Potential role of neuroprotective agents in the treatment of patients with acute ischemic stroke

Opinion statement Currently, intravenous recombinant tissue plasminogen activator is the only US Food and Drug Administration-approved therapy for acute ischemic stroke. Although efficacious, its usefulness is limited, mainly because of the very limited time window for its administration. Neuroprotective treatments are therapies that block the cellular, biochemical, and metabolic elaboration of injury during or after exposure to ischemia, and have a potential role in ameliorating brain injury in patients with acute ischemic stroke. More than 50 neuroprotective agents have reached randomized human clinical trials in focal ischemic stroke, but none have been unequivocally proven efficacious, despite successful preceding animal studies. The failed neuroprotective trials of the past have greatly increased understanding of the fundamental biology of ischemic brain injury and have laid a strong foundation for future advance. Moreover, the recent favorable results of human clinical trials of hypothermia in human cardiac arrest and global brain ischemia have validated the general concept of neuroprotection for ischemic brain injury. Recent innovations in strategies of preclinical drug development and clinical trial design that rectify past defects hold great promise for neuroprotective investigation, including novel approaches to accelerating time to initiation of experimental treatment, use of outcome measures sensitive to treatment effects, and trial testing of combination therapies rather than single agents alone. Although no neuroprotective agent is of proven benefit for focal ischemic stroke, several currently available interventions have shown promising results in preliminary trials and may be considered for cautious, off-label use in acute stroke, including hypothermia, magnesium sulfate, citicoline, albumin, and erythropoietin. Overall, the prospects for safe and effective neuroprotective therapies to improve stroke outcome remain promising.     

缺血性卒中的神经保护药:现状与挑战

作为缺血性卒中的一种治疗策略,神经保护药被用于拮抗脑缺血时的一系列有害分子生物学事件.文章综述了神经保护药治疗急性缺血性卒中的现状,以及从临床前研究证据向临床试验转化所面临的挑战.应将血管内皮细胞-胶质细胞-神经元作为一个整体进行研究.     

急性缺血性脑血管病药物性脑保护的研究进展

兴奋毒性、钙超载、自由基反应、梗死周围除极、炎症和凋亡是造成缺血性脑损伤的中心环节.脑保护是治疗急性缺血性脑血管病的主要策略之一.处于临床研究阶段的脑保护剂有钙通道拮抗剂、兴奋性氨基酸受体拮抗剂、γ-氨基丁酸受体激动剂、抗氧化剂和自由基清除剂等等.     

Fibrinolytic therapy in acute stroke

Acute ischemic stroke is a major cause of morbidity and mortality in Europe, North America, and Asia. Its treatment has completely changed over the past decade with different interventional approaches, such as intravenous trials, intra-arterial trials, combined intravenous/intra-arterial trials, and newer devices to mechanically remove the clot from intracranial arteries. Intravenous thrombolysis with tissue plaminogen activator (tPA) within 4.5 hours of symptoms onset significantly improved clinical outcomes in patients with acute ischemic stroke. Pharmacological intra-arterial thrombolysis has been shown effective until 6 hours after middle cerebral artery occlusion and offers a higher rate of recanalization compared with intravenous thrombolysis, whereas combined intravenous/ intra-arterial thrombolysis seems to be as safe as isolated intravenous thrombolysis. The more recent advances in reperfusion therapies have been done in mechanical embolus disruption or removal. Merci Retriever and Penumbra System have been approved for clot removal in brain arteries, but not as a therapeutic modality for acute ischemic stroke since it is no clear whether mechanical thrombectomy improves clinical outcome in acute stroke. However, mechanical devices are being used in clinical practice for patients who are ineligible for tPA or who have failed to respond to intravenous tPA. We summarize the results of the major thrombolytic trials and the latest neurointerventional approaches to ischemic stroke.     

Challenges in Acute Ischemic Stroke Clinical Trials

There have been only 3 positive Phase III randomized clinical trials in acute ischemic stroke, all reperfusion therapies (NINDS; PROACT II; ECASS III). The only approved acute stroke therapy is <3-hour IV tPA. Although numerous compounds have shown benefit in animal models of brain infarction, there has never been a positive Phase III randomized clinical trial of a neuroprotectant in acute ischemic stroke. There are many challenges to acute stroke clinical trials but chief among these are the very short therapeutic window (??time is brain??) and the issue of stroke heterogeneity. Stroke is a syndrome and only a very small percentage of all stroke patients present to hospitals in time to consider reperfusion therapy. Many drugs have been rushed to trial prematurely based on inadequate preclinical testing. Many trials have been seriously underpowered due to overly optimistic treatment expectations and the risk of brain hemorrhage has precluded aggressive multimodal treatment strategies. Rather than simply relying on a clock, new imaging methods are being developed to identify patients with ??tissue at risk?? and ??salvageable brain?? regardless of time of stroke onset. The 7 STAIR conferences have been convened to address these and other challenges to acute ischemic stroke trial design and completion.     

Reperfusion Therapies for Acute Ischemic Stroke: An Update

Acute ischemic stroke is a major cause of morbidity and mortality in developed countries. Intravenous thrombolysis with tissue plasminogen activator (tPA) within 4.5 hours of symptoms onset significantly improves clinical outcomes in patients with acute ischemic stroke. This narrow window for treatment leads to a small proportion of eligible patients to be treated. Intravenous or intra-arterial trials, combined intravenous/intra-arterial trials, and newer devices to mechanically remove the clot from intracranial arteries have been investigated or are currently being explored to increase patient eligibility and to improve arterial recanalization and clinical outcome. New retrievable stent-based devices offer higher revascularization rates with shorter time to recanalization and are now generally preferred to first generation thrombectomy devices such as Merci Retriever or Penumbra System. These devices have been shown to be effective for opening up occluded vessels in the brain but its efficacy for improving outcomes in patients with acute stroke has not yet been demonstrated in a randomized clinical trial. We summarize the results of the major systemic thrombolytic trials and the latest trials employing different endovascular approaches to ischemic stroke.     

Transient ischemic attack: risk stratification and treatment

A major challenge facing the physician evaluating patients with transient ischemic attack is determining which patients are at highest short-term risk of stroke. A number of stratification schemes have been recently developed incorporating easily obtainable clinical information about the individual patient. Further, emerging data suggest a role for brain and vascular imaging in risk stratification. Many aspects of acute management of transient ischemic attack, such as which patients should be hospitalized and choice of acute antithrombotic therapy, remain controversial because of a lack of evidence from controlled trials. For longer-term prevention, there is much firmer evidence from multiple large randomized trials, and these data are reviewed in this article.     

Therapeutic hypothermia: past, present, and future

Cardiac arrest causes devastating neurologic morbidity and mortality. The preservation of the brain function is the final goal of resuscitation. Therapeutic hypothermia (TH) has been considered as an effective method for reducing ischemic injury of the brain. The therapeutic use of hypothermia has been utilized for millennia, and over the last 50 years has been routinely employed in the operating room. TH gained recognition in the past 6 years as a neuroprotective agent in victims of cardiac arrest after two large, randomized, prospective clinical trials demonstrated its benefits in the postresuscitation setting. Extensive research has been done at the cellular and molecular levels and in animal models. There are a number of proposed applications of TH, including traumatic brain injury, acute encephalitis, stroke, neonatal hypoxemia, and near-drowning, among others. Several devices are being designed with the purpose of decreasing temperature at a fast and steady rate, and trying to avoid potential complications. This article reviews the historical development of TH, and its current indications, methods of induction, and potential future.     

Thrombolytic therapy in cerebrovascular disorders.

The knowledge obtained from the ongoing investigational trials of tPA for acute ischemic stroke will not only help establish the appropriate dose range and complication rates but will also further develop the clearly mandatory rapid, aggressive team approach needed to truly treat acute ischemic strokes successfully. Experimental cerebral ischemia data have pointed to the need to treat acute clinical stroke within only a few hours or less to effectively reduce stroke morbidity and mortality. Specifically, with reversible MCA occlusion models of focal cerebral ischemia (dogs and cats), the animals uniformly survive without neurological deficit if the occlusion is for less than 2 to 3 hours. Similarly in primates, MCA occlusion for 3 hours or less will lead to clinical improvement and a decrease in infarct size, with complete recovery generally associated with less than 2 hours of MCA occlusion. Therefore, it appears unlikely that ischemic brain can be salvaged if vascular occlusion persists longer than 4 to 6 hours (similar to the pathophysiology of myocardial ischemia). Further, at least one third of ischemic stroke patients reperfuse spontaneously (and obviously too late) within 48 hours of stroke onset. Several factors believed to be related to successful outcome after thrombolytic therapy are summarized in Table 16. A schematic approach to determining the response to thrombolytic agents in acute ischemic stroke is outlined in Table 17. Zivin succinctly reviews thrombolysis for stroke, both experimental and clinical, and summarizes some of the difficulties of the early clinical stroke trials with thrombolytic agents and speculates about future prospects. He believes tPA may prove valuable in the treatment of some forms of thromboembolic stroke. Its usefulness may depend in part on how quickly the drug can be initiated and the risk of side effects; factors that will require further study. The currently used doses of tPA may be too low to lyse large cerebral arterial clots and, therefore, if current trials do not show a positive treatment response, further trials with higher doses may be indicated. The implications of a potentially effective treatment for truly acute stroke are enormous: stroke will need to be considered by all (lay public through to caregivers) as a true medical emergency, analogous to MI and trauma.(ABSTRACT TRUNCATED AT 400 WORDS)     

调节性T淋巴细胞与缺血性卒中

卒中是一种高致死率和高致残率的脑血管病类型,其中缺血性卒中约占80％.目前认为,炎症机制在缺血性卒中的病理生理学进展中发挥重要作用.外周T淋巴细胞在脑缺血后24 h内浸润受损区域,参与脑组织炎症过程的进展.作为T淋巴细胞的一个亚群,调节性T细胞主要定位于缺血半暗带,但目前对其在缺血性脑损伤中的作用仍存在着争议.研究调节性T细胞在脑缺血中的作用机制,有助于进一步认识缺血性卒中的发病机制和发现新的治疗靶点.     

What animal models have taught us about the treatment of acute stroke and brain protection

Stroke research has progressed in leaps and bounds in the past decades. A driving force is the increasing availability of new research tools in this field (eg, animal stroke models). Animal stroke models have been extensively applied to advance our understanding of the mechanisms of ischemic brain injury and to develop novel therapeutic strategies for reducing brain damage after a stroke. Animal stroke models have been useful in characterizing the molecular cascades of injury processes. These “injury pathways” are also the targets of therapeutic interventions. The major achievements made in the past 2 decades applying animal stroke models include 1) the identification of the mediator role of excitotoxin and oxygen free radicals in ischemic brain injury; 2) the confirmation of apoptosis as a major mechanism of ischemic cell death; 3) the characterization of postischemic gene expression; 4) the delineation of postischemic inflammatory reaction; 5) the application of transgenic mice to confirm the roles of purported mediators in ischemic brain injury; 6) development of novel magnetic resonance imaging sequences for early noninvasive detection of ischemic brain lesions; and, 7) the development of novel therapeutic strategies based on preclinical findings derived from animal stroke models.     

Bone marrow-derived mesenchymal stromal cells for the repair of central nervous system injury

Transplantation of bone marrow-derived mesenchymal stromal cells (MSCs) into the injured brain or spinal cord may provide therapeutic benefit. Several models of central nervous system (CNS) injury have been examined, including that of ischemic stroke, traumatic brain injury and traumatic spinal cord injury in rodent, primate and, more recently, human trials. Although it has been suggested that differentiation of MSCs into cells of neural lineage may occur both in vitro and in vivo, this is unlikely to be a major factor in functional recovery after brain or spinal cord injury. Other mechanisms of recovery that may play a role include neuroprotection, creation of a favorable environment for regeneration, expression of growth factors or cytokines, vascular effects or remyelination. These mechanisms are not mutually exclusive, and it is likely that more than one contribute to functional recovery. In light of the uncertainty surrounding the fate and mechanism of action of MSCs transplanted into the CNS, further preclinical studies with appropriate animal models are urgently needed to better inform the design of new clinical trials.     

Timing of estrogen therapy after ovariectomy dictates the efficacy of its neuroprotective and antiinflammatory actions

Recent studies describing the seemingly contradictory actions of estrogens in ischemic stroke injury have led us to reevaluate the circumstances under which estrogen therapy (ET) provides benefits against cerebral stroke and decipher its mechanisms of action. One prominent feature that follows stroke injury is massive central and peripheral inflammatory responses. Evidence now suggests that postischemic inflammatory responses strongly contribute to the extent of brain injury, and 17beta-estradiol (E(2)) may protect the ischemic brain by exerting antiinflammatory actions. In an attempt to explain recently reported dichotomous effects of E(2) in stroke injury, we tested the hypothesis that an extended period of hypoestrogenicity both prevents E(2) from protecting the brain against ischemia and simultaneously suppresses its antiinflammatory actions. We report that E(2) exerts profound neuroprotective action when administered immediately upon ovariectomy, but not when administered after 10 weeks of hypoestrogenicity. Consistently, E(2) treatment given immediately at the time of ovariectomy attenuated central and peripheral production of proinflammatory cytokines after ischemic stroke. In contrast, E(2) did not suppress production of proinflammatory molecules when it was administered after 10 weeks postovariectomy. These results demonstrate that a prolonged period of hypoestrogenicity disrupts both neuroprotective and antiinflammatory actions of E(2). Our findings may help to explain the results of the Women's Health initiative that reported no beneficial effect of ET against stroke because the majority of the subjects initiated ET after an extended period of hypoestrogenicity.     

Antithrombotic and thrombolytic therapy for ischemic stroke

Antithrombotic therapy is the mainstay of treatment for stroke prevention. Multiple antiplatelet agents are now proven options for patients at risk for stroke, whereas warfarin anticoagulation remains the preferred therapy for most patients with atrial fibrillation. Recent clinical trials have clarified the role of anticoagulation in acute stroke and in secondary prevention of noncardioembolic stroke. Intravenous tissue plasminogen activator is the only approved therapy for patients with acute ischemic stroke. Intra-arterial thrombolysis is emerging as a promising therapy in selected patients.     

外周血白细胞与缺血性卒中

动脉粥样硬化是缺血性卒中的病理学基础,外周血白细胞参与动脉粥样硬化的发生和进展过程,并造成血管内皮损伤。急性缺血性卒中后外周免疫细胞发生一系列变化,引起炎性细胞向脑组织浸润。白细胞计数增高与冠状动脉粥样硬化性心脏病的发生和预后密切相关。也有研究显示,外周血白细胞计数增高可能会影响缺血性卒中的发生、神经功能缺损、复发和死亡。文章对外周血白细胞与缺血性卒中的关系进行了综述。     

What's New in Stroke? The Top 10 for 2004/05

During the past decade, stroke has emerged from the dark ages of therapeutic nihilism to the current dawn of treatment activism, fueled by an unprecedented amount of high-quality clinical research. Here, the choices for the "Top 10" studies of 2004/05 influencing the management of patients with stroke and threatened stroke are reviewed. Nine are randomized, clinical trials involving a total of 61,810 participants. Three studies involved intracerebral hemorrhage, an important stroke subtype in which few trials have previously been carried out. Three studies involved acute treatment of stroke, and their results emphasize that "time is brain," and minutes count, in management of acute ischemic and hemorrhagic stroke. The 10th study was a longitudinal cohort analysis of participants with atrial fibrillation pooled from six clinical trials that validated predictive schemes to identify those who benefit most from anticoagulation. The practical management implications of these studies refine and improve care of geriatric patients with cerebrovascular disease.     

钙通道阻滞剂在认知障碍防治中的应用

认知障碍是一个具有重要医学和社会意义的问题,血管危险因素是其重要的病因。大量临床试验和汇总分析表明,钙通道阻滞剂不仅能治疗各种痴呆,还能预防急性缺血性卒中、高血压、蛛网膜下腔出血和脑外伤患者认知障碍的发生。     

钙通道阻滞剂在认知障碍防治中的应用

认知障碍是一个具有重要医学和社会意义的问题，血管危险因素是其重要的病因。大量临床试验和汇总分析表明，钙通道阻滞剂不仅能治疗各种痴呆，还能预防急性缺血性卒中、高血压、蛛网膜下腔出血和脑外伤患者认知障碍的发生。     

Hypoperfusion and its augmentation in patients with brain ischemia

Opinion statement Control of hypertension is a well-established goal of the primary and secondary prevention of stroke. However, management of blood pressure in the setting of acute brain ischemia is complicated by the possible effect of blood pressure changes on cerebral perfusion. In acute stroke, patients may have an ischemic penumbra of brain tissue, which has impaired perfusion but which is not irreversibly damaged. The ischemic penumbra may be salvaged with reperfusion. Lowering of blood pressure in this setting, however, would hasten the progression of the penumbra to infarction. With the exception of patients treated with thrombolytic agents, blood pressure reduction is not recommended in acute ischemic stroke for this reason. Preliminary studies suggest that there may be a role for interventions to elevate blood pressure as a treatment for acute stroke patients. Despite interest in induced hypertension as a treatment of stroke dating back to the 1950s, this practice has not achieved widespread use owing to concerns about potential adverse effects such as intracerebral hemorrhage, cerebral edema, and myocardial ischemia. It is commonly used, however, to treat patients with threatened cerebral ischemia due to vasospasm after subarachnoid hemorrhage. Until future studies clarify the effectiveness of induced hypertension in stroke treatment, maintaining adequate blood pressure and fluid volume is recommended for patients with acute ischemic stroke, particularly if the neurologic deficits are fluctuating or the patient has persistent large-vessel occlusive disease.     

米诺环素对缺血性卒中的神经保护作用

米诺环素为第2代半合成四环素类抗生素,多种动物实验模型和临床试验表明其具有神经保护作用,其机制与抑制凋亡、减轻炎性反应、缩小梗死体积和减轻血管损伤有关.文章对急性缺血性卒中临床前期和早期临床试验中米诺环素的神经保护作用进行了综述.