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Transient or permanent loss of tissue perfusion due to ischaemic stroke can lead to damage to the neurovasculature, and disrupt brain homeostasis, causing long-term motor and cognitive deficits. Despite promising pre-clinical studies, clinically approved neuroprotective therapies are lacking. Most studies have focused on neurons while ignoring the important roles of other cells of the neurovascular unit, such as astrocytes and pericytes. Astrocytes are important for the development and maintenance of the blood–brain barrier, brain homeostasis, structural support, control of cerebral blood flow and secretion of neuroprotective factors. Emerging data suggest that astrocyte activation exerts both beneficial and detrimental effects following ischaemic stroke. Activated astrocytes provide neuroprotection and contribute to neurorestoration, but also secrete inflammatory modulators, leading to aggravation of the ischaemic lesion. Astrocytes are more resistant than other cell types to stroke pathology, and exert a regulative effect in response to ischaemia. These roles of astrocytes following ischaemic stroke remain incompletely understood, though they represent an appealing target for neurovascular protection following stroke. In this review, we summarise the astrocytic contributions to neurovascular damage and repair following ischaemic stroke, and explore mechanisms of neuroprotection that promote revascularisation and neurorestoration, which may be targeted for developing novel therapies for ischaemic stroke.

Autophagy is a highly regulated, catabolic process, through which macromolecules such as damaged organelles and proteins are degraded and recycled to maintain cellular homeostasis. Various studies have shown the role of autophagy activation in the brain cells such as astrocytes, microglia, neurons and capillary endothelial cells upon an ischaemic insult. The underlying mechanism and the role of autophagy in ischaemic stroke, however, are yet to be fully elucidated. Recent studies have suggested that insufficient or excessive autophagy results in nerve damage and cell death whereas mild/moderate autophagy has a neuroprotective effect. It has been proposed that autophagy may be a therapeutic target in stroke treatment; however, there is a lot of debate as to whether induction or diminution of autophagy plays a role in neuronal survival after cerebral ischaemia and indicate that it has a dual role depending on the time of induction of autophagy. This review has summarized the role of autophagy in ischaemic stroke and explored effects of pharmacological autophagy modulators in ischaemic stroke treatment. Further studies are needed for translating the potential therapeutic approach in stroke treatment aiming at characterizing the timing, amount and specificity of the autophagy modulation.

Stroke mostly occurs in elderly people and patient outcomes after stroke are highly influenced by age. A better understanding of the causes of stroke in the elderly might have important practical implications not only for clinical management, but also for preventive strategies and future health-care policies. In this Review, we explore the evidence from both human and animal studies relating to the effect of old age-in terms of susceptibility, patient outcomes and response to treatment-on ischemic stroke. Several aging-related changes in the brain have been identified that are associated with an increase in vulnerability to ischemic stroke in the elderly. Furthermore, risk factor profiles for stroke and mechanisms of ischemic injury differ between young and elderly patients. Elderly patients with ischemic stroke often receive less-effective treatment and have poorer outcomes than younger individuals who develop this condition. Neuroprotective agents for ischemic stroke have been sought for decades but none has proved effective in humans. One contributing factor for this translational failure is that most preclinical studies have used young animals. Future research on ischemic stroke should consider age as a factor that influences stroke prevention and treatment, and should focus on the management of acute stroke in the elderly to reduce the incidence and improve outcomes in this vulnerable group.

This study investigated the effects of 2-(1-chloro-4-hydroxyisoquinoline-3-carboxamido) acetic acid (IOX3), a selective small molecule inhibitor of hypoxia-inducible factor (HIF) prolyl hydroxylases, on mouse brains subject to transient focal cerebral ischaemia. Male, 8- to 12-week-old C57/B6 mice were subjected to 45 min of middle cerebral artery occlusion (MCAO) either immediately or 24 h after receiving IOX3. Mice receiving IOX3 at 20 mg/kg 24 h prior to the MCAO had better neuroscores and smaller blood-brain barrier (BBB) disruption and infarct volumes than mice receiving the vehicle, whereas those having IOX3 at 60 mg/kg showed no significant changes. IOX3 treatment immediately before MCAO was not neuroprotective. IOX3 up-regulated HIF-1α, and increased EPO expression in mouse brains. In an in vitro BBB model (RBE4 cell line), IOX3 up-regulated HIF-1α and delocalized ZO-1. Pre-treating IOX3 on RBE4 cells 24 h before oxygen-glucose deprivation had a protective effect on endothelial barrier preservation with ZO-1 being better localized, while immediate IOX3 treatment did not. Our study suggests that HIF stabilization with IOX3 before cerebral ischaemia is neuroprotective partially because of BBB protection, while immediate application could be detrimental. These results provide information for studies aimed at the therapeutic activation of HIF pathway for neurovascular protection from cerebral ischaemia. We show that IOX3, a selective small molecule (280.66 Da) HIF prolyl hydroxylase inhibitor, could up-regulate HIF-1α and increase erythropoietin expression in mice. We further demonstrate that HIF stabilization with IOX3 before cerebral ischaemia is neuroprotective partially because of blood-brain barrier (BBB) protection, while immediate application is detrimental both in vivo and in vitro. These findings provide new insights into the role of HIF stabilization in ischaemic stroke.

Despite advances in the diagnosis and treatment of acute ischaemic stroke in the past two decades, stroke has remained the third cause of mortality and the single leading cause of disability worldwide. The immediate goal of acute ischaemic stroke therapy is to salvage the ischaemic penumbra through recanalisation of the occluded cerebral blood vessel. This is currently achieved through thrombolytics, which are pharmacological agents that can break up a clot blocking the flow of blood. To date, the only approved thrombolytic for treatment of acute ischaemic stroke is recombinant tissue plasminogen activator (alteplase, rt-PA), however, alteplase is substantially underused because of concerns regarding adverse bleeding risk. This limitation has fuelled the search for other thrombolytic agents, which display greater fibrin dependence and selectivity, but lack detrimental effects within the central nervous system. Development of alternative fibrinolytic agents that might be easier and safer to administer could lead to wider acceptance and use of thrombolytic therapy for stroke. Although other thrombolytic agents (e.g. streptokinase) have failed to show benefit over alteplase, there is still on-going research in search of alternative agents with higher target specificity and better safety profile. The potential thrombolytic agents with trials in progress include desmoteplase, tenecteplase, reteplase, plasmin and microplasmin. This review summarises current therapies with thrombolytics (e.g. alteplase and urokinase), their limitations and side effects, and also discusses ongoing clinical studies with the various potential emerging thrombolytic agents.

The best neuroprotectant for acute ischaemic stroke would always be the rapid return of oxygen and glucose to physiological levels. This is currently provided by thrombolysis which restores blood flow to the ischaemic region. The attempt to confer neuroprotection by targeting the brain parenchyma has shown promise in experimental stroke models, but has unequivocally failed to translate to the clinic. Neuroprotective therapy primarily targets the biochemical cascade that produces cell death following cerebral ischaemia. However, these agents may also alter signal transduction that controls cerebral blood flow, for example glutamate, which may affect the outcome after ischaemia. In these cases, neuroprotection may potentially be due to the improved access to oxygen and glucose rather than biochemical prevention of cell death. Improvement in cerebral blood flow is an important but often overlooked effect of neuroprotective therapy, analogous to the protective effects of drug-induced hypothermia. This short review will discuss cerebral blood flow alteration and protection of the brain in the context of ischaemic preconditioning, oxygen sensing and thrombolysis. Future neuroprotection studies in cerebral ischaemia require stringent monitoring of cerebral blood flow, plus other physiological parameters. This will increase the chances that any protection observed may be able to translate to human therapy.

The knowledge of brain syndromes is essential for stroke physicians and neurologists, particularly those that can be extremely difficult and challenging to diagnose due to the great variability of symptom presentation and yet of clinical significance in terms of potential devastating effect with poor outcome. The diagnosis and understanding of stroke syndromes has improved dramatically over the years with the advent of modern imaging, while the management is similar to general care as recommended by various guidelines in addition to care of such patients on specialized units with facilities for continuous monitoring of vital signs and dedicated stroke therapy. Such critical care can be provided either in the acute stroke unit, the medical intensive care unit or the neurological intensive care unit. There may be no definitive treatment at reversing stroke syndromes, but it is important to identify the signs and symptoms for an early diagnosis to prompt quick treatment, which can prevent further devastating complications following stroke. The aim of this article is to discuss some of the important clinical stroke syndromes encountered in clinical practice and discuss their management.

No pharmacological intervention has been shown convincingly to improve neurological outcome in stroke patients after the brain tissue is infarcted. While conventional therapeutic strategies focus on preventing brain damage, stem cell treatment has the potential to repair the injured brain tissue. Stem cells not only produce a source of trophic molecules to minimize brain damage caused by ischaemia/reperfusion and promote recovery, but also potentially turn to new cells to replace those lost in ischaemic core. Although preclinical studies have shown promise, stem cell therapy for stroke treatment in human is still at an early stage and it is difficult to draw conclusions from current clinical trials about the efficacy of the different treatments used in humans. This article reviews the potential of various types of stem cells, from embryonic to adult to induced pluripotent stem cells, in stroke therapy, highlights new evidence from the ongoing clinical trials and discusses some of the problems associated with translating stem cell technology to a clinical therapy for stroke.

The pathogenesis of stroke is multifactorial, and inflammation is thought to have a critical function in lesion progression at early time points. Detection of inflammatory processes associated with cerebral ischemia would be greatly beneficial in both designing individual therapeutic strategies and monitoring outcome. We have recently developed a new approach to imaging components of the inflammatory response, namely endovascular adhesion molecule expression on the brain endothelium. In this study, we show specific imaging of vascular cell adhesion molecule (VCAM)-1 expression in a mouse model of middle cerebral artery occlusion (MCAO), and a reduction in this inflammatory response, associated with improved behavioral outcome, as a result of preconditioning. The spatial extent of VCAM-1 expression is considerably greater than the detectable lesion using diffusion-weighted imaging (25% versus 3% total brain volume), which is generally taken to reflect the core of the lesion at early time points. Thus, VCAM-1 imaging seems to reveal both core and penumbral regions, and our data implicate VCAM-1 upregulation and associated inflammatory processes in the progression of penumbral tissue to infarction. Our findings indicate that such molecular magnetic resonance imaging (MRI) approaches could be important clinical tools for patient evaluation, acute monitoring of therapy, and design of specific treatment strategies.

Objective To assess the association of socioeconomic deprivation (SED) with survival after stroke in China. Design A systematic literature review and a new population-based cohort study. Setting and participants In urban and rural communities in Anhui, China, 2978 residents aged ≥60 years took part in baseline investigation and were followed up for 5 years; five published studies were identified for a systematic review. Primary and secondary outcome measures 167 of 2978 participants (5.6%) had doctor-diagnosed stroke at baseline or 1 year later. All-cause mortality in the follow-up. Results In the Anhui cohort follow-up of 167 patients with stroke, 64 (38.3%) died. Multivariate adjusted hazard ratio (HR) of mortality in patients with educational level of less than or equal to primary school was 1.88 (95% CI 1.05 to 3.36) compared to those having more than primary school education. Increased HR of mortality in patients living in a rural area was at borderline significant (1.64, 0.97 to 2.78), but the HR in patients with lower levels of occupation and income was not significant. Published studies showed a significant increase in stroke mortality in relation to some SED indicators. Pooled relative risk (RR) of mortality in patients with low education was 3.07 (1.27 to 7.34), in patients with low income 1.58 (1.50 to 1.65) and in patients living in rural areas 1.47 (1.37 to 1.58). Conclusions The evidence suggests the presence of a mortality gradient after stroke for material as well as social forms of deprivation in China. Inequalities in survival after stroke persist and need to be taken into account when implementing intervention programmes.