Deans' stroke musings

Changing stroke rehab and research worldwide now.Time is Brain!Just think of all the trillions and trillions of neurons that DIE each day because there are NO effective hyperacute therapies besides tPA(only 12% effective). I have 493 posts on hyperacute therapy, enough for researchers to spend decades proving them out. These are my personal ideas and blog on stroke rehabilitation and stroke research. Do not attempt any of these without checking with your medical provider. Unless you join me in agitating, when you need these therapies they won't be there.

What this blog is for:

Shortly after getting out of the hospital and getting NO information on the process or protocols of stroke rehabilitation and recovery I started searching on the internet and found that no other survivor received useful information. This is an attempt to cover all stroke rehabilitation information that should be readily available to survivors so they can talk with informed knowledge to their medical staff. It's quite disgusting that this information is not available from every stroke association and doctors group.
My back ground story is here:http://oc1dean.blogspot.com/2010/11/my-background-story_8.html

Thursday, September 21, 2017

Anti-Inflammatory Targets for the Treatment of Reperfusion Injury in Stroke

I don't know the difference between reperfusion injury and the neuronal cascade of death and since we have NO strategy to solve anything in stroke it doesn't make a damn bit of difference. 
I have 13 posts on reperfusion injury back to 2013, with a number of suggested interventions. I'm positive that not a single one ever made it into clinical practice, but you can always ask your doctor to try these because, 'What the hell', they might help.

Anti-Inflammatory Targets for the Treatment of Reperfusion Injury in Stroke

imageAtsushi Mizuma and imageMidori A. Yenari*
  • Department of Neurology, University of California, San Francisco and Veterans Affairs Medical Center, San Francisco, CA, United States
While the mainstay of acute stroke treatment includes revascularization via recombinant tissue plasminogen activator or mechanical thrombectomy, only a minority of stroke patients are eligible for treatment, as delayed treatment can lead to worsened outcome. This worsened outcome at the experimental level has been attributed to an entity known as reperfusion injury (R/I). R/I is occurred when revascularization is delayed after critical brain and vascular injury has occurred, so that when oxygenated blood is restored, ischemic damage is increased, rather than decreased. R/I can increase lesion size and also worsen blood barrier breakdown and lead to brain edema and hemorrhage. A major mechanism underlying R/I is that of poststroke inflammation. The poststroke immune response consists of the aberrant activation of glial cell, infiltration of peripheral leukocytes, and the release of damage-associated molecular pattern (DAMP) molecules elaborated by ischemic cells of the brain. Inflammatory mediators involved in this response include cytokines, chemokines, adhesion molecules, and several immune molecule effectors such as matrix metalloproteinases-9, inducible nitric oxide synthase, nitric oxide, and reactive oxygen species. Several experimental studies over the years have characterized these molecules and have shown that their inhibition improves neurological outcome. Yet, numerous clinical studies failed to demonstrate any positive outcomes in stroke patients. However, many of these clinical trials were carried out before the routine use of revascularization therapies. In this review, we cover mechanisms of inflammation involved in R/I, therapeutic targets, and relevant experimental and clinical studies, which might stimulate renewed interest in designing clinical trials to specifically target R/I. We propose that by targeting anti-inflammatory targets in R/I as a combined therapy, it may be possible to further improve outcomes from pharmacological thrombolysis or mechanical thrombectomy.

Introduction

Treatment of acute ischemic stroke has largely been limited to strategies to restore blood flow. Pharmacological recanalization, particularly tissue plasminogen activator (tPA) has been the mainstay for acute treatment for the past 20 years (1, 2), but in recent years, several studies have shown that mechanical embolectomy is also effective (3). However, the short time frame for safe intervention is still limited even considering recent studies that suggest additional criteria for treating “wake up stroke” (4) and longer time windows of up to 24 h for embolectomy (5). It is still estimated that less than 10% of all acute stroke patients benefit from reperfusion strategies. One of the reasons for such a short time window is that intervention beyond this time window actually increases risk and leads to worsened outcome (6). If these recanalization therapies are applied too late, there is an increased risk of cerebral hemorrhage, which can sometimes prove fatal (7). The mechanism of cerebral hemorrhage complicating ischemic stroke is a consequence of a phenomenon known as “reperfusion injury” (R/I) (8) to which inflammation is a major contributing cause.
While the restoration of cerebral blood flow (CBF) is a major goal of acute stroke treatment, it can also lead to more extensive brain tissue damage in the adjacent penumbral territory (9). If recanalization is carried out after a critical time window, the sudden restoration of oxygenated blood into ischemically compromised brain tissue may overwhelm already compromised endogenous antioxidant systems and damaged vascular endothelia leading to brain edema and extravasation of blood cells. The generation of reactive oxygen species (ROS) from compromised mitochondria not only leads to direct cellular damage but also can trigger the activation of both the peripheral (leukocytes) and brain resident (microglia) immune pathways, which in turn, elaborate various damaging immune mediators and effectors including more ROS. This vicious cycle in acute ischemic stroke is referred to as cerebral R/I (Figure 1) (10, 11).
FIGURE 1
www.frontiersin.org Figure 1. Ischemia-induced inflammation in association with reperfusion injury. Once brain ischemia occurs, oxygen and glucose supplies are reduced. If ischemia occurs for more than a certain time period (likely a few hours, but the precise duration is not well established) and blood flow is restored (reperfusion), worsened injury can paradoxically occur to the brain. This is often referred to as reperfusion injury. A major component of reperfusion injury involves subsequent inflammatory reactions induced through various mechanisms. Reperfusion leads to the introduction of ROS from oxygenated blood and can stimulate an immune response in the ischemic brain. Necrotic, ischemia-injured cells lyse and release their contents into the extracelluar space which can act as ligands for various immune receptors. Among these include nucleic acids which are one of many described damage-associated molecular pattern (DAMPs, see text for details). DAMPs can then bind TLRs and stimulate several inflammatory responses (microglial activation, overexpression of proinflammatory cytokines, chemokines) which lead to worsened brain injury. Inflammatory signaling also causes immune cells to generate more effector molecules such as ROS and iNOS/NO. In the periphery, cytokines and adhesion molecules can attract circulating immune cells to the ischemic brain where they infiltrate the damaged tissue and further amplify ischemic injury. Some circulating immune cells and platelets can also plug the microvasculature of the ischemic brain and cause secondary reductions in local CBF. In addition to brain cells, these inflammatory reactions can also cause damage to brain endothelia causing BBB disruption, edema and hemorrhagic transformation. Thus, the restoration of CBF can cause more extensive brain tissue damage. This vicious cycle is often called reperfusion injury. ROS, reactive oxygen species; DAMPs, damage-associated molecular patterns; TLR, toll-like receptor; MMPs, matrix metalloproteinases; iNOS, inducible nitric oxide synthase; NO, nitric oxide; BBB, blood–brain barrier; CBF, cerebral blood flow.
The evidence for R/I was previously demonstrated using experimental stroke models. A few groups have reported that ischemic injury is greater in animals where reperfusion occurs [temporary middle cerebral artery occlusion (tMCAO) for 2–3 h] compared to animals where there is no reperfusion (pMCAO) (12, 13). In a series of experiments where the duration of MCAO was varied and compared to pMCAO, tMCAO for less than 2 h led to smaller infarct sizes compared to pMCAO (14). Occlusion durations of more than 2 h led to paradoxically larger infarct volumes. However, direct evidence for R/I is less clear at the clinical level. While a rare “hyperperfusion syndrome” of accelerated brain edema and transient clinical worsening following abrupt revascularization has been described (15), it is not clear whether this results in permanent worsened outcome. Further, the neurotoxicity of tPA has been shown in previous studies, where endogenous tPA may directly contribute to worsened outcome (16). Further, it is quite clear that revascularization after certain time windows can worsen outcomes compared to no intervention (6) and could be said to represent R/I in humans. Hence, targeting aspects of R/I might suggest an opportunity to synergistically improve neurological outcome for thrombolysis and/or mechanical embolectomy.
While the concept of R/I as a therapeutic target surrounding revascularization, the efficacy of treatment in experimental reperfusion models does not necessarily predict the results of clinical trials. A PubMed search for experimental studies covering the terms “reperfusion injury, cerebral ischemia, and inflammation” revealed that 888 studies have been performed using the tMCAO model. However, only one agent (edaravone) has actually been transition to the clinical level in Japan. Experimental reperfusion models do not fully replicate what happens in clinical stroke. Hence some reports argue that experimental reperfusion models were inappropriate for clinical translation (17). Regardless, the timing of treatment is different for each clinical case. These factors are major problems that cannot be avoided. However, some novel mechanisms associated with R/I have been established in over the years by studying experimental models and may suggest therapeutic targets which could be studied at the clinical level in this new era of recanalization.
In this review, we will focus on the mechanism of R/I in acute ischemic stroke and reconsider its treatment, with a focus on proinflammatory targets, including some already in use at the clinical level.

More at link.

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