Agents In Acute Ischemic Stroke Research Articles

Neuroprotective agents in acute ischemic stroke.

Recent scientific data suggest that there is a "window of opportunity" between the onset of brain ischemia and irreversible neuronal death. Although neurons can withstand complete absence of blood flow for only minutes, collateral circulation typically surrounds the "core" of the stroke. In these brain regions known as the ischemic penumbra, brain tissue can survive for several hours following stroke onset. Recent studies suggest that neuroprotective agents would give these viable neurons the chance for recovery. This article reviews the mechanisms of ischemic neuronal injury, mechanism of action of neuroprotective agents, current neuroprotective clinical trials, and guidelines for patient care management.

NF- κB is activated and ICAM-1 gene expression is upregulated during reoxygenation of human brain endothelial cells

Reperfusion injury is mediated, in part, by the upregulated expression of genes in microvascular endothelial cells that encode for inflammatory cytokines and adhesion molecules. The redox-regulated transcription factor, nuclear factor kappa B (NF- κB), may play a major role in the induced expression of these genes. In this study we use cultured human brain microvascular endothelial cells (HBMEC) to investigate whether reoxygenation of hypoxic HBMEC results in the activation of NF- κB and the upregulation of the adhesion molecule, ICAM-1. When HBMEC were subjected to hypoxia followed by reoxygenation but not hypoxia alone, an NF- κB complex composed of p65 and p50 Rel proteins was rapidly activated within 15–30 min. Four hours later, expression of the ICAM-1 gene was significantly upregulated. The antioxidant pyrrolidine dithiocarbamate and the proteasome inhibitor, n-Tosyl-Phe-chloromethyl ketone, blocked both the activation of NF- κB and the upregulation of the ICAM-1 gene. These results indicate that NF- κB is activated in HBMEC by reoxygenation and may play a significant role in the upregulation of the ICAM-1 gene. Agents which inhibit NF- κB activation may be potential therapeutic agents in acute ischemic stroke.

Anticoagulant and defibrinogenating agents in acute ischemic stroke and cerebral venous thrombosis.

Anticoagulants have been used in patients with acute ischemic stroke to limit infarct volume and to prevent reinfarction and thrombotic complications like deep venous thrombosis. Three important randomized trials of anticoagulants have been reported recently. One trial showed that nadroparin reduced the percentage of patients with poor outcome at 6 months. One unblinded trial of subcutaneous unfractionated heparin showed that heparin reduced the rate of early recurrent stroke, but this benefit was offset by an increase in hemorrhages. A trial of the heparinoid ORG 10172 showed no efficacy overall at 3 months, although there was an increase in patients with very favorable outcomes at 7 days. The defibrinogenating agent ancrod has shown promise in a series of small clinical trials, but efficacy has not been established. There are no reliable data on the use of antithrombotic agents to prevent reocclusion after thrombolytic therapy. Anticoagulants are generally recommended in patients with cerebral venous thrombosis, but the recommendation is supported by only one small and methodologically limited trial.

Safety and Efficacy of Fibrinolytic Agents in Acute Ischemic Stroke

The modern concepts of recanalization strategies by using fibrinolytic agents are discussed. Therapeutic thrombolysis in cerebral ischemia has entailed the use of streptokinase, urokinase, and recombinant tissue plasminogen activator by either systemic or intra-arterial infusion. At the present time, experience suggests that early recanalization is followed by neurological improvement, and use of thrombolytic agents does not increase the incidence of hemorrhagic transformation. In addition, studies of repeated intravenous administration of low-dose thrombolytic agents, another mode of thrombolytic agent usage, which have been conducted uniquely in Japan, are critically reviewed, and the role for treating ischemic stroke is discussed.

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)