SC51089. LY294002 blocked the increase in phospho-AKT evoked by SC51089 and abolished the associated protective effect. The AKT activation induced by SC51089 was associated with phosphorylation of PTEN, the phosphatase that negatively regulates AKT. Furthermore, SC51089 attenuated the mitochondrial translocation of the proapoptotic protein BAD. These data indicate that EP1 receptor inhibition improves the survival of hippocampal slices by preventing the attenuation in AKT activity induced by OGD, and by reducing the mitochondrial translocation of BAD. The findings provide evidence for a link between EP1 receptors and the PI3K/AKT survival pathway and shed light on the molecular mechanisms of the prosurvival effect of EP1 receptor inhibition.

Transcriptional regulation of neurogenesis: potential mechanisms in cerebral ischemia

Recent data provides evidence that new neurons are born in cerebral ischemia. Although ultimate evidence for their functional importance is lacking, correlational data suggest that they contribute to recovery. Therefore, the underlying mechanisms of neurogenesis are interesting as a basis for pharmacological enhancement of the phenomenon. Neurogenesis is a multistep process that includes proliferation of precursor cells, migration of the newborn cells to the site of lesion, differentiation, integration into neuronal circuits, and survival. All these steps rely on gene transcription. However, only preliminary data about the specific transcriptional control of neurogenesis in cerebral ischemia have been obtained so far. To promote this investigation, we review currently available information on six pathways (Notch, Wnt/beta-catenin, NF-kappaB, signal transducers and activators of transcription (STA) 3, HIF-1, and cyclic AMP response element-binding protein [CREB]) that have been shown to regulate transcription in neurogenesis and that have been implicated in cerebral ischemia. With the exception of CREB, direct involvement in postischemic neurogenesis is quite conjectural and much more must be learned to draw practical conclusions.

Advance in studies of N-methyl-D-aspartate receptor's role and its mechanisms in cerebral ischemia

脑缺血时,N-甲基-D-天门冬氨酸受体(NMDA-R),尤其是NR2B通过酪氨酸或丝/苏氨酸磷酸化作用其结构和功能发生改变,激活下游细胞信号传导通路,诱导神经元兴奋毒性、细胞凋亡.其受体和非受体酪氨酸激酶途径受金属离子、细胞因子、氧化应激、原癌基因等的调节.NMDA-R拮抗剂单独用药时可产生封顶效应,而联合用药可产生更强的神经元保护作用。

Therapeutic hypothermia: neuroprotective mechanisms

Hypothermia has long been known to be a potent putative neuroprotectant. Experimental evidence and clinical experience show that hypothermia protects the brain from cerebral injury. Recent insights into the mechanisms of cerebral ischemia and reperfusion suggest reasons why hypothermia may be an ideal modality for stroke therapy. Hypothermia protects brain tissue in multiple ways. It retards energy depletion, reduces intracellular acidosis, lessens the ischemia related accumulation of excitotoxic neurotransmitters, and attenuates the influx of intracellular calcium. Additionally, hypothermia suppresses the generation of oxygen free radicals involved in secondary damage associated with reperfusion. It also suppresses the mechanisms related to blood-brain barrier degeneration and postischemic remodeling. The clinical application of therapeutic hypothermia and its limitations will be summarized in this paper. Therapeutic hypothermia is likely to undergo phase III clinical trials in various clinical settings. Novel technologies are being developed to optimize the safety and efficacy of this promising approach.

Postinjury Administration of Pituitary Adenylate Cyclase Activating Polypeptide (PACAP) Attenuates Traumatically Induced Axonal Injury in Rats

Pituitary adenylate cyclase activating polypeptide (PACAP) has several different actions in the nervous system. Numerous studies have shown its neuroprotective effects both in vitro and in vivo. Previously, it has been demonstrated that PACAP reduces brain damage in rat models of global and focal cerebral ischemia. Based on the protective effects of PACAP in cerebral ischemia and the presence of common pathogenic mechanisms in cerebral ischemia and traumatic brain injury (TBI), the aim of the present study was to investigate the possible protective effect of PACAP administered 30 min or 1 h postinjury in a rat model of diffuse axonal injury. Adult Wistar male rats were subjected to impact acceleration, and PACAP was administered intracerebroventricularly 30 min (n = 4), and 1 h after the injury (n = 5). Control animals received the same volume of vehicle at both time-points (n = 5). Two hours after the injury, brains were processed for immunohistochemical localization of damaged axonal profiles displaying either beta-amyloid precursor protein (beta-APP) or RMO-14 immunoreactivity, both considered markers of specific features of traumatic axonal injury. Our results show that treatment with PACAP (100 microg) 30 min or 1 h after the induction of TBI resulted in a significant reduction of the density of beta-APP-immunopositive axon profiles in the corticospinal tract (CSpT). There was no significant difference between the density of beta-APP-immunopositive axons in the medial longitudinal fascicle (MLF). PACAP treatment did not result in significantly different number of RMO-14-immunopositive axonal profiles in either brain areas 2 hours post-injury compared to normal animals. While the results of this study highlighted the complexity of the pathogenesis and manifestation of diffuse axonal injury, they also indicate that PACAP should be considered a potential therapeutic agent in TBI.

Brain Metabolism and Mechanisms of Cerebral Ischemia

Brain Metabolism and Mechanisms of Cerebral Ischemia

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Incidence and mechanisms of cerebral ischemia in early clinical head injury.

Antemortem demonstration of ischemia has proved elusive in head injury because regional CBF reductions may represent hypoperfusion appropriately coupled to hypometabolism. Fifteen patients underwent positron emission tomography within 24 hours of head injury to map cerebral blood flow (CBF), cerebral oxygen metabolism (CMRO2), and oxygen extraction fraction (OEF). We estimated the volume of ischemic brain (IBV) and used the standard deviation of the OEF distribution to estimate the efficiency of coupling between CBF and CMRO2. The IBV in patients was significantly higher than controls (67 +/- 69 vs. 2 +/- 3 mL; P < 0.01). The coexistence of relative ischemia and hyperemia in some patients implies mismatching of perfusion to oxygen use. Whereas the saturation of jugular bulb blood (SjO2) correlated with the IBV (r = 0.8, P < 0.01), SjO2 values of 50% were only achieved at an IBV of 170 +/- 63 mL (mean +/- 95% CI), which equates to 13 +/- 5% of the brain. Increases in IBV correlated with a poor Glasgow Outcome Score 6 months after injury (rho = -0.6, P < 0.05). These results suggest significant ischemia within the first day after head injury. The ischemic burden represented by this "traumatic penumbra" is poorly detected by bedside clinical monitors and has significant associations with outcome.

Interferon regulatory factor-1 immunoreactivity in neurons and inflammatory cells following ischemic stroke in rodents and humans

Interferon regulatory factor-1 (IRF-1), a transcription factor that controls the expression of genes related to inflammation and injury, may be involved in the mechanisms of cerebral ischemia. In this study, we used immunohistochemistry to determine whether IRF-1 protein is up-regulated after cerebral ischemia, and to define the identity of the cells that express IRF-1 in the postischemic brain. In mice, IRF-1 immunoreactivity was present in intravascular neutrophils 24 h after middle cerebral artery occlusion. At 96 h, immunoreactivity was observed in neutrophils infiltrating the ischemic tissue and in neurons at the outer border of the ischemic territory. IRF-1 immunoreactivity was also found in neurons and inflammatory cells in the brain of patients who died 1-2 days after ischemic stroke. The neuronal expression of IRF-1, in conjunction with the finding that IRF-1 deletion is beneficial to the post-ischemic brain, suggests that expression of IRF-1-dependent genes in neurons plays a role in ischemic neuronal death.

Early stroke: a dynamic process.

In the acutely infarcted brain, cytokines are released into cerebrospinal fluid and blood. Interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α, among others, may play a role in the acute increases in plasma adrenocorticotropic hormone, cortisol, epinephrine, norepinephrine, and vasopressin.1–6 Increases in cytokines and hormones may in turn induce changes in other variables. When recorded on admission in acute stroke patients, many variables have been found to be associated with poor outcome in acute stroke. Body temperature7 is one such variable, blood glucose another,8–18 and C-reactive protein (CRP)19–22 and white blood cell count (WBC)20,23 serum cortisol and ferritin24 are further examples. Elevated plasma and cerebrospinal fluid levels of glutamate, glycine,25 ferritin,26 and IL-627 were also associated with deteriorating stroke. It seems plausible that these variables generally are unaffected at stroke onset and then increase in the early hours after onset, depending on the severity of the stroke. We found this to be the case with temperature,28 which in a large series of patients was normal when measured within 2 hours of stroke onset, but which rose at 4 to 6 hours after stroke onset in patients with severe neurological deficits. At 8 to 10 hours after stroke onset, elevated temperature was associated with poor outcome. This association arose several hours after onset of severe stroke. Thus, the initial severity of the stroke …

Bright and dark sides of nitric oxide in ischemic brain injury

There is increasing evidence that nitric oxide (NO), a free radical that can act both as a signaling molecule and a neurotoxin, is involved in the mechanisms of cerebral ischemia. Although early investigations yielded conflicting results, the introduction of more-selective pharmacological tools and the use of molecular approaches for deletion of genes encoding for NO synthase have provided a better understanding of the role of NO in the mechanisms of ischemic brain damage. The evidence reviewed in this article suggests that NO is protective or destructive depending on the stage of evolution of the ischemic process and on the cellular source of NO. Defining the role of NO in cerebral ischemia provides the rationale for new neuroprotective strategies based on modulation of NO production in the post-ischemic brain.

Inhibitory Mechanisms in Cerebral Ischemia: a Brief Review

SHUAIB, A. AND M.M. BREKER-KLASSEN. Inhibitory mechanisms in cerebral ischemia: a brief review. NEUROSCI BIOBEHAV REV 21 [2] 219–226, 1997.—Cessation of cerebral blood flow results in severe damage to neurons and other brain structures. This is secondary to a combination of energy loss, excessive excitation promoting intracellular Ca 2+ buildup, relative lack of inhibitory responses, generation of oxygen free radicals, especially during the reperfusion period and several other destructive cascades. Therapies aimed at decreasing the ill effects of glutamate are either not effective or have serious side-effects. Ca 2+ entry blockers are generally not effective in cerebral ischemia, and data with protective effects of oxygen free radical scavengers in the post-ischemic period have shown conflicting results. There is recent interest with the use of agents that increase cerebral inhibitory responses after an ischemic insult. Such agents are effective when used before, during or up to 4 h after the ischemic insult. Many such medications have few side-effects and are in clinical use for other indications. This review will summarize inhibitory mechanisms that may be important in cerebral ischemia, and provide experimental evidence for their potential efficacy. © 1997 Elsevier Science Ltd. All rights reserved.

Cerebral ischemia: pharmacological bases of drug therapy.

The cascade of reactions caused by ischemia in brain tissue is complex and not completely understood, but intensive investigation has led to convincing hypotheses. A disturbed calcium homeostasis and oxygen radicals seem to play a major role in postischemic neuronal damage. In accordance to these hypotheses drugs with different mechanisms of action have been developed. The aim of this paper is to give an overview over pathobiochemical mechanisms in cerebral ischemia and possibilities of pharmacological intervention.

Induction of cerebral thrombosis with phenytoin in rats.

This study was conducted to explore whether intra-arterial infusion of phenytoin causes cerebral ischemia and to examine the mechanism of cerebral ischemia induced by phenytoin. Ten rats were infused with phenytoin (150 microL, 3.75 mg) retrogradely from the left external carotid artery, followed by perfusion of carbon black transcardially. The removed brain was photographed from above, and the nonperfused area was compared with control rats (n = 10) with the use of an image analyzer. Eight animals with or without phenytoin treatment were perfusion-fixed for transmission electron microscopic analyses of cerebral vasculature. To determine the effect of tissue plasminogen activator (TPA) on phenytoin-infused rat cerebrum, 20 rats were treated with or without TPA (120,000 IU) 5 minutes after the phenytoin infusion (n = 10 each). All rats suffered from respiratory distress 25 to 40 minutes after the injection and received carbon black transcardially. The nonperfused area was seen in the territory of the left internal carotid artery. Thrombi were observed from arterioles to capillaries. Under electron microscopy, endothelial cells were partially exfoliated, and the vascular lumen was obstructed by thrombi predominantly consisting of platelets. Eight rats with TPA survived more than 60 minutes, whereas only 2 rats survived without the treatment (P < .005). Nonperfused areas were 7 +/- 5% and 50 +/- 11% of cerebral surface area in rats with and without TPA treatment, respectively (P < .001). Intra-arterial infusion of phenytoin results in a nonperfused area in rat cerebrum primarily due to thrombosis of arterioles and capillaries.

Endothelin, cerebral ischaemia and infarction.

Endothelin-1 (ET-1) is a 21 aminoacid peptide with potent vasoconstrictor properties. It is synthesised and released by endothelial cells in both the peripheral and cerebral vasculature and is also localised within neurones in discrete brain areas where it may contribute to the central regulation of blood pressure. We have shown that intracisternal ET-1 in conscious rats induces a marked pressor response that is associated with an intense widespread reduction in cerebral blood flow. Subsequent studies with local application of ET-1 to the middle cerebral artery (MCA) revealed a dose dependent reversible vasoconstriction of the artery that resulted in profound reductions in local cerebral blood flow and the development of cerebral infarction. Thus abluminal application of ET-1 to the MCA offers a simple model of reversible focal cerebral ischaemia in the rat that complements the existing models of permanent MCA occlusion. The ET-1 model will help to provide new insights into the mechanisms of cerebral ischaemia and reperfusion injury, and to evaluate the usefulness of novel strategies of neuroprotection.

Diffusion anisotropy of cerebral ischaemia.

Focal cerebral ischemia was produced by occlusion of the middle cerebral artery with a silicone cylinder in Wistar rats. Diffusion-weighted echo-planar images (DW-EPIs) using the motion-probing gradient (MPG) method were acquired at 1-3 hours and 24-48 hours after occlusion. Apparent diffusion coefficients (ADCs) were calculated from these images in ischemic lesions and in normal unoccluded regions. Results were as follows. 1. Ischemic lesions could be detected on the DW-EPIs at 1 hour after occlusion. 2. The ADC of water in the brain tissue was smaller than that of free water as a result of restricted diffusion. 3. Anisotropic diffusion that probably can be attributed to the myelin sheath was observed in the normal deep white matter. 4. In the ischemic lesions, the ADC decreased rapidly within 1-3 hours after occlusion and then slightly further declined after 24-48 hours. In the ischemic deep white matter, diffusion anisotropy disappeared at 24-48 hours after occlusion. Diffusion-weighted imaging may have applications in the examination of pathophysiological mechanisms in cerebral ischemia by means of evaluation of ADC and diffusion anisotropy.