The complexity of neurobiological processes in acute ischemic stroke

Abstract

There is an urgent need for improved diagnostics and therapeutics for acute ischemic stroke. This is the focus of numerous research projects involving in vitro studies, animal models and clinical trials, all of which are based on current knowledge of disease mechanisms underlying acute focal cerebral ischemia. Insight in the chain of events occurring during acute ischemic injury is essential for understanding current and future diagnostic and therapeutic approaches.

In this review, we summarize the actual knowledge on the pathophysiology of acute ischemic stroke. We focus on the ischemic cascade, which is a complex series of neurochemical processes that are unleashed by transient or permanent focal cerebral ischemia and involves cellular bioenergetic failure, excitotoxicity, oxidative stress, blood–brain barrier dysfunction, microvascular injury, hemostatic activation, post-ischemic inflammation and finally cell death of neurons, glial and endothelial cells.

Introduction

Ischemic stroke is the second most common cause of death and the leading cause of acquired disability in adults [1], [2]. In western countries, stroke causes 10–12% of all deaths [3]. Only in recent years have advances allowed for relevant improvement in the outcome of this devastating disease. A new era in acute stroke care began in 1995, when it was shown that early intravenous administration of recombinant tissue plasminogen activator (rt-PA) improved outcome in a carefully selected patient group with acute ischemic stroke [4]. More than 10 years later, rt-PA is the only approved therapy for ischemic stroke [5] and has proven to be safe and effective in routine clinical practise [6]. Nevertheless, utilization rates of rt-PA remain low [7], mainly due to the short window of opportunity for treatment and fear of hemorrhagic complications. Ongoing developments in acute stroke therapy mainly focus on timely recanalisation either by new thrombolytics or by mechanical thrombus removal and on neuroprotection, which aims to reduce the intrinsic vulnerability of the penumbra [2], [8].

Advances in diagnosing acute ischemic stroke would also warmly be welcomed. Clinical diagnosis of stroke has only limited value [9], [10] and advanced neuroimaging techniques often are needed, not only to confirm the clinical suspicion of stroke but also for reliable estimation of cerebral tissue that can be rescued by effective therapy [11], [12], [13], [14], [15].

Obviously, there is an urgent need for improved diagnostics and therapeutics for acute stroke. This is the focus of numerous research projects involving in vitro studies, animal models and clinical trials, all of which are based on the current knowledge of the disease mechanisms underlying acute focal cerebral ischemia. The continuous flow of information from fundamental and clinical research can be overwhelming, but insight in the chain of events occurring during acute ischemic injury is essential for understanding current and future therapeutic and diagnostic approaches.