Immune Modulation as a Key Mechanism for the Protective Effects of Remote Ischemic Conditioning After Stroke

What will it take to get this written into a protocol and distributed worldwide?  If you want this done, tell survivors EXACTLY how many sessions of this will deliver recovery. Survivors will deliver the work needed with protocols NOT GUIDELINES.

You mean these earlier pieces of research were not enough to write up a protocol on this? And your hospital has been incompetent for how many years?

Leg wraps raise hopes of saved lives after strokes May 2013 

Leg compressions may enhance stroke recovery August 2012 

The latest here:

 

Immune Modulation as a Key Mechanism for the Protective Effects of Remote Ischemic Conditioning After Stroke

Sima Abbasi-Habashi¹, Glen C. Jickling^1,2 and Ian R. Winship^1,3*

• ¹Neuroscience and Mental Health Institute, University of Alberta, Edmonton, AB, Canada
• ²Division of Neurology, Faculty of Medicine, University of Alberta, Edmonton, AB, Canada
• ³Neurochemical Research Unit, Department of Psychiatry, University of Alberta, Edmonton, AB, Canada

Remote ischemic conditioning (RIC), which involves a series of short cycles of ischemia in an organ remote to the brain (typically the limbs), has been shown to protect the ischemic penumbra after stroke and reduce ischemia/reperfusion (IR) injury. Although the exact mechanism by which this protective signal is transferred from the remote site to the brain remains unclear, preclinical studies suggest that the mechanisms of RIC involve a combination of circulating humoral factors and neuronal signals. An improved understanding of these mechanisms will facilitate translation to more effective treatment strategies in clinical settings. In this review, we will discuss potential protective mechanisms in the brain and cerebral vasculature associated with RIC. We will discuss a putative role of the immune system and circulating mediators of inflammation in these protective processes, including the expression of pro-and anti-inflammatory genes in peripheral immune cells that may influence the outcome. We will also review the potential role of extracellular vesicles (EVs), biological vectors capable of delivering cell-specific cargo such as proteins and miRNAs to cells, in modulating the protective effects of RIC in the brain and vasculature.

Introduction

The incidence, mortality, and prevalence of neurological disorders are increasing worldwide, primarily because of the growing elderly population (1). Stroke is one of the most common neurovascular conditions with a prevalence of 101.5 million people worldwide (2021 Heart Disease and Stroke Statistical Update) (1). Of these strokes, 76% were classified as ischemic stroke (~77.2 million), ~ 20% as intracerebral hemorrhage (~20.7 million), and about 8% as subarachnoid hemorrhage (8.4 million) (1). Acute ischemic stroke (AIS) occurs when a major artery that supplies oxygen and nutrients to the brain becomes obstructed, leading to the formation of two injury zones: The ischemic core and the “penumbra.” The infarct core is severely hypoperfused, such that neurons undergo rapid and irreversible necrotic cell death (2). In response to ischemia and cell death in the core, inflammatory signals are released into the peripheral circulation, attracting immune cells to the damaged area and exacerbating the inflammatory response. The core of the ischemic region is surrounded by a relatively hypoperfused zone called the penumbra, which defines the tissue at risk for further infarction (3). Because cell death in this penumbral region occurs gradually, it is possible to rescue this peri-infarct area in the hyper-acute phase of AIS prior to cell death and infarct expansion.

One important factor contributing to the viability of penumbral tissue is the existence of strong collateral circulation that reduces ischemia in the penumbra, reducing injury, and improving the clinical outcomes (4). Pial collateral vessels—also called leptomeningeal collaterals–are auxiliary vascular networks on the brain surface that connect the distal part of major branches of the anterior and posterior cerebral artery (ACA, PCA) with the distal branches of the middle cerebral artery (MCA). These vascular anastomoses provide oxygen and essential nutrients via retrograde blood flow to the deprived ischemic tissue when the primary artery is blocked (5). Currently approved treatments for AIS, such as thrombolysis through recombinant tissue plasminogen activator (rtPA) administration or recanalization via mechanical endovascular treatment (EVT, i.e., mechanical thrombectomy), work in a time dependent manner and have a limited therapeutic window (6). While good collateral blood flow can extend this window, rapid restoration of flow to the brain remains the best treatment for acute stroke. However, this is restricted to ~10–20 percent of stroke sufferers who can make it to a primary stroke treatment center in time. Treatments that can improve collateral blood flow may extend the window for recanalization therapy and improve outcome for stroke patients (5).

Even after flow is restored in an occluded cerebral vessel, cellular injury can be exacerbated by reperfusion injury (7). Recanalization of the occluded artery can lead to damage to the integrity of the capillary endothelium, known as ischemia/reperfusion (IR) injury. Restored flow can increase BBB permeability when a high blood volume re-enters the already collapsed vasculature. Following this reperfusion, activated endothelial cells (ECs) produce reactive oxygen species (ROS), which further triggers the influx of inflammatory cells to the ischemic site (8). Increased leukocyte stimulation, trafficking and release of proinflammatory chemoattractant substances amplifies local inflammation. Elevated expression of adhesion molecules on ECs can further potentiate interactions between circulating blood cells and ECs, particularly neutrophil-endothelial interactions that can lead to neutrophil aggregation in the capillary bed (9). Reducing IR injury is key to improving outcome after recanalization therapy. So far, several approaches have been attempted to inhibit leukocytes aggregation and attenuate IR injury, but none have proven effective in clinic (10). Additional therapies are urgently needed to protect brain tissue from the ischemic and post-reperfusion damage. One such approach may be remote ischemic conditioning (RIC) (11, 12). RIC has shown to be a clinically safe and straightforward intervention which helps to attenuate the detrimental effects of ischemia. Multiple molecular signaling pathways contribute to the protective effects of RIC against reperfusion injury, with key signaling pathways converging on transcription factors that regulate cell survival and apoptosis (13). Of these signaling cascades, the reperfusion injury salvage kinase (RISK) and the survivor activating factor enhancement (SAFE) pathways are well-characterized. Below, we will review RIC for stroke treatment, its established mechanisms, and discuss RIC induced modulation of inflammatory immune cells and their gene expression profiles.

RIC: Concept and Origin

Remote Ischemic Conditioning (RIC) is a therapy that involves brief, intermittent episodes of sublethal ischemia and reperfusion that is applied to a peripheral tissue, organ or a vascular territory. This peripheral signal is then transmitted to the distal target organ (e.g., brain or heart) to relay protection against prolonged ischemia and subsequent IR injury (14, 15).

In 1986, ischemic preconditioning was described by Murry et al. in relation to cardiac ischemia (16). A preconditioning (PC) intervention was directly applied to the dog heart via four cycles (each for 5 min) of alternative occlusion/reflow of the left anterior descending (LAD) coronary artery prior to initiation of 40 min cardiac ischemia (16). Their results showed that PC was associated with a considerable reduction in myocardial infarction size. However, in another animal cohort, the same PC protocol preceding 3 h of sustained coronary occlusion failed to salvage the heart tissue injury, suggesting that PC has a protective time window and it may only delay the cellular death up to a few hours and then dissipates (16). Thereafter, additional investigations advanced the theory of “two time windows for protection” based upon these results (17–19). The early phase of protection occurs immediately, within minutes after the PC application, and lasts for ~3 h. It is thought that the early phase is mainly caused by rapid alterations in protein kinase signaling pathways that converge on the mitochondria to stop the apoptotic pathways (20, 21). The late phase starts 18–24 h after PC and lasts for ~4 days. The protection during the late period is probably due to de novo synthesis of proteins that are involved in inflammation, ischemia and vascular dynamics (12, 22, 23), and the suppression of genes involved in IR injury.

In 1993 the conditioning concept was extended to remote ischemic conditioning (RIC), in which ischemia is induced to an organ far from the target organ, often using a blood pressure cuff, offering a safe and feasible approach (24).

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