A Review of Neuroinflammatory Mechanisms in Ischemic Stroke: Background and Therapeutic Approaches

It seems to me that this should have been totally unnecessary. A summary of all the processes involved in neuronal death should be publicly available. Then we would all be speaking to the same problems needing to be solved. But it seems we have no one in stroke with any sense of business processes.
This just needs updating which will never occur since we have NO stroke leadership.
Dr. Michael A. Moskowitz in 2010 had some great ideas needing followup;

The Science of Stroke: Mechanisms in Search of Treatments

 

A Review of Neuroinflammatory Mechanisms in Ischemic Stroke: Background and Therapeutic Approaches

research-article

Attila Sas^1∗, László Horváth¹, Csaba Oláh^{2, 3} and Attila Valikovics¹

Show details

Abstract

In this review, we will discuss the relevant clinical details of acute ischemic stroke and its currently very limited therapeutic opportunities, sequentially emphasizing its populational and economical burden. Based on our increasing knowledge in molecular and cell biology of immunological mechanisms of ischemic stroke, we will introduce the main processes in the background of arterial vessel occlusion, ensuing tissue damage and following reparation. After that, we will compare the obtained results from animal models with clinical studies and thus the possible causes of foregoing failures. Following this, we will demonstrate the most important drugs tested and/or being tested in human or animal studies from the field of neuroprotection. Finally, we raise possible opportunities that can be considered in development or clinical applications of neuroprotectants.

Keywords: acute ischemic stroke, stroke induced immunodepression, neuro-inflammation, neuroprotection, future perspectives

1. Introduction

In 2013, the Stroke Council of the American Heart Association/American Stroke Association laid an up-to-date definition of ischemic stroke. According to this, it is defined as brain, spinal cord or retinal cell death attributable to ischemia, based on neuropathological, neuroimaging and/or clinical evidence of permanent injury. In a clinical spectrum, it can be accompanied by symptoms or can be asymptomatic. Transient ischemic attack (TIA) is defined as a transient episode of neurological dysfunction caused by focal brain, spinal cord or retinal ischemia, without acute infarction [1].

Estimates from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD 2010) ranked stroke as the second most common cause of death [2] and the third most common cause of disability-adjusted life-years (DALYs) [3] worldwide in 2010. Expressed by numbers, roughly 10% of the 52,769,700 deaths [2] and about 4% of the 2,490,385,000 DALYs [3] worldwide were due to stroke. Further analysis of the GBD study showed that although stroke mortality rates and mortality-to-incidence ratios have decreased in the past two decades, the global burden of stroke in terms of the absolute number of people affected every year, stroke survivors, related deaths, and DALYs lost are great and increasing, with most of the burden in low-income and middle-income countries. If these trends in stroke incidence, mortality, and DALYs continue, by 2030, there will be almost 12 million stroke deaths, 70 million stroke survivors, and more than 200 million DALYs lost globally [4]. Furthermore, stroke changes the lives not only of those who experience a stroke but also of their family and other caregivers [5].

We can classify the stroke subtypes by aetiology. According to this, 80–85% of all stroke events are ischemic, the other 15–20% are of haemorrhagic origin [6]. The theme of our review is about ischemic stroke, so from now on, we will discuss only this subtype—means, that if ‘stroke’ is written, it refers to ischemic stroke automatically.

The ischemic stroke has its well-known risk factors, some of them are the common vascular risk factors. Among these, we can find so called non-modifiable ones: genetics, age, ethnicity/race, and low birth weight. Fortunately an international case-control study of 6000 individuals found that 10 potentially modifiable risk factors explained 90% of the risk of stroke [7]. These are—with no purpose of detailed description—physical inactivity with or without diet and nutrition failure (containing dyslipidaemia, obesity and body fat distribution, metabolic syndrome, diabetes mellitus) hypertension, cigarette smoking, atrial fibrillation and other cardiac conditions, carotid artery stenosis, sickle cell disease, migraine, alcohol consumption, drug abuse, sleep-disordered breathing [8].

Despite the intensive populational stroke education of these methods of primary prevention, the number of stroke patients increases to date.

After so many years of unsuccessful therapeutic approaches, recombinant tissue plasminogen activator (rtPA) was approved by the U.S. Food and Drug Administration (FDA) in 1996 for the treatment of acute ischemic stroke [9]. Since then, scores of stroke patients have been treated worldwide with this drug, managed by comprehensive stroke centres.

In a selected patient population (see detailed inclusion and exclusion criteria as per applied protocol), intravenous or intra-arterial thrombolysis can be a reliable choice. With this method of recanalisation, the treatment physician must calculate certain complications and a relatively poor outcome in several cases [10].

Most of these severely disabled stroke patients have intra- or extra-cranial large arterial vessel occlusion. In the past decade, a new form of acute revascularisation treatment, the endovascular stroke treatment (EST), appeared. After the failure of the first ‘unhappy’ trials with first-generation devices; in the past few years, smashing successes were achieved with the newer stent retrievers. These results—especially combined with iv thrombolysis—were comparably better than iv thrombolysis alone, and patient safety with risk/benefit ratio is also very promising [11].

Although several patients can benefit from the above mentioned methods of acute stroke treatment, they still have a few significant weak spots, above all, the narrow therapeutic time window.

Even in the countries with the best achievements, just like Austria with about 10% of stroke patients, can receive either or other treatment, the others, with wider stroke onset-to-treatment time have no or minimal chance of revascularisation, thus of good clinical outcome.

There is an urgent need to aim this enormous patient population with an effective treatment.

Neuroprotection would be a promising choice for this group, but until now, controversial results came to light in this field.

Hereinafter, we will introduce the main known reactions, immune responses in the brain following acute arterial vessel occlusion and potential therapeutic targets in this process.

More at link.