Use the labels in the right column to find what you want. Or you can go thru them one by one, there are only 34,483 posts. Searching is done in the search box in upper left corner. I blog on anything to do with stroke. DO NOT DO ANYTHING SUGGESTED HERE AS I AM NOT MEDICALLY TRAINED, YOUR DOCTOR IS, LISTEN TO THEM. BUT I BET THEY DON'T KNOW HOW TO GET YOU 100% RECOVERED. I DON'T EITHER BUT HAVE PLENTY OF QUESTIONS FOR YOUR DOCTOR TO ANSWER.
Changing stroke rehab and research worldwide now.Time is Brain!trillions and trillions of neuronsthatDIEeach day because there areNOeffective hyperacute therapies besides tPA(only 12% effective). I have 523 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. Did your doctor somehow miss the recovery protocol that Pedro Bach-y-Rita used to recover fully back in 1958 with only a partial brain?
What this blog is for:
My blog is not to help survivors recover, it is to have the 10 million yearly stroke survivors light fires underneath their doctors, stroke hospitals and stroke researchers to get stroke solved. 100% recovery. The stroke medical world is completely failing at that goal, they don't even have it as a goal. 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 lays out what needs to be done to get stroke survivors closer to 100% recovery. It's quite disgusting that this information is not available from every stroke association and doctors group.
Why? Didn't all this earlier research produce protocols on its' use? NO? So incompetency reigned and your lack of recovery is because of ALL THAT FUCKING INCOMPETENCY!
Sponsor:Joyce ChenInformation Provided by Qingliang T. Wang, MD, PhD
Study Start (Estimated)2026-02-02
Primary Completion (Estimated) 2028-12-01
Study Completion (Estimated)2028-12
Enrollment (Estimated)1164
Study TypeInterventional
Last Update Posted2026-02-11
Brief Summary
The goal of this study is to determine if Minocycline, when added to standard care, can improve survival and functional outcomes in patients with moderate acute stroke (ischemic or hemorrhagic) aged 18 years and older. The main questions it aims to answer are: 1. Does Minocycline improve \*National Institutes of Health Stroke Scale\* (NIHSS) scores at hospital discharge and 90 days post-stroke? 2. Does Minocycline reduce stroke-related disability, all-cause in hospital mortality (mRS -\*Modified Rankin Scale\* = 6) and at 90 days besides reducing brain bleeding complications compared to standard care? Researchers will compare patients receiving oral Minocycline plus standard care to those receiving standard care only to see if Minocycline leads to better neurological outcomes and lower mortality. Participants will: 1. Be randomly assigned by block to receive either: Minocycline 200 mg orally once daily for five days within 24 hours from symptoms onset + Standard Care, or Standard Care only 2. Undergo neurological assessments using NIHSS \*National Institutes of Health Stroke Scale\* and Modified Rankin Scale (mRS) at admission, discharge, 30 days post-stroke, 90 days post-stroke 3. Be monitored for: a) hemorrhagic transformation of ischemic strokes; b) Adverse events and mortality outcomes; c) Safety and efficacy signals through interim analyses NIHSS: \*National Institutes of Health Stroke Scale\*, which is stroke severity scale, mRS: \*Modified Rankin Scale\*, which is stroke disability scale To learn more, visitClinicalTrials.gov
First of all, stop using the term, neuroprotection! Neuronal cascade of death is the correct term! It gives absolutely NO SENSE OF URGENCY! If you tell your patients, you know nothing about stopping the 5 causes of the neuronal cascade of death in the first week thus letting die hundreds of millions to billions of neurons. They might just get angry with your incompetence!
Send me hate mail on this: oc1dean@gmail.com. I'll print your complete statement with your name and my response in my blog. Or are you afraid to engage with my stroke-addled mind? I would like to know why you aren't solving stroke to 100% recovery, because this doesn't solve stroke recovery at all!
You'll have to ask your competent? doctor why the hell edaravone is approved in Japan since 2001 but not the US.
Has your stroke hospital done anything with any of these in the last decade? OR ARE THEY COMPLETELY FUCKING INCOMPENT AT EVERYTHING IN STROKE?
You can easily see how much research is out there to be implemented and your hospital is totally incompetent if not done.
1
Affiliated Hospital of Nantong University, Nantong, Jiangsu Province, China
2
School of Medicine, Nantong University, Nantong, Jiangsu Province, China
The final, formatted version of the article will be published soon.
You don't have a Frontiers account ? You can
register here
cause of combined disability and mortality globally. While reperfusion therapies play a critical role in the management of acute ischemic stroke (AIS), their applicability is limited, leaving many patients with significant neurological deficits and poor prognoses.Neuroprotective agents have garnered attention for their potential as adjunct therapies; however, their relative efficacy remains unclear. This study utilized a network metaanalysis (NMA) to systematically compare the efficacy of neuroprotective agents in improving neurological function and prognosis in stroke patients. Methods: This study adhered to PRISMA guidelines and the Cochrane Handbook for systematic reviews. Randomized controlled trials (RCTs) were identified through comprehensive searches of the PubMed, Embase, and Cochrane Library databases. Two independent reviewers conducted the selection process, data extraction, and quality assessment. Outcomes included 90-day modified Rankin Scale(90d-mRS)、change of National Institutes of Health Stroke Scale score from baseline to 90-day/14-day/7-day (90day/14d/7d-NIHSS) and 90-day/14-day Barthel Index (90d/14d-BI).Data analyses were performed using RevMan 5.4 and Stata 14.0. Results: A total of 42 RCTs involving 12,210 participants were included in this analysis. The interventions assessed included Cerebrolysin, Citicoline, Edaravone, Edaravone Dextranol, HUK, Minocycline, NA-1, NBP, Vinpocetine, and Control. The NMA results demonstrated that NBP ranked highest for the 90d-mRS, 90d-NIHSS, 14d-NIHSS, and 14d-BI outcomes. Edaravone was found to be the most effective intervention for the 7d-NIHSS and 90d-BI outcomes.The findings of this study indicate that different neuroprotective agents exhibit distinct advantages at specific stages of recovery. NBP showed outstanding performance in improving 90d-mRS and 90d-NIHSS, underscoring its potential in long-term rehabilitation. Edaravone demonstrated significant superiority in 7d-NIHSS scores, highlighting its role in early neuroprotection. These results provide valuable insights for individualized clinical treatment. To further validate the efficacy and safety of neuroprotective agents, future studies should involve larger sample sizes and conduct multicenter, large-scale randomized controlled trials.
Previous studies said this: Substantial studies have demonstrated that minocycline, a
second-generation semisynthetic antibiotic belonging to the tetracycline
family, can inhibit neuroinflammation, inflammatory mediators and
microglia activation,
and improve neurological outcome.
Why didn't yours?
With all these positive results on
minocycline, WHOM is going to create the protocol on this and get it
distributed to all stroke hospitals and all 10 million yearly stroke survivors now and into the future?
Minocycline,
in animal models and 2 small randomized controlled human trials, is a
promising neuroprotective agent in acute stroke. We analyzed the
efficacy and safety of intravenous minocycline in acute ischemic and
hemorrhagic stroke.
Methods—
A
multicenter prospective randomized open-label blinded end point
evaluation pilot study of minocycline 100 mg administered intravenously,
commenced within 24 hours of onset of stroke, and continued 12 hourly
for a total of 5 doses, versus no minocycline. All participants received
routine stroke care. Primary end point was survival free of handicap
(modified Rankin Scale, ≤2) at day 90.
Results—
Ninety-five
participants were randomized; 47 to minocycline and 48 to no
minocycline. In the intention-to-treat population, 29 of 47 (65.9%)
allocated minocycline survived free of handicap compared with 33 of 48
(70.2%) allocated no minocycline (rate ratio, 0.94; 95% confidence
interval, 0.71–1.25 and odds ratio, 0.73; 95% CI, 0.31–1.71). A
meta-analysis of the 3 human trials suggests minocycline may increase
the odds of handicap-free survival by 3-fold (odds ratio, 2.99; 95% CI,
1.74–5.16) but there was substantial heterogeneity among the trials.
Conclusions—
In
this pilot study of a small sample of acute stroke patients,
intravenous minocycline was safe but not efficacious. The study was not
powered to identify reliably or exclude a modest but clinically
important treatment effect of minocycline. Larger trials would improve
the precision of the estimates of any treatment effect of minocycline.
With all these positive results on minocycline, WHOM is going to create the protocol on this and get it distributed to all stroke hospitals and all 10 million yearly stroke survivors now and into the future?
Accumulating research substantiates the statement that inflammation
plays an important role in the development of stroke. Both
proinflammatory and anti-inflammatory mediators are involved in the
pathogenesis of stroke, an imbalance of which leads to inflammation.
Anti-inflammation is
a kind of hopeful strategy for the prevention and treatment of stroke.
Substantial studies have demonstrated that minocycline, a
second-generation semisynthetic antibiotic belonging to the tetracycline
family, can inhibit neuroinflammation, inflammatory mediators and
microglia activation,
and improve neurological outcome. Experimental and clinical data have
found the preclinical and clinical potential of minocycline in the
treatment of stroke due to its anti-inflammation properties and
anti-inflammation-induced pathogeneses, including antioxidative stress,
antiapoptosis, inhibiting
leukocyte migration and microglial activation, and decreasing matrix
metalloproteinases activity. Hence, it suggests a great future for
minocycline in the therapeutics of stroke that diminish the inflammatory
progress of stroke.
With ANY BRAINS AT ALL, our stroke leadership would fire up research on this for stroke. But that will never occur, two problems;
1. We have NO STROKE LEADERSHIP.
2. There are no brains in stroke.
The minocycline approach was researched/published in October 2009SO 11 TEARS OF EPIC FAILURE EVERYWHERE IN STROKE! Proving once again that the existing stroke associations are worthless.
Dr. Teresa Murray, associate
professor in Biomedical Engineering and the Center for Biomedical
Engineering and Rehabilitation Sciences at Louisiana Tech University, is
collaborating with former Louisiana Tech doctoral student Dr. Chelsea
Pernici and professors at the University of Arizona to help develop
solutions to traumatic brain injury.
Murray and Pernici are working with Dr. Jonathan Lifshitz and Dr.
Rachel Rowe, director and research assistant professor, respectively,
with the Translational Neurotrauma Research Program at the University of
Arizona College of Medicine – Phoenix, to develop a treatment that
could prevent memory and emotional problems in patients suffering from
axonal injury caused by traumatic brain injuries (TBIs).
The study was led by Murray and Pernici who used a new imaging
technology to show how diseases and injuries affect the brain over time
and how medicines could reduce brain damage. This novel imaging was
created in Murray’s lab. Through this technology, the group of
researchers were able to repeatedly image the same axons in the brain
before and after brain injury, providing proof of TBI-related axonal
pathology.
Using a novel combination of high-resolution imaging and a GRIN lens
implanted in the brain of mice, the team documented axonal injury and
the recovery process after a blunt injury to the brain. GRIN lenses are
microscopic glass lenses that allow scientists to focus closely on the
cells for good image quality. These lenses are smaller than Lincoln’s
nose on a U.S. penny and were adopted by a handful of biologists to
better study the brain.
Murray developed an improved GRIN lens system to see more details of
brain cells. Her team also designed 3D-printed hardware to help them
find the exact same cells for each imaging session. Her improved GRIN
lenses allowed the team to find and evaluate the same injured axons over
several weeks post injury.
“The fine communication elements of neurons — axons — are torn,
ruptured and damaged, which contributes to a multitude of clinical
symptoms,” Lifshitz said. “To date, these processes have been inferred
from fixed histological sections, clinical imaging and cells in culture.
No one has observed an axon prior to injury, the consequence of injury
and the outcome. Here, we show that axons do sustain injury and can
either recover or become truncated.”
Tracking the time in which axons become affected, the team employed a
clinically approved drug, minocycline, to reduce inflammation, which
slowed axon injury, recovered them from injury and preserved function.
The team tested the drug’s effectiveness for immediate use within 45
minutes of the incident, compared to delayed use at three days post
injury – both time points showed positive effects. The minocycline drug
treatment promoted the recovery of injured axons. With treatment, a much
larger percentage of the damaged axons healed, compared to those
without treatment.
“Most brain injuries cause damage to just a few axons,” Murray said.
“These few axons can’t be seen on MRIs and CT scans. So, most TBI
patients are sent home with the hope that they will get better over
time. However, even a few damaged axons can disrupt communication in the
brain and affect neurological function.”
“The novel fluorescence imaging method using GRIN lenses allows
researchers to study brain cells in both time and space, offering a
unique opportunity to better understand the effect of drugs on brain
structure over time,” Pernici added. “It’s exciting to see that although
axons become damaged after TBI, the injury can resolve and with this
method, we have the opportunity to better understand that timescale.”
The team plans to continue their research by pairing minocycline with
another drug to further reduce this early damage. If successful, this
treatment could lessen the chances of memory loss and emotional problems
for people suffering a TBI.
“This study provides hope that we can use minocycline effectively if
the drug can be taken early in the process and not given long-term. This
could help reduce the inflammation, and thus some of the permanent
damage caused by brain injury,” Murray said.
No drug currently on the market is clinically used to prevent axon injury. The results of their research were published in Scientific Reports on May 8.
Drinking low-calorie cranberry juice may help lower risk of heart disease, diabetes and stroke
Black
Raspberry Extract Increased Circulating Endothelial Progenitor Cells
and Improved Arterial Stiffness in Patients with Metabolic Syndrome: A
Randomized Controlled Trial
The hardening of our ageing arteries has been a tricky process to pin
down, but new research might finally have the answer. It might even
take us closer to treatments that limit this blood vessel condition,
which can increase the risk of heart attack, dementia and stroke.
While it's already known that calcium deposits are the reason why
arteries stiffen with age, it doesn't tell us why that build-up
accumulates. According to this latest study, the process could be
triggered by a molecule called poly(ADP-Ribose) or PAR.
PAR
is a repair protein that gets produced when cells or cell DNA gets
damaged; as it binds very strongly with calcium, it starts mopping up
calcium into larger droplets. Those droplets then solidify, sticking to
artery walls and reducing their elasticity, the study reveals.
"This
hardening, or biomineralisation, is essential for the production of
bone, but in arteries it underlies a lot of cardiovascular disease and
other diseases associated with ageing like dementia," says cell biologist Cathy Shanahan from King's College London in the UK.
"We
wanted to find out what triggers the formation of calcium phosphate
crystals, and why it seems to be concentrated around the collagen and
elastin which makes up much of the artery wall."
The release of PAR was spotted in various cell cultures, including human blood vessel samples, using a technique called Nuclear Magnetic Resonance (NMR) spectroscopy, which is able to analyse samples down to the molecular level.
The
implication of a protein produced by cell damage makes a lot of sense,
given that ageing, high blood pressure and smoking are all known to
increase the risk of stiffening arteries. And what they have in common
is the DNA damage they are known to cause; so if the researchers are
right, the damage ends up calling on PAR to fix it, in turn hardening
the arteries as a byproduct.
"Up until now we haven't known what controls this process and therefore how to treat it," says biochemist Melinda Duer from the University of Cambridge in the UK.
"We
never would have predicted that it was caused by PAR. It was initially
an accidental discovery, but we followed it up – and it's led to a
potential therapy."
That potential therapy could centre around an existing antibiotic called minocycline.
It's already used to treat acne, and because it's been through the
necessary safety testing, the whole process of adapting it for
preventing arterial stiffening could be sped up.
Through some
short-term initial tests on rats, the team was able to demonstrate the
effectiveness of minocycline in inhibiting the production of PAR.
Clinical trials could happen within the next 18 months, according to the
researchers.
It's worthwhile to note that this part of the research was provided for and funded by Cycle Pharmceuticals, a company whose work explicitly includes finding ways to repurpose drugs that already exist on the market.
While
we might not be able to stop artery stiffening completely as a natural
consequence of ageing – and healthy lifestyle habits still play an
important role – minocycline or a similar drug does appear to have the
potential to lower the risk of health problems associated with these
calcium deposits.
That said, antibiotic therapy doesn't come without its own host of side-effects and costs,
so time will tell whether this approach will truly lead to a practical
solution. Still, the more we learn about the intricacies of our
cardiovascular health, the better we can help our ageing population.
Proof once again that the stroke medical world is totally dysfunctional. These systematic reviews are a complete waste of time. As research comes in it should be the responsibility of the researchers to update the existing knowledge base of that research in that publicly available database of stroke research and protocols. Reviews like this would never need to occur.
Research back to May 2012 proves how fucking incompetent your doctor and stroke hospital are. Why are you allowing such incompetence? Do you never ask your doctor what was the last research applied in their hospital?
1The Department of Cerebrovascular Diseases, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, China
2The Henan Medical Key Laboratory of Translational Cerebrovascular Diseases, Zhengzhou, China
3Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada
4Department of Clinical Neurosciences, University of Calgary, Calgary, AB, Canada
Objectives: This study aimed to assess the efficacy of minocycline for the treatment of acute ischemic stroke.
Background: While there have been
meta-analysis that surveyed the efficacy of minocycline in the treatment
of acute stroke, they have some methodological limitations. We
performed a new systematic review which was distinct from previous one
by adding new outcomes and including new studies.
Methods: Document retrieval was
executed through PubMed, Cochrane Central Register of Controlled Trials,
the Stroke Center, NIH's Clinical Trials, Current Controlled Trials,
and the WHO International Clinical Trials Registry Platform Search
Portal before Jan 2018. The data meeting the inclusion criteria were
extracted. Before meta-analysis, publication bias and heterogeneity of
included studies were surveyed. Random and fixed-effects models were
employed to calculate pooled estimates and 95% confidence intervals
(CIs). Additionally, sensitivity and subgroup analyses were implemented.
Result: For clinical studies, 4 trials
with 201 patients in the minocycline group, and 195 patients in the
control group met the inclusion criteria; 3 were randomized trials. At
the end of 90-day follow up or discharge day, results showed that the
groups receiving minocycline were superior to the control group, with
significant differences in the NIHSS scores (mean difference [MD],
−2.75; 95% CI, −4.78, 0.27; p = 0.03) and mRS scores (MD, −0.98; 95% CI, −1.27, −0.69; p < 0.01), but not Barthel Index Score (MD, 9.04; 95% CI, −0.78, 18.07; p
= 0.07). For rodent experiments, 14 studies were included. Neurological
severity scores (NSS) was significantly improved (MD, −1.38; 95% CI,
−1.64, −1.31; p < 0.01) and infarct volume was obviously reduced (Std mean difference [SMD], −2.38; 95% CI, −3.40, −1.36; p < 0.01) in the minocycline group. Heterogeneity among the studies was proved to exist for infarct volume (Chi2 = 116.12, p < 0.01; I2 = 0.89) but not for other variables.
Conclusions: Based on the results in our study, minocycline appears as an effective therapeutic option for acute ischemic stroke.
Originally published27 Aug 2018Stroke. 2018;49:2261-2267
The central nervous system and the immune system are tightly interconnected through complex communicating networks.1
Immune cells are distributed in specific central nervous system
compartments. Microglia are the innate immune cells resident in the
brain parenchyma. Macrophages surround the blood vessels and also line
the leptomeninges and the choroid plexus together with dendritic cells
and lymphocytes, among other immune cells, where they play
immunosurveillance functions. Therefore, the immune system keeps a close
watch on brain function and reacts when brain homeostasis is lost
because of injuries or diseases. Sterile organ damage may turn immune
cells into harmful agents and for this reason they are regarded as
targets for therapeutic intervention in acute stroke.2
Stroke induces strong inflammatory reactions involving the local
production of cytokines, such as TNF-α (tumor necrosis factor-α) by
various brain cells, including human neurons,3
activation of glial and endothelial cells, blood-brain barrier damage,
and infiltration of different types of leukocytes after an orchestrated
time course.4
Given the variety of leukocyte subsets trafficking to the ischemic
brain tissue, this review will focus on neutrophils,
monocyte/macrophages, and T and NK (natural killer) lymphocytes. For
further information, the readers are addressed to previous reviews on
dendritic cells5 and B lymphocytes.6
The different immune cells are considered separately in the next
sections, but leukocyte infiltration surely comprises intercellular
crosstalks by mechanisms that are not entirely known.
Neutrophils
Neutrophils
are among the first cells attracted to the brain after ischemic stroke
where they are detected in the microvessels within the first hour7 and peak at 1 to 3 days.4,7,8
Neutrophils are short-lived innate immune cells containing different
types of granules with antimicrobial pro-oxidant and proteolytic enzymes
that can damage the tissues. Accordingly, neutrophils are regarded as
detrimental following compelling evidence associating these cells with
blood-brain barrier breakdown and brain injury.7,9 Also, higher blood neutrophil counts are associated with larger infarct volumes in acute ischemic stroke patients.10
Nevertheless, the pathogenic role of neutrophils in ischemic stroke is
still not conclusive. For instance, there are conflicting results in the
literature on the potential benefit of neutrophil depletion in
experimental ischemia models.9,11
Furthermore, we lack entire demonstration that neutrophils reach the
ischemic tissue before substantial neuronal death has occurred.11
Nonetheless, neutrophils can exert detrimental effects already from the
vessel wall. Adhesion of neutrophils to the inflamed endothelium after
ischemia/reperfusion is involved in the no-reflow phenomenon,
obstructing blood flow in precapillary arterioles, postcapillary
venules, and the capillary bed.7,12
In addition, neutrophils in the vessel lumen and at perivascular
locations can damage the blood-brain barrier by releasing proteolytic
enzymes and pro-oxidant molecules (Figure).9 Moreover, neutrophils can produce NETs (neutrophil extracellular traps) promoting clot formation.13 NETs can precipitate thrombotic events and impair tPA (tissue-type plasminogen activator)-induced thrombolysis.14
In turn, thrombolysis may exacerbate detrimental effects of neutrophils
because tPA promotes neutrophil transmigration to the reperfused tissue
by proteolytic activation of plasmin and matrix metalloproteinases.15
These effects might contribute to explain why neutrophilia and high
neutrophil-to-lymphocyte ratio are associated with the risk of
hemorrhagic transformation in ischemic stroke patients treated with tPA.16
After permanent middle cerebral artery occlusion (MCAo) in mice, we
observed the formation of intravascular NETs and found NETs in
perivascular locations and in the brain parenchyma.17
Figure.
Schematic representation of leukocyte infiltration to the ischemic
brain tissue. Neutrophils are attracted to the activated endothelium and
reach perivascular spaces after extravasation from intracerebral
venules and leptomeningeal vessels. Activated neutrophils are
prothrombotic and can damage the blood-brain barrier (BBB). The presence
of neutrophils in the brain parenchyma is observed only under certain
circumstances, but the conditions determining that neutrophils remain in
perivascular spaces or reach the parenchyma are still poorly defined.
Attracted by certain chemokines, immature proinflammatory monocytes
infiltrate the ischemic tissue where they mature to macrophages, acquire
signs of alternative polarization, and seem to be involved in tissue
repair. Current experimental evidence suggests that lymphocytes, in
particular T cells and γδ T cells, play detrimental roles in the acute
phase of stroke by promoting thromboinflammation and tissue damage.
Natural killer (NK) cells are attracted to the ischemic tissue, but
their function is not fully clear. RBC indicates red blood cells.There
is also some controversy on whether neutrophils actually reach the
ischemic brain parenchyma at all. An elegant study by Enzmann et al18
noticed the massive accumulation of neutrophils in perivascular spaces
surrounding venules within the ischemic tissue after
ischemia/reperfusion in mice. Most neutrophils remained perivascular,
and only a few were detected in the brain parenchyma.18
This is an important observation because it highlights that
perivascular spaces are a niche for neutrophils where they accumulate
after transient MCAo. We also detected neutrophils in perivascular
locations and leptomeningeal spaces in the mouse after permanent MCAo.17
These results suggest that, besides extravasating from intracerebral
venules, neutrophils extravasate from leptomeningeal vessels and migrate
from the subpial space along the vessels penetrating the cortex.17 However, our study17 and previous studies7
found neutrophils in the ischemic brain parenchyma using models of
permanent MCAo. Ischemic conditions involving severe endothelial damage,
vessel rupture, and microbleeds or hemorrhagic transformation, are
expected to facilitate the presence of neutrophils in the brain
parenchyma. Other conditions, such as high blood glucose, also promote
neutrophil infiltration.19 A recent study20
analyzed the postmortem brain of 16 ischemic stroke patients and
confirmed the presence of neutrophils in the leptomeninges and
perivascular spaces, but neutrophils were rare in the infarcted
parenchyma with the exception of 1 patient deceased 3 days after stroke
with no signs of infection. Interestingly, the time to death of this
series of patients was 1 day in 2 cases, 3 days in the case above
mentioned, and then times ranged from 8 days to 240 days poststroke.20
Neutrophils display a specific time-window of attraction to the damaged
tissues after acute injuries, and they have a short life in tissues.
Therefore, the time to death of ischemic stroke patients is critical to
look for the presence of neutrophils in the brain parenchyma. More
studies of human tissue within the first days poststroke are necessary
to understand under which conditions neutrophils might gain access to
the infarcted brain parenchyma.
Despite
many advances, there are aspects of neutrophil behavior in stroke that
are still difficult to interpret. For instance, neutrophils with
anti-inflammatory and repair phenotypes were found in the ischemic brain
tissue of experimental animals,21 neutrophils of ischemic stroke patients show a reduced oxidative burst and NET formation,22 and microglia surrounding blood vessels phagocyte neutrophils.23
The possibility that neutrophils were passive bystanders under some
circumstances but active players in others depending on specific
features of the ischemic lesion needs further consideration.
Monocyte/Macrophages
After
brain ischemia, microglia acquire a reactive morphology resembling
macrophages. Classically, immunohistochemical studies have described the
presence of reactive microglia/macrophages peaking at ≈4 days
postischemia in rats or mice, but it was not possible to distinguish
whether these cells derived from resident microglia or they infiltrated
from the periphery. Nowadays, flow cytometry, cell type-specific
fluorescent reporter mice, adoptive transfer of fluorescent cells,
generation of chimeras, and recently identified specific microglia
markers, allow differentiating resident reactive microglia from
infiltrating macrophages. Monocyte infiltration is detected within the
first 24 hours postischemia, peak at 4 days, and some of these cells
persist for weeks and acquire features of tissue macrophages. Immature
CCR2+Ly6Chi proinflammatory monocytes are the subset of monocytes first attracted to the ischemic brain tissue.24–26
These cells might be released by the bone marrow, but a study reported
that monocytes reaching the ischemic brain originate in the spleen.25
Infiltrating
macrophages were classically associated with inflammation and brain
damage after ischemic stroke. In mice, monocyte infiltration is largely
dependent on CCR2 (C-C motif chemokine receptor type 2), the receptor of
the chemokine CCL2 (C-C motif chemokine ligand 2), also known as MCP1
(monocyte chemoattractant protein 1). To investigate the role of
monocytes, several studies used CCR2-deficient mice or CCR2 inhibitors,
with the limitation that besides the subset of Ly6Chi monocytes other cells, like some T cells, also express CCR2. CCR2-deficiency reduced the ischemic brain lesions in mice.27 Challenging this view, CCR2 drug inhibitors exacerbated the brain lesion.28 Furthermore, anti-CCR2 blocking antibodies impaired spontaneous long-term functional recovery,29 depletion of monocytes/macrophages worsened the ischemic lesion,30 and infiltrating macrophages prevented hemorrhagic transformation of the ischemic lesion.24
By systemic injection of fluorescent monocytes after brain ischemia, we
observed fluorescent cells in the subpial space, and along the vessels
penetrating the cortex,26
supporting the view that a subset of infiltrating macrophages establish
persistent interactions with the blood vessels (Figure).
The
phenotype of activated macrophages depends on the environmental
stimuli. The M1 and M2 phenotypes are prototypical states of macrophage
polarization achieved in culture after exposure to certain cytokines.
The M1 phenotype is proinflammatory whereas the M2 phenotype promotes
resolution of inflammation and repair. Macrophages infiltrating the
ischemic tissue, including the Ly6Clo population and some of the Ly6Chi monocytes, acquire features of alternatively polarized M2 macrophages during the first week postischemia.26,28–30
Studies of human ischemic infarcts reported that macrophages initially
showed proinflammatory features that with lesion maturation transformed
into anti-inflammatory phenotypes.20
Interestingly, a study noticed that after ischemia in mice, the
expression of M2 markers increased within the first week but then
decreased, whereas proinflammatory markers persisted and predominated at
week 2, suggesting a long-lasting inflammatory status.31
The
factors that contribute to the time-dependent changes in macrophage
phenotypes in the ischemic brain tissue are not entirely identified.
Increased anaerobic glycolysis and activation of the hypoxia-inducible
factor-1 are associated with proinflammatory M1 phenotypes, whereas
energy production in M2 phenotypes rather relies on fatty acid
oxidation.32
In M1 activated macrophages, arginine metabolism occurs through
inducible nitric oxide synthase leading to generation of reactive oxygen
and nitrogen species that damage proteins, lipids, and DNA. In
contrast, M2 macrophages metabolize arginine through arginase-1
generating polyamines involved in cell division and collagen synthesis,
among other functions.32
However, under pathological conditions 1 single phenotypic feature may
not be sufficient to attribute any specific phenotype to the cells.
Likely, cellular metabolic adaptations to ischemia and reperfusion
together with the cytokine environment and phagocytic activity have an
impact on the phenotype and function of macrophages and microglia.
Lymphocytes
T Cells
Severe stroke reduces the numbers of lymphocytes in the circulation and lymphoid organs.33 In contrast, T-cell numbers increase in the ischemic brain within the first 24 hours and can persist for long times.4
During the first hours after ischemia/reperfusion, T cells facilitate
adhesion of platelets and leukocytes to the vascular endothelium34 causing a phenomenon called thromboinflammation35
by which molecular and cellular players in thrombosis and coagulation
promote proinflammatory pathways exacerbating the brain lesion.36
However, the interaction of T cells with platelets may also have
hemostatic effects preventing hemorrhagic transformation after severe
ischemic stroke.37 T cells are found in subpial and cortical vessels and infiltrating the ischemic lesion.38,39 In addition, the choroid plexus is a gateway for T cells migrating to the periphery of cortical infarction.40 Importantly, CD8+ cytotoxic T cells were detected in human ischemic infarcts.20 Also, ischemic stroke patients show increased frequency of CD4+CD28null cells in blood associated with stroke severity and serum levels of proinflammatory cytokines.41 CD4+CD28null
T cells are an interesting subset of T cells because they have enhanced
effector functions, are associated with senescent T cells, and expand
under inflammatory conditions.42 At later phases, CD4+ cells accumulate in the brain of mice peaking at day 14 and persisting at day 30 after ischemia/reperfusion.43
Furthermore, emerging evidence suggests that antigen-mediated T-cell
responses take place in subacute or chronic stages after stroke and may
worsen stroke outcome.43–47
However, in central nervous system trauma, protective autoimmunity
mediated by T-cell responses is involved in promoting recovery.48
Overall, T cells seem to play innate functions and interact with
players in thrombosis and hemostasis in the acute phase of stroke,
whereas at later stages they exert adaptive functions that could affect
stroke outcome in the long term.
γδ T Cells
Subsets
of unconventional innate T cells with invariant T-cell receptor could
play a role in acute ischemic brain damage. Growing evidence supports
that γδ T cells are pathogenic in experimental brain
ischemia/reperfusion by secreting IL (interleukin)-17 and exacerbating
the inflammatory response.49–51 Moreover, IL-17A+ lymphocytes were detected in the postmortem brain of stroke patients.50 Interestingly, γδ T cells are abundant in the gut from where they seem to traffic to the leptomeninges after brain ischemia.52
T helper 17 cells (Th17) and γδ T cells increase in the blood of stroke
patients in association with increased levels of IL-17A, IL-23, IL-6,
and IL-1β.53
In spite of the fact that IL-17 producing cells are a small subset of
cells, they seem to play a prominent role in orchestrating the
inflammatory response in acute stroke and exacerbating the lesion
(Figure).
Regulatory Lymphocytes
Regulatory
lymphocytes exert immunomodulatory and immunosuppressor functions.
Several lines of evidence support beneficial effects of regulatory T
cells (Treg)54 and regulatory B cells55 in experimental brain ischemia. However, other studies found acute detrimental effects of Treg in brain ischemia/reperfusion56 as previously reviewed.57
Although the number of Treg found in the ischemic brain parenchyma
during the first days poststroke is low, Treg strongly accumulate in the
ischemic lesion 15 days poststroke where potentially they could inhibit
autoimmune responses.43
Increased apoptosis of Tregs, loss of Tregs in peripheral blood, and
impaired suppressive function of the remaining Treg population has been
reported in ischemic stroke patients.53,58,59
However, other studies reported upregulation of Tregs in stroke
patients in spite that decreased Treg function was observed,
particularly in female patients.60 Notably, an increased proportion of Treg cells was reported in the spleen of mice 4 days after transient MCAo.61
NK Cells
NK innate lymphocytes show a rapid and transient increase in the ischemic brain tissue.4,8 A study reported no benefits of depleting NK cells in permanent or transient MCAo.44 In contrast, another study suggested pathogenic actions of NK cells by promoting inflammation and neuronal cytotoxicity.62
This study reported infiltration of NK cells in the ischemic brain
tissue of humans and mice where NK cell numbers peaked as soon as 3
hours postischemia and then declined.62
Interestingly, the β2-nACh-R (nicotinic acetylcholine) receptor seems
to be involved in the NK cell decline observed in the ischemic tissue
from 3 hours postischemia.63
Induced-persistence of NK cells in the ischemic tissue achieved by
interfering with this cholinergic receptor did not modify lesion size
but increased systemic IFNγ (interferon γ), protected from bacterial
infection, and enhanced poststroke survival.63
More studies are needed to validate the putative capacity of brain
infiltrating NK cells to prevent poststroke infection, the role of
central acetylcholine in this process, as well as the suggested rapid
pathogenic effect of NK cells worsening the acute ischemic brain lesion.
Therapeutic Intervention
Strategies
designed to prevent negative actions of leukocytes have been taken to
the clinic in acute ischemic stroke patients but with no success to
date.64 Several studies with drugs blocking the action of neutrophils were investigated.11,64
As an example, the ASTIN trial (Acute Stroke Therapy by Inhibition of
Neutrophils) investigated a compound known as UK-279 276, a recombinant
neutrophil inhibitory factor that selectively binds the CD11b integrin
of macrophage-1 antigen (CD11b/CD18).65
The treatment did not improve recovery above placebo. This trial
followed encouraging results of a few preclinical studies with
UK-279 276 in experimental models of brain ischemia/reperfusion.66 However, only a fifth of patients in the ASTIN trial received tPA.65
Monocyte/macrophages
may acutely exacerbate the inflammatory responses, but experimental
studies have identified their involvement in resolution of inflammation,
vascular protection, and recovery of function,24,27–29
possibly linked to the phagocytic and vasculoprotective roles of these
cells. These protective actions of monocytes are in line with the
beneficial effects of administration of autologous bone marrow–derived
mononuclear cells (MNC) after experimental ischemic stroke.67
MNC contain myeloid and lymphoid cells, as well as hematopoietic and
mesenchymal stem cells. MNC administration 24 hours after MCAo improved
functional recovery, reduced lesion size and proinflammatory cytokines,
and enhanced vessel density and neurogenesis,68 and these benefits were long lasting.69
Furthermore, MNC reduced blood-brain barrier permeability and decreased
the severity of hemorrhagic transformation after tPA in an embolic
stroke model.70 However, MNC therapy did not improve outcome in hypertensive rats.71 MNC reach the periphery of brain infarction soon after administration,68
and then the cells seem to differentiate into smooth muscle cells and
endothelial cells, incorporate into vessel walls, and enhance the growth
of leptomeningeal anastomoses, the circle of Willis, and basilar
arteries.69
Phase I trials administering MNC to ischemic stroke patients have shown
safety, but the clinical efficacy of this cell therapy awaits
demonstration.72
Anti-inflammatory treatments, such as minocycline, have not been successful in the clinic.64 Experimental evidences, including a cross-laboratory preclinical study in mouse models of brain ischemia,73
support the therapeutic potential of the IL-1Ra (IL-1β receptor
antagonist). A recent clinical trial with subcutaneous administration of
IL-1Ra showed safety and reduction of plasma IL-6.74
However, the analysis excluded a major clinical benefit of the
treatment, and negative effects potentially attributable to interactions
of IL-1Ra with tPA became apparent.74
Experimental
studies support damaging effects of T lymphocytes in the acute phase of
stroke. Accordingly, fingolimod, a drug approved for
remitting-relapsing multiple sclerosis that sequesters lymphocytes in
the lymph nodes preventing lymphocyte access to the inflamed tissues,
showed beneficial effects in preclinical studies and small clinical
trials in acute ischemic stroke patients, including patients receiving
thrombolysis.64
By acting on S1P1 (sphingosine-1-phosphate receptor 1), fingolimod
induces sustained lymphopenia, but current data do not show higher
incidence of poststroke infection in patients receiving fingolimod.
Fingolimod also acts on endothelial S1P1 receptor increasing vascular
barrier function that might contribute to the observed benefits of this
drug in ischemic stroke. Given that the benefits of fingolimod seem to
be mediated by S1P1, whereas certain side effects are dependent on other
S1P receptors, selective S1P1 agonists were studied in experimental
stroke showing reduced lesion size after ischemia/reperfusion in mice.75
In contrast to the benefits of blocking T-cell trafficking, systemic
administration of regulatory T lymphocytes in rodent models of ischemic
stroke reduced infarct size, ameliorated the neurological functions,76 and reduced hemorrhagic transformation after tPA.77
Leukocyte
recruitment to inflammatory sites is attenuated by blocking α4β1
integrin (VLA-4 [very late antigen-4]) with natalizumab, an antibody in
clinical use for multiple sclerosis treatment. Blockade of VLA-4 with
CD49d antibody was investigated in a multicentric preclinical study in
mice using 2 different models of cerebral ischemia.78
CD49d antibody attenuated leukocyte infiltration and reduced infarct
volume in small cortical lesions but not in large infarctions.
Natalizumab was investigated in ischemic stroke patients in the ACTION
trial (Effect of Natalizumab on Infarct Volume in Acute Ischemic
Stroke).79
Natalizumab did not meet the primary end point of the study, but
secondary and exploratory end points suggested improvement of clinical
outcomes,64,79
encouraging the second ACTION2 trial. This phase-IIb trial was recently
completed and the notes released by the sponsor (Biogen) state that
natalizumab did not improve clinical outcomes compared with placebo.
Final Remarks
Experimental
studies support detrimental effects of certain types of leukocytes in
acute ischemic stroke. However, to date, this knowledge has not been
translated into clinical treatments. No doubt immunomodulatory
interventions in the acute phase of stroke need fine-tuning and
long-term experimental studies to ensure that repair processes in
subacute and chronic phases are not disturbed and the neurological
deficits are attenuated. Cell therapies based on administration of
autologous MNC have shown promising results in preclinical studies by
promoting functional recovery, but clinical efficacy remains to be
demonstrated. Results of various experimental models of brain ischemia
suggest the possibility that the putative pathogenic contribution of
certain leukocytes to the acute ischemic lesion might differ depending
on lesion severity, regions affected, and degree of reperfusion.
Importantly, most of the studies described above were obtained in young
healthy male mice in spite of the fact that aging, sex, and
comorbidities influence the phenotype and function of immune cells.
Identification of the ischemic conditions where leukocytes might have a
meaningful contribution to the brain lesion, the relevant subsets of
leukocytes, and the time-window for intervention, requires more
investigation. Combining immunomodulatory strategies with reperfusion
therapies offer the opportunity to attenuate negative responses of the
immune system that might impair reperfusion at the microvascular bed or
trigger detrimental effects on the brain tissue.
Acknowledgments
I acknowledge relevant studies used to prepare this article that could not be cited because of word count restriction.
Sources of Funding
Supported by the Spanish Ministerio de Economía y Competitividad (SAF2017-87459-R).
Disclosures
None.
Footnotes
Correspondence
to Anna M. Planas, PhD, Institut d’Investigacions Biomèdiques de
Barcelona (IIBB), Consejo Superior de Investigaciones Científicas
(CSIC), Rosselló 161, Planta 6, 08036-Barcelona, Spain. Email anna.planas@iibb.csic.es
Yuchen Wang
1,2
Mengqi Li
1,2
Qiuhong JI
1*
Zhaofu Sheng
Yang Liu1,2, 
Hongmin Li
V. Wee Yong
Mengzhou Xue