Use the labels in the right column to find what you want. Or you can go thru them one by one, there are only 33,729 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.
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.
Ask your doctor EXACTLY HOW you're going to do more exercise when they haven't gotten you 100% recovered. THIS IS YOUR DOCTOR'S RESPONSIBILITY. Don't let them weasel out of it by quoting the craptastic saying; 'All strokes are different, all stroke recoveries are different.' That lazy excuse should never come out of any competent stroke medical person.
Oops, I'm not playing by the polite rules of Dale Carnegie, 'How to Win Friends and Influence People'.
Telling supposedly smart stroke medical persons they know nothing about stroke is a no-no even if it is true.
Politeness
will never solve anything in stroke. Yes, I'm a bomb thrower and proud
of it. Someday a stroke 'leader' will try to ream me out for making them look bad by being truthful , I
look forward to that day.
In this interview, we speak to Esmée Bakker about her latest
research which investigated the impact physical activity has on
cardiovascular disease.
Please could you introduce yourself, tell us about your background
in physiology, and what inspired your latest research into
cardiovascular disease?
I am a postdoctoral researcher and epidemiologist at the Department
of Physiology at the Radboud university medical center (the
Netherlands). During my Bachelor's and Master’s Biomedical Sciences
degree, I developed a strong interest in cardiovascular/exercise
physiology, physical activity, and epidemiology. Thereafter, I
enthusiastically started a dual Ph.D. position entitled ‘Physical
Activity and Sedentary Behaviour in the Prevention of Cardiovascular
Disease’ at Radboudumc (the Netherlands) and Liverpool John Moores
University (UK).
During my Ph.D. work, I found that CVD patients are generally highly
sedentary and physically inactive. In addition, literature about the
dose-response relationship between physical activity and health was
limited and inconsistent in this population. Therefore, we started this
study where we investigated the dose-response relationship of physical
activity in groups with different cardiovascular health statuses.
Often, moderate physical activity is recommended to help with risk
reduction surrounding non-communicable disease and mortality. Why is
this?
Regular physical activity provides important health benefits by
improving cardiorespiratory fitness, blood pressure, glucose and
cholesterol levels, bone health, balance and coordination, someone’s
mental health, and overcoming weight gain.
By improving these so-called risk factors, physical activity plays an
important role in the prevention of chronic diseases such as
cardiovascular diseases, brain-related diseases, and cancer.
Image Credit: ESB Professional/Shutterstock.com
Until now, the relationship between cardiovascular health status and physical activity has remained unknown. Why is this?
Most studies examining the dose-response relationship between
physical activity and cardiovascular health are performed in the general
population. Some studies were performed in CVD patients, but the
results were inconsistent and studies only included CVD patients. This
is one of the first studies which compared the dose-response association
between different cardiovascular health status groups.
Can you describe how you carried out your latest research into how
cardiovascular health status affects the relationship between physical
activity and health outcomes? What did you discover?
For this study, we used data from the Lifelines cohort, a database
with information of more than 150,000 people of the Northern Provinces
of the Netherlands. Participants of the Lifelines cohort have been
examined very extensively. They have completed various questionnaires,
including one on exercise. We linked this information to data from
Statistics Netherlands and used information from the national death and
hospital registry. This allowed us to examine the relationship between
physical activity and major cardiovascular diseases and mortality.
We
found that for healthy individuals and those with cardiovascular risk
factors, such as hypertension, hypercholesterolemia, and diabetes,
increasing physical activity volumes led to a gradual risk reduction up
to a point at which a plateau occurs. Cardiovascular disease patients
demonstrated a different pattern, however, with every increase in
physical activity volume leading to a further risk reduction of
mortality and cardiovascular events. This finding emphasizes that more
exercise is better for CVD patients.
Your research also discovered that health benefits appear to level
off above a certain level of physical activity in healthy individuals.
Why might this be?
This question is not fully answered yet, but we speculate that
physical activity improves your risk factors until a certain point. When
your blood pressure, glucose, and cholesterol level are healthy and
normal, it will not further decrease after a certain point if you
perform more physical activity.
When we look at the literature, we see that some studies showed a
similar dose-response relationship as we found when they examined the
effects of physical activity on for example diabetes and obesity. This
might explain the plateau phase that we see in our study, in which
individuals do not further improve their health after a certain amount
of physical activity.
However, the point where health benefits appear to level off is
around 4-6 times the international physical activity guidelines, which
advise individuals to perform at least 150 minutes of moderate-intensity
physical activity, or 75 minutes of vigorous physical activity or an
equivalent combination per week. In general, people do not perform these
high volumes of physical activity, so this study finding should not
withhold individuals to be physically active.
Furthermore, in this study, we looked at mortality and major
cardiovascular diseases. If you are physically active to improve your
mental health, you should perform as much physical activity as you like.
Image Credit: santoelia/Shutterstock.com
Were there any limitations to your research? If so, what are they,
and what further research needs to be carried out to further validate
your findings?
The most important limitation of our study was that physical activity
was self-reported. People tend to overestimate their physical activity,
which could result in an overestimation of physical activity volumes in
our study.
In addition, the design of this study was observational. Randomized
controlled trials are necessary to confirm our results, however for
this, we need trials including a large group of people and those people
need to perform physical activity for a long time, which makes it
difficult to perform those studies.
How will your research help individuals suffering from cardiovascular disease?
Hopefully, our study motivates individuals with cardiovascular
diseases to increase their physical activity as much as possible.
Furthermore, the outcomes from this study are useful to further optimize
physical activity recommendations by taking cardiovascular health
status into account, so that every individual, irrespective of
cardiovascular health status, can optimally benefit from a physically
active lifestyle.
Your research has shown that a ‘one-guideline-fits-all’ approach is
not adequate. Why is this and what should be recommended to individuals
instead?
Our study showed that the shape of the dose-response relationship is
different for healthy individuals and those with risk factors compared
to individuals with cardiovascular diseases.
In individuals with cardiovascular diseases, we should encourage that ‘more is better’ regarding physical activity.
What are the next steps for you and your research?
Our study included moderate to vigorous physical activity. In future
studies, I will examine the effect of other types of activities such as
light intensity physical activity, resistance exercise, and reduced
sitting. In addition, I will continue my research in individuals with
cardiovascular diseases.
This paper was part of my Ph.D. thesis which I defended in March
2020. Currently, I work at the Department of Physiology of the Radboud
university medical center (Netherlands) as a postdoctoral researcher,
where I combine physiology with epidemiology.
In the upcoming years, I aim to continue this line of research in
which my long-term goal is to find the best physical activity
prescription to improve cardiovascular health for primary and secondary
prevention.
You have got to be kidding me! There are mentors and senior researchers so fucking out-of-date they allowed this research? But then this the Journal of Integrative Medicine so maybe they don't understand real medicine.
There
is a growing interest in the use of music therapy in neurological
rehabilitation. Of all the major neurological illnesses, stroke
rehabilitation has been observed to have some of the strongest potential
for music therapy’s beneficial effect. The current burden of stroke has
raised the need to embrace novel, cost-effective, rehabilitation
designs that will enhance the existing physical, occupation, and speech
therapies. Music therapy addresses a broad spectrum of motor, speech,
and cognitive deficits, as well as behavioral and emotional issues.
Several music therapy designs have focused on gait, cognitive, and
speech rehabilitation, but most of the existing randomized controlled
trials based on these interventions have a high risk of bias and are
statistically insignificant. More randomized controlled trials with
greater number of participants are required to strengthen the current
data. Fostering an open and informed dialogue between patients,
healthcare providers, and music therapists may help increase quality of
life, dispel fallacies, and guide patients to specific musical
interventions.
Long but really good, if your doctor does nothing with this you don't actually have a doctor, you have someone playing a doctor and not very well. Fire them.
Jianhua Peng,1,2,3,4Dipritu Ghosh,2Jinwei Pang,1Lifang Zhang,5Shigang Yin,2,3,4 and Yong Jiang1,2,3,4
1Department of Neurosurgery, The Affiliated Hospital of Southwest Medical University, Luzhou 646000, China
2Laboratory
of Neurological Diseases and Brain Function, The Affiliated Hospital of
Southwest Medical University, Luzhou 646000, China
3Institute of Epigenetics and Brain Science, Southwest Medical University, Luzhou 646000, China
4Academician
(Expert) Workstation of Sichuan Province, The Affiliated Hospital of
Southwest Medical University, Luzhou 646000, China
5Sichuan Clinical Research Center for Neurosurgery, The Affiliated Hospital of Southwest Medical University, Luzhou 646000, China
Academic Editor: Basak Caner
Received12 Dec 2021
Revised19 Mar 2022
Accepted31 Mar 2022
Published28 Apr 2022
Abstract
In
ischemic stroke (IS), accumulation of the misfolded proteins in the
endoplasmic reticulum (ER) and mitochondria-induced oxidative stress
(OS) has been identified as the indispensable inducers of secondary
brain injury. With the increasing recognition of an association between
ER stress and OS with ischemic stroke and with the improved
understanding of the underlying molecular mechanism, novel targets for
drug therapy and new strategies for therapeutic interventions are
surfacing. This review discusses the molecular mechanism underlying ER
stress and OS response as both causes and consequences of ischemic
stroke. We also summarize the latest advances in understanding the
importance of ER stress and OS in the pathogenesis of ischemic stroke
and discuss potential strategies and clinical trials explicitly aiming
to restore mitochondria and ER dynamics after IS.
1. Introduction
Stroke
is defined as the sudden loss of neurological function because of a
vascular accident and is the leading cause of death and disability
worldwide [1]. The underlying molecular
mechanism in ischemic and hemorrhagic stroke has been extensively
studied. However, morbidity and mortality associated with both
conditions remain high. Ischemic stroke (IS) directly results from
disruption of blood circulation to the brain and makes up approximately
87% of all known cases of stroke [1].
Strategies aiming to reduce damage and disability associated with
ischemic stroke focus on regulating endogenous protective mechanisms,
thus minimizing the postischemic stroke insults. Those novel approaches
are the regulation of endoplasmic reticulum (ER) stress, oxidative
stress (OS), and antioxidant treatment in postischemic stroke
conditions.
The endoplasmic reticulum (ER) is widely distributed
within neuronal dendrites, dendritic spines, axons, presynaptic nerve
terminals, and growth cones and is an essential cellular organelle for
secreted and membrane protein folding [2]. Disruption of this standard mechanism of ER induces a pathological state known as ER stress [3].
ER stress triggers an adaptive response called unfolded protein
response (UPR), which initially leads to inhibition of protein synthesis
followed by later upregulation of protein folding genes and disposal of
misfolded proteins [3]. Transcriptional and
translation aspects of the UPR protect neurons from being overwhelmed by
misfolded ER proteins; however, if the disruption period is prolonged,
the UPR aims towards apoptosis. Unlike other cells in the human body,
postmitotic neuronal cells are highly susceptible to ER stress because
of the loss of replicating power and primarily depend on UPR for its
survival. Similarly, glial cells have homogeneous susceptibility towards
ER stress because of their highly developed secretory pathways.
On
the other hand, OS directly results from excitotoxicity in
cerebrovascular accidents. The release of the neurotransmitter glutamate
has been identified as the primary culprit behind excitotoxicity. Under
the hypoperfusive state, there is a diminished level of oxygen and
glucose, which elevates glutamate release, causing overexcitation of
postsynaptic neurons. Glutamate excitotoxicity has also been associated
with mitochondrial dysfunction, generation of reactive oxygen species
(ROS), reactive nitrogen species (RNS), disruption of calcium
homeostasis, and loss of mitochondrial membrane potential. Severe
mitochondrial damage can further elicit increased levels of ROS and
eventually lead to apoptosis.
This review summarizes the
correlation between ER stress and OS, secondary brain damage as a direct
result of ER stress and OS, potential target therapies, and future
advancement in this field.
2. Pathophysiology of ER Stress and Oxidative Stress after Ischemic Stroke
2.1. Oxidative Stress after Ischemic Stroke
OS
is considered a principal factor of brain injury in cerebrovascular
accidents. Excessive ROS production poststroke is the main culprit
behind OS. Therefore, stroke leads to the peroxidation of lipids,
proteins, and nucleic acids, leading to mitochondrial dysfunction and
DNA damage, which subsequently induces cell death (Figure 1).
2.1.1. The Mechanism Involved in Oxidative Stress after Ischemic Stroke
OS
is defined as an imbalance between oxidants and antioxidants in favor
of the oxidants, leading to a disruption of redox signaling and control
and molecular damage [4]. Despite being
relatively smaller than other vital organs in the body, the human brain
consumes 20% of the total basal oxygen (O2) to support adenosine
triphosphate (ATP) intensive neuronal activity and is highly susceptible
to ischemia. OS has been identified as one of the foremost causes of
brain injury after IS. Transient or permanent disruption of cerebral
blood flow is typical of IS and thereby causes brain tissue injury and
even death. People might argue that restoring blood supply to the
ischemic region might reduce the ischemic insults.
However,
studies showed that restoring the blood supply to the ischemic region
might further escalate the ischemic injury due to many ROS molecules
produced during this process. This paradoxical phenomenon is called
reperfusion injury [5]. ROS molecules play a
crucial role in producing OS-related neuronal damage after IS. There are
three main types of ROS molecules produced during an ischemic insult,
namely, superoxide anion (O2−), hydroxyl radical (OH−), and hydrogen
peroxide (H2O2). After cerebral ischemia, the associated brain damage is
caused by the excessive amount of ROS through (1) interfering with and
inhibition of protein synthesis, along with DNA damage; (2)
mitochondrial structural damage, impairing electron transport chain and
reducing ATP production; (3) lipid peroxidation (LPO) of the unsaturated
fatty acids in the cell membrane; and (4) disruption of the blood-brain
barrier (BBB).
Under physiological conditions, ROS production is
highly scrutinized by the antioxidant system. However, ischemic insults
disrupt the equilibrium in favor of ROS production. The human body
comprises of two antioxidant systems, namely, the enzymatic antioxidant
system, which include superoxide dismutase (SOD), glutathione peroxidase
(GPX), glutathione, and catalase, and the nonenzymatic antioxidant
system, including glutathione, melatonin, carotenoids, vitamin C, and
vitamin D. Thus, stroke-induced OS has mainly been associated with
excess ROS production, and use of antioxidant therapy is advocated in
clinical practice.
2.1.2. Mitochondrial Damage
Mitochondrial damage is an essential pathological event during the early stages of IS [6].
Mitochondria are the primary source of postischemic stroke ROS
generation. The excessive ROS production by mitochondria after stroke
attenuates the electron transport chain, decreases ATP production, and
subsequently damages mitochondrial structure and function. Studies have
been undertaken to determine the involvement of OS and mitochondrial
dysfunction in stroke and found that postischemia reduction in ROS
production protects against OS. Furthermore, mitochondrial ROS
production or mitochondrial OS removal can provide a favorable outcome
in postischemic stroke conditions.
Protein kinase A
(PKA)/cAMP-response element-binding protein (CREB) and
12/15-lipooxygenase (12/15-LOX) have been identified as regulators of
mitochondrial ROS production. Xue and colleagues reported that
activation of PKA triggers CREB phosphorylation, preserves mitochondrial
function, and minimizes ROS production in ischemic conditions, thereby
protecting the cerebral cortical neurons from OS [7]. Similarly, inhibition of the 12/15-LOX pathway has also been identified as beneficial in ischemic conditions [8, 9]. Thus, it is crucial to maintain mitochondrial ROS production to achieve a favorable prognosis in postischemic conditions.
2.2. ER Stress and Response
Under
the ischemic condition, neuronal apoptosis is instigated by
proapoptotic genes, namely, Bcl-2 family members including
Bcl-2-associated X protein (Bax) and Bcl-2 homologous antagonist killer
(Bak), which cause mitochondrial structural damage and enable the
release of cytochrome C. Release cytochrome C interacts with apoptotic
protease activating factor-1 (Apaf-1) to form the apoptosome, and
caspase-9 is activated [10]. Activation of
caspase-9 further creates downstream activation of the caspase-3, which
cleaves poly [ADP-ribose] polymerase 1 (PARP-1), leading to DNA damage.
Overactivation of PARP-1 harms ATP and nicotinamide adenine dinucleotide
(NADH) production, which translates into energy failure and cellular
necrosis [11]. Similarly, histone methylation
of p53 has been closely associated with apoptosis in postischemic
stroke, and demethylation of the methylated histone is catalyzed by
Jumonji domain-containing proteins (JMJD) family. Among them, JMJD3 has
been more associated with Bax and caspase-3 and is expressed throughout
the brain, including neurons [12].
ER acts as the primary site for the processing and folding newly synthesized proteins and plays a critical role in calcium (Ca2+) storage and signaling. Depleting ER Ca2+ and OS can trigger impairment of ER function and activate UPR. Under chronic ER stress, UPR evokes cellular apoptosis [13]. Thus, ER stress plays a critical role after IS.
2.2.1. Unfolded Protein Response
The
UPR mainly serves to restore ER function by inhibiting protein
synthesis, disposal of misfolded proteins, and later upregulation of
protein folding genes. The activation of UPR response is triggered by
protein kinase RNA-like endoplasmic reticulum kinase (PERK), activating
transcription factor 6 (ATF6), and inositol-requiring kinase 1α (IRE1α). PERK, ATF6, and IRE1α under the physiological condition in neurons interact with Grp78. ER dysfunction results in phosphorylation of PERK and IRE1α and cleavage of ATF6 (P90) to ATF6 (P50) [14]. Activated PERK phosphorylates eukaryotic factor 2a (elF2α), which suppresses global protein synthesis and activates transcription factor 4 (ATF-4).
Under prolonged ER stress, PERK activation and subsequent elF2α
phosphorylation elevate ATF4, inducing cell death by upregulation of
Bcl-2 family members and the critical transcription factor C/EBP
homologous protein (CHOP), which in turn regulates transcription of
Bcl-2 family members. Wang et al. reported that PERK-mediated p-eIF2α suppresses protein synthesis in the postischemic brain, neuroprotective in experimental stroke. Thus, PERK activation or elF2α
phosphorylation plays a crucial role in determining the cellular fate
by alternating the levels of apoptosis after IS. Furthermore,
caspase-12, an ER membrane-associated caspase, is upregulated by
glutamate excitotoxicity, which facilitates caspase cascade, further
provoking cellular death.
Munoz and colleagues identified that PERK is a crucial regulator of mitochondrial function and morphology during ER stress [15]. Similarly, Ca2+ and glutamate have also been an intertwined relation in ER stress and mitochondrial dysfunction in ischemic conditions [16]. Therefore, we can determine the central regulators of OS and their correlation with mitochondrial dysfunction and ER stress.
2.2.2. ER Stress Link to Inflammation and BBB Disruption
In
the central nervous system, the close link between ER stress and
inflammation is likely to contribute to the integration of metabolic
homeostasis and ER function. Inflammatory response limits tissue damage
and facilitates tissue repair under ER stress. However, prolonged stress
will directly link inflammation with cell death. After ischemic events,
UPR seeks to inform cells in disordered homeostasis through
inflammatory pathways, which is very important to reduce the innate
immune response to ER stress [17]. ER stress
determines cell fate through several previously reported inflammatory
response-related pathways, including toll-like receptors (TLR) signaling
pathway, nuclear factor κB (NF-κB) signaling pathway, Jun
N-terminal kinase/activator protein 1 (JNK/AP1) signaling pathway, and
mitogen-activated protein kinase (MAPK) signaling pathway [18].
As
a vital organelle for protein secretion and modification, disruption of
proper ER function leads to the impairment of UPR and leads to the
abnormality of cell structure and function. Ischemic conditions trigger
ER stress, which triggers UPR and ER to enter a pathological state with
Ca2+ equilibrium loss. In contrast, Ca2+ overload in endothelial cells has been identified as the main factor of cerebral swelling and BBB disruption [19].
Cerebral edema and BBB disruption occur quickly after IS, causing
intracellular swelling, and subsequently, cerebral edema enters the
stage of ionic and vasogenic edema. Thus, effective treatment of ER
stress is particularly crucial for BBB integrity and cerebral edema.
3. Pharmacological Therapies
Current
clinical treatment of IS primarily focuses on the acute and subacute
stages of the injury process. The critical stage of the disease is
defined as the time frame within 4.5 hours from the appearance of the
first symptoms. However, current guidelines on thrombolytic [20] and endovascular [21]
treatment are limited to various factors such as economic level or
uneven understanding of stroke, and the proportion of patients who can
receive thrombolysis or endovascular therapy within 4.5 or 6 hours is
still deficient. On the other hand, patients receiving thrombolysis or
mechanical thrombectomy within the said window of time still may suffer
from secondary brain injury [22]. Therefore, finding and developing new therapeutic targets demise secondary brain injuries (Table 1).
3.1. Mitochondria as a Potential Target
Mitochondria
are the main source of postischemic stroke intracellular ROS
generation. Changes in ROS levels affect the expression or activity of
proteins associated with mitochondrial dynamics, which in turn affects
mitochondrial fusion and division [23].
Mitochondrial fission divides mitochondrion into two smaller
mitochondria and is regulated by dynamin-1-like protein (Drp1).
Mitochondrial fission conventionally occurs at the ER-mitochondrial
contact site. During ischemic conditions, an increase in ROS level
promotes Drp1 activation through phosphorylation of Ser616 [24].
Interestingly, Drp1 serine 637 phosphorylation inhibits mitochondrial
fission. Phosphorylation of Drp1 at tyrosine 266, 368, and 449 leads to
mitochondrial division and neuronal death [25].
Zhang and colleagues demonstrated that mitochondrial division increases
the production of ROS. However, inhibition of mitochondrial division
can restore ROS levels to normal [26]. Mitochondrial division is Drp1-dependent, and knock out (KO) of Drp1 reduces OS-induced mitochondrial fragmentation [27].
Interestingly, inhibition of Drp1 also reduces the oligomerization of
Bax and apoptotic factors after IS, thereby reducing cerebral infarction
volume [28].
3.1.1. Treatment Targeting Mitochondria after Ischemic Stroke
Mitochondrial
dynamics after IS are closely linked to failure in energy metabolism,
ROS, apoptosis, and autophagy. Therefore, the molecular mechanisms
associated with mitochondrial dynamics are essential to be targeted to
produce a favorable prognosis in postischemic stroke patients.
Zhou
and colleagues demonstrated that atractylenolide III and AG490
(inhibitor of JAK2) therapy in middle cerebral artery occlusion (MCAO)
mice reduces Drp1 phosphorylation (p-Drp1), translocation, and
mitochondrial division through Janus kinase 2/signal transducer and
activator of transcription 3 (JAK2/STAT3) pathway, thereby attenuating
cerebral edema and neurological deficits [29].
Like Drp1, OPA1 (OPA1 mitochondrial dynamin-like GTPase) is essential
for mitochondrial fusion, reducing infarct size, inhibition of neuronal
death, and reducing cerebral reperfusion stress through the Yap-Hippo
pathway [30]. Under cobalt chloride-induced
hypoxia in the mouse hippocampal cell culture, a decrease in Opa1 and
p-Drp1 levels was observed. Treatment with
4-chloro-N-(naphthalen-1-ylmethyl)-5-(3-piperazin-1-ylphenoxy)
thiophene-2-sulfonamide (B355252) restores levels of Opa1 and p-Drp1,
preserves mitochondrial stability, restores mitochondrial membrane
potential, and reduces ROS production [31].
Other potential treatment options include miR-7a-5p injections after cerebral ischemia, which can subdue α-synuclein. α-Synuclein promotes mitochondrial fragmentation, OS, autophagy, and promote neuronal death. Thus, subduing α-synuclein levels with miR-7a-5p injections after IS can be beneficial [32].
In a mouse model of bilateral common carotid artery occlusion,
subcutaneous injection of granulocyte colony-stimulating factor (G-CSF)
could reduce autophagy marker Beclin-1 and apoptosis-related proteins,
such as Bax, Bak, and Drp1. However, G-CSF also promotes mitochondrial
fusion protein, Opa1. Consequently, G-CSF maintains mitochondrial
dynamics by reducing apoptosis and protecting neurons in cerebral
ischemia [33]. Nitric oxide synthase 3 (NOS3) inhibitor regulates mitochondrial Rho GTPase2 levels, thus promoting axon functional recovery.
However,
the clinical application of these potential target therapies is
subjected to further in-depth studies assessment in terms of efficacy,
toxicity studies, and clinical trials. Thus, a potential target therapy
answering all the underlying postischemia disruption can be expected in
the near future.
3.2. ER as a Targeted Treatment
Autophagy
is defined as the process of degradation of worn-out proteins, damaged
organelles, and misfolded proteins through a lysosome-dependent
regulation mechanism to maintain cellular homeostasis. As discussed
earlier, ischemic conditions trigger ER stress, which triggers UPR and
ER to enter a pathological state with Ca2+ equilibrium loss.
This signifies ER stress in tight association with autophagy within the
central nervous system. The ER stress is associated with autophagy
through three signaling pathways, namely, PERK, ATF6, and IRE1α [34].
Therefore, regulating these key pathways may provide an expected
outcome by minimizing cellular loss in postischemic conditions.
3-Methyladenine
(3-MA) is a phosphatidylinositol 3-kinases (PI3K) inhibitor. PI3K
controls mTOR activation, a key regulator of autophagy [35].
However, 3-MA is showcased to aggravate cerebral ischemia-induced ER
stress and increase activated proapoptotic caspase-12 and caspase-3
protein levels in vivo and vitro [36].
Interestingly, it reduced the expression of autophagy genes and
autophagy and UPS co-regulatory genes. The positive outcome of 3-MA can
be attenuated by using an autophagy inducer, rapamycin, during
hypoxia-reoxygenation-induced brain injury [37].
ER stress-induced by tunicamycin and thapsigargin has been documented to protect against ischemic brain injuries [38].
Preischemic stroke melatonin treatment was reported to reduce acute
neuronal injuries through inhibiting ER stress-dependent autophagy via
PERK and IRE1 signaling pathways [39]. However,
other research showcases the complexity of crosstalk between ER stress
and autophagy in IS. Neither reduction of ER stress nor enhancing
autophagy have a neuroprotective effect in neurons under ischemic
conditions [40]. Because of the discrepancy and
unknown molecular mechanism between ER stress and autophagy, in-depth
studies need to be conducted. Nevertheless, ER stress remains a critical
factor in IS.
3.2.1. Treatment Options for Endoplasmic Reticulum Stress
Hairy
and enhancer of split 1 (Hes1) have been identified as a regulator of
ER stress. A study by Li and colleagues showed that knocking down Hes1
aggravates IS in the temporary middle cerebral artery occlusion model by
ER stress-dependent apoptosis via PERK/elF2α/ATF4/CHOP signaling pathway [41].
Similarly, Homer1a, a short scaffold protein overexpression, was
illustrated to preserve mitochondrial function by regulating cytochrome c
release, less ROS production, reduced ATP and mitochondrial membrane
potential loss, decreased caspase-9 activation, and inhibition of ER
stress by inhibiting the PERK pathway [42]. Therefore, Hes1 and Homer1a might be potential target treatment opportunities.
Over
the years, microRNA (miR) studies have established themselves as a
crucial factor in postischemic stroke conditions as target treatments.
miR-9-5p has been shown to attenuate IS by targeting endoplasmic
reticulum metallopeptidase 1 (ERMP1), thus minimizing ER stress in the
MCAO rat model [43]. Similarly, upregulation of miR-216a provides neuroprotection against ischemic injury by negative regulation of JAK2/STAT3 [44]. Dong and colleagues exemplify the role of miR-7 in ER stress through HERPUD2 [45]. However, like other forms of target treatments, the data gathered does not proceed with their use in clinical practice.
Posiphen
is a stereoisomer of the acetylcholinesterase inhibitor phenserine, and
it has implicated its use in mild cognitive impairment and Alzheimer’s
disease [46]. Recently, studies have shown the beneficial role of Posiphen in the reduction of ER stress [47], and combined therapy with pifithrin-α enhances neurogenesis and functional recovery after IS [48].
Although Posiphen has substantial evidence implicating potential use in
the early phase of postischemic stroke in favor of the desired
prognosis, yet, the studies fail to imply the prognostic value of
Posiphen use in the late stage of postischemic stroke.
Celecoxib
is a well-known anti-inflammatory, recently proclaimed to reduce ER
stress by decreasing the expression of glucose-related protein 78
(GRP78), CHOP, and caspase-12 after 48 hours of reperfusion.
Additionally, celecoxib was also showcased to enhance the IRE1-UPR
pathway, further reducing ER stress [49].
Several
other potential targets can be listed to reduce ER stress after and
before the IS. Still, for this review, we focus on the possible target
treatment that satisfies our target pathways and keeps the review simple
for the reader’s digestion.
3.3. Reactive Oxygen Species
After
an intracerebral ischemic accident, the most sensible treatment option
is to restore the blood supply in the ischemic region. However, by doing
so, the patients are subjected to a paradoxical phenomenon known as
ischemic reperfusion injury (IRI). It has been postulated that IRI is
closely associated with an increase in OS by upregulating ROS
production. Although ROS plays an essential role in intracellular
signaling and immune response, cellular antioxidants cannot scavenge
redundant ROS production, creating many pathological responses and
ultimately cellular damage [50]. To minimize IRI, the administration of antioxidant reagents for scavenging ROS has been widely applied.
3.3.1. Antioxidant Treatment after Ischemic Stroke
Antioxidant
treatment to regulate global ROS production is a viable strategy for
treating IS. After a cerebrovascular accident, cyclooxygenases and
mitochondria generate ROS due to their enzymatic activity; however, ROS
generation is the principal function of the NADPH oxidase (NOXs) family
NOX2 and NOX4 activity which is the major contributor of OS following a
cerebrovascular accident [51].
Inhibiting
NOXs may be an efficient strategy for minimizing ROS-related cellular
damage. Apocynin, a naturally occurring NOX inhibitor, was showcased to
decrease infarct volume by reducing the level of apoptosis and
inhibiting OS. However, the therapeutic window for apocynin is narrow [52].
Other known NOX inhibitors include Gp91ds-tat and ebselen; however,
their use postischemia is highly scrutinized because of the low oral
bioavailability, associated side effects, and nonspecific nature [53, 54].
Even with substantial drawbacks, a placebo-controlled, double-blinded
clinical trial was conducted on 300 patients diagnosed with acute IS
(< 48 hours) to determine the efficacy of ebselen. The trial
concluded with the verdict that the use of ebselen 300 mg/d,
administered within 24 hours, produces a favorable outcome in patients
with IS [55]. Even though with clear
indications of a favorable outcome and little to no side effects,
ebselen remains debatable. NADPH oxidase inhibitors are promising
treatment options but are need to be subjected to further experimental
studies.
With recent development in the mode of delivery of drugs,
nanomedicine has gained popularity in producing specific ROS scavenger
effects with a promising prognosis. The efficacy of nanomedicines is
highly associated with the types of material the delivery vessel is made
of. t-PA@iRNP is a thrombolytic and antioxidant nanomedicine that
encapsulates tissue plasminogen activator (t-PA) in conjugation with
4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl (4-amino-TEMPO), size of
∼50 nm, and pH acidic trigger of 6.2. Administration of t-PA@iRNP
provides dual benefits of thrombolytic activity and a significant
decrease in ROS production in the MCAO mice model. Furthermore, the
antioxidant effect of 4-amino-TEMPO efficiently avoids subarachnoid
hemorrhage induced by t-PA, providing potential dual therapy via
synergic effect [56, 57].
Polyoxometalate (POM) nanoclusters are also novel bioresponsive
nanomaterial containing molybdenum ions (Mo5+ and Mo6+). Intrathecal
administration of POM in rats reduces IRI-induced OS, apoptosis, edema,
and infarct volume of the brain up to ∼50% [58]. The practical and precise use of nanomedicine can provide a new avenue for future treatment options.
4. Clinical Studies
Clinical
studies or clinical trials are prospective biomedical research studies
on human patients to determine the dosage, safety, and efficacy of a new
potential treatment. Over the years, several trials were conducted to
determine effective treatment options for IS. However, because of the
complicated and intertwined pathophysiological mechanism of IS, an
effective treatment option is yet to be discovered.
As mentioned earlier, G-CSF maintains mitochondrial dynamics by reducing apoptosis and protecting neurons in cerebral ischemia [33]. However, phase ΙΙ trial on forty-nine acute IS patients administered with 150 μg/body/day and 300 μg/body/day
of G-CSF within 24 hours of the onset of symptoms did not show
functional recovery or reduction in infarct volume at 3 months after
onset, compared to the placebo group [58]. The
investigators suspect that the lack of effectiveness of G-CSF is due to
the small sample size and plans to conduct further trials as combination
therapy with t-PA. However, with a long-standing history of G-CSF
trials, no clinical trial data published to date were able to show
significant triumphant effects of G-CSF treatment in a large cohort of
IS patients.
Glutamate, a neurotransmitter, has been identified as
the main culprit behind excitotoxicity. Glutamate excitotoxicity has
also been associated with mitochondrial dysfunction, ROS generation,
RNS, calcium homeostasis disruption, and mitochondrial membrane
potential loss. One of the suggested methods of attenuating glutamate
excitotoxicity is blocking the N-methyl-D-aspartate (NMDA) receptor.
Caffeinol (a combination of a low dose of caffeine and ethanol) was
demonstrated to have an anti-ischemic property through the NMDA
antagomir effect [59]. A clinical trial carried
on twenty IS patients, treated with a combination of caffeinol
(caffeine 8-9 mg/kg + ethanol 0.4 g/kg intravenously, started by 4 hours
after symptom onset), hypothermia, and t-PA, suggest feasible treatment
approach with no adverse effects towards caffeinol [60].
However, the trial failed to demonstrate the prognostic effect of the
said combination treatment compared to placebo. It mainly focused on the
feasibility and tolerability, thus, creating concern regarding the
necessity of the said complex approach.
ROS scavenger compounds
have powerful implications in postischemic stroke conditions to minimize
the OS and prevent secondary brain damage. One such promising scavenger
compound is edaravone, a member of the substituted 2-pyrazolin-5-one
class [61]. A newer form, edaravone dexborneol,
produced a more favorable functional outcome among female patients with
acute IS in a multicenter, randomized, double-blind, comparative, phase
III clinical trial compared to edaravone when administered within 48
hours of the onset of symptoms [62]. Xu and
colleagues also demonstrated dose-depended functional recovery of the
edaravone dexborneol group compared to the edaravone group with a higher
modified Rankin score (mRSscore) in medium-dose (37.5 mg by 30-min
intravenous infusion every 12 hours, for 14 consecutive days) group [63].
Recently,
the role of iron as a target to prevent stroke-induced ROS-depended
neurodegeneration was put under the spotlight due to new emerging
evidence showing that regulation of ferroptosis in the ischemic brain
parenchyma is protective in experimental IS [64, 65].
A double-blinded, randomized, placebo-controlled, dose-finding phase II
clinical trial of intravenous deferoxamine along with t-PA in acute IS
patients (
)
was carried out to evaluate the safety, tolerability, and therapeutic
efficacy of iron chelator deferoxamine mesylate (DFO). Participants were
randomly divided into placebo, 20 mg/kg/day DFO, 40 mg/kg/day DFO, and
60 mg/kg/day DFO group with primary t-PA treatment. Continuous placebo
administration and all DFO arms were initiated during t-PA infusion and
carried out for 72 hours. Iron saturation was determined using blood
transferrin levels. A positive trend to efficacy was observed in
moderate-severe IS patients (NIHSS >7) receiving 40-60 mg/kg/day DFO
with 50-58% good outcome at 90 days compared to 31% in the placebo group
[66].
While discussing some of the
previous clinical studies, it is appropriate to talk about some of the
propitious ongoing studies as well. Various multifactorial aspects of IS
are still under examination. For instance, a multicenter, prospective,
randomized, open-label, blinded end-point (PROBE) trial is being carried
out to determine the efficacy of exenatide in acute IS patients.
Exenatide is a glucagon-like peptide-1 receptor (GLP1R) agonist, widely
used as a medication to treat diabetes mellitus type 2. Postischemic
stroke hyperglycemia occurs in 50% of the patients, reducing
thrombolysis efficacy, increasing the risk of hemorrhage, and increasing
infarct size, translating into a poor prognosis in patients. The
proposed mechanism of action of exenatide in acute IS conditions is to
reduce OS, inflammation, and edema. The primary outcome of the study is
to measure the improvement in the neurological outcome of patients
administered with exenatide within 9 hours of the onset of symptoms (5 μg subcutaneously twice daily for five days) along with standard treatment protocols (NCT03287076).
As mentioned earlier, overactivation of PARP-1 due to caspase cascade results in energy failure and cellular death [13],
and inhibition of PARP-1 can be beneficial. JPI-289 is a PARP-1
inhibitor, which was shown to reduce infarct volume and improve
neurological function and neuroprotection in the MCAO animal study model
[67]. The positive outcome in the animal study
model has led to a multicenter, randomized, double-blind,
placebo-controlled, phase IIa clinical trial to evaluate the efficacy
and safety of JPI-289 in acute IS patients. The primary aim of the study
is to determine the infarct growth ratio from the initial presentation
(4 days from the initial presentation). Patients will be administered
with JPI-289 within 6.5 hours from the initial symptom development along
with standard treatment protocols (NCT03062397).
The
complexity of the previous NMDA receptor inhibition approach using a
combination of caffeinol, hypothermia, and t-PA is not feasible under
clinical settings because of the highly sophisticated nature of the
procedure with constant monitoring and also maybe due to failure in
obtaining consensus from the patient’s family.
2-Hydroxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethyl-benzylamino)-benzoic
acid (Neu2000) is a derivate of aspirin and sulfasalazine, showcased to
prevent both NMDA neurotoxicity and OS with a single bolus in the MCAO
animal study model [68]. However, the safety
and efficacy of Neu2000 in human IS patients have not been explored. A
phase II, double-blind, randomized, placebo-controlled, multicenter
study was undertaken in South Korea (2016) to determine the safety and
efficacy of Neu2000; however, the study has not published the trial
results so far (NCT02831088) (Table 2).
The
Inconsistency in the outcome of the treatment options is due to the
challenge of enrolling a sufficient number of representative patients
with comparable characteristics and differences in patient demographics.
The difference in demographics translates into a difference in genetic
and habitual behavior. So, to determine a dose-dependent
multidemographic prognostic value of a potential drug, large
multicenter, randomized, double-blinded cohort studies need to be
carried out.
5. Prospective and Conclusion
In
this review, we have summarized new advancements in recent years
concerning the mechanisms of brain ischemia, ER stress, and OS. As
outlined above, UPR, mitochondrial damage, and ROS production are the
main focus of ischemic redox research. It is clear that ER stress, OS,
and ROS exert significant effects in the process of secondary cerebral
ischemic damage, and the difference in severity determines the
prognostic outcome in the postischemic stroke conditions. What is
interesting is the fact that ER stress and OS are a double-edged sword.
Therefore, re-establishing cellular homeostasis after an ischemic
incident needs to be carried out with caution.
Perhaps the answer
to ischemic redox stress may lie within the epigenetic aspect of the
research. IS is a complex, multifactorial disease in which a wide
plethora of pathological processes are simultaneously set in motion, and
modulation of a single molecular factor is unlikely to be sufficient to
attenuate or reverse the progression of stroke pathology. Epigenetic
alterations such as DNA methylation, histone modifications, and RNA
modifications are potent modulators of gene regulation. An accumulating
body of evidence suggests that they play a pivotal role in regulating
brain remodeling after stroke [69–71]. Further efforts are being made to understand the underlying epigenetic regulation in IS [72, 73].
Because of the complexity of IS, we speculate that epigenetics research
is still at its inception point, and prolonged, in-depth studies are
required before we find an answer to IS.
On the other hand, the
nanomedicine drug delivery system is a promising treatment option,
especially t-PA@iRNP. In the hyperacute stage of IS, administration of
t-PA is advocated for qualified patients in clinical practice because of
the sentimental nature of the drug [74].
Various combination therapy with t-PA have been suggested over the
years, but none like t-PA@iRNP. If t-PA@iRNP can prove its proclaimed
prognostic effect in clinical trials [56], there is a chance of potentially safer treatment option in the hyperacute stage of IS.
Remote
ischemic conditioning (RIC) is a process by which cycles of temporary
ischemia, typically through a manual or electronic tourniquet, applies
to a limb above systolic blood pressure, which confers systemic
protection against future ischemic attack injuries in remote vascular
territories. RIC is popularized as a viable treatment approach for IS in
recent years. RIC is an experimental medical procedure that aims to
boost the body’s natural protection mechanism against tissue injury
under ischemic conditions to reduce the severity of the ischemic injury.
Although RIC has been shown to reduce infarct size and improve
functional outcomes in the experimental animal models [75],
it is still an experimental procedure in human beings, and large-scale
trials are necessary to determine the true benefits. Many clinical
studies are being carried out in different countries to evaluate the
viability of RIC in the different ischemic populations (NCT03868007, NCT03740971, NCT03481777, and NCT03375762). We speculate that these ongoing clinical studies will provide sufficient knowledge to establish the viability of RIC in IS.
In
conclusion, IS is a multifactorial, multilevel complex disease
involving a plethora of ROS and ER stress processes. The treatment
method for such a disease cannot be one-dimensional. Future research
studies need to understand the multifactorial nature of IS and the
feasibility of treatment options in clinical settings.
Aberrant
neurogenesis is a major factor in psychiatric and neurological
disorders that have significantly attracted the attention of
neuroscientists. Curcumin is a primary constituent of curcuminoid that
exerts several positive pharmacological effects on aberrant
neurogenesis. First, it is important to understand the different
processes of neurogenesis, and whether their dysfunction promotes
etiology as well as the development of many psychiatric and neurological
disorders; then investigate mechanisms by which curcumin affects
neurogenesis as an active participant in pathophysiological events.
Based on scientometric studies and additional extensive research, we
explore the mechanisms by which curcumin regulates adult neurogenesis
and in turn affects psychiatric diseases, i.e., depression and
neurological disorders among them traumatic brain injury (TBI), stroke,
Alzheimer’s disease (AD), Gulf War Illness (GWI) and Fragile X syndrome
(FXS). This review aims to elucidate the therapeutic effects and
mechanisms of curcumin on adult neurogenesis in various psychiatric and
neurological disorders. Specifically, we discuss the regulatory role of
curcumin in different activities of neural stem cells (NSCs), including
proliferation, differentiation, and migration of NSCs. This is geared
toward providing novel application prospects of curcumin in treating
psychiatric and neurological disorders by regulating adult neurogenesis.
I go to live music, mostly jazz, as often as possible. A major failure point is the total inability to use both hands to clap. One handed clapping against my thigh is ridiculous and quiet. I should be able to go to any occupational therapist in the world and have EXACT PROTOCOLS that will fix my hand.
Last night was at Red Cedar Spirits:
Randy Napoleon on guitar; Associate Professor of Jazz Guitar
at MSU(Michigan State University)
Rodney Whitaker on bass;Director of Jazz Studies at MSU(Michigan State University)
Eric Law; Outstanding Alto Saxophone at the Jack Rudin Jazz Championship
This is what my left hand looks like 5 seconds after opening it with my right hand. Wrist and finger spasticity have completely kicked in making clapping impossible
Complications
such as cognitive impairment are common in stroke victims. The goal of
this study was to see if there was a link between blood iron levels and
post-stroke cognitive impairment (PSCI) within 2 weeks after stroke.
Methods
A
total of 313 patients with ischemic stroke were recruited and separated
into two groups: PSCI (n = 202) and non-PSCI (n = 111). The Mini-mental
state examination scale was used to evaluate the cognitive status
within 2 weeks after stroke (acute phase). The serum iron levels were
divided into 4 layers: Q1 ≤ 11.7 μmol/L, Q2 11.8-15.1 μmol/, Q3
15.2-19.3 μmol/L, Q4 ≥ 19.4 μmol/L, respectively. The connection between
serum iron and PSCI was then investigated further using binary logistic
regression, which was adjusted for confounders.
Results
The
difference in serum iron levels between the PSCI and non-PSCI group was
initially conducted by the Mann-Whitney test, and a significant
difference was found (14.5 (11.0-17.8) vs. 16.9 (13.7-21.8), p <
.001), with no confounders being adjusted. After adjusting for
confounding factors, the binary regression analysis showed that the Q4
layer showed the lowest risk of PSCI, with the Q1 layer being the
reference. (odds ratio (OR) = 0.297, 95% confidence interval (CI) =
0.136-0.649, p = 0.002).
Conclusion
A
decreased risk of early-onset PSCI was linked to high serum iron
levels. Low serum iron levels were found to be a risk factor for acute
cognitive impairment following stroke, which could help physicians
identify and take intervention measures early to reduce the risk of
cognitive impairment after stroke.
Tandem lesion (or tandem occlusion) is a
term used in cerebrovascular imaging and intervention to refer to the
simultaneous presence of high-grade stenosis or occlusion of the
cervical internal carotid artery and thromboembolic occlusion of the
intracranial terminal internal carotid artery or its branches, usually
the middle cerebral artery1.
Correspondence to
Dr Francesco Diana, Neuroradiology, University Hospital 'San Giovanni
di Dio e Ruggi d’Aragona', 84131 Salerno, Campania, Italy; francesco.diana.md@gmail.com
Abstract
Background
Emergent carotid artery stenting (eCAS) is performed during mechanical
thrombectomy for acute ischemic stroke due to tandem occlusion. However,
the optimal management strategy in this setting is still unclear.
Objective
To carry out a systematic review and meta-analysis to investigate the
safety and efficacy of eCAS in patients with tandem occlusion.
Methods
Systematic review followed the PRISMA guidelines. Medline, EMBASE, and
Scopus were searched from January 1, 2004 to March 7, 2022 for studies
evaluating eCAS and no-stenting approach in patients with stroke with
tandem occlusion. Primary endpoint was the 90-day modified Rankin Scale
score 0–2; secondary outcomes were (1) symptomatic intracerebral
hemorrhage (sICH), (2) recurrent stroke, (3) successful recanalization
(Thrombolysis in Cerebral Infarction score 2b–3), (4) embolization in
new territories, and (5) restenosis rate. Meta-analysis was performed
using the Mantel-Haenszel method and random-effects modeling.
Results
Forty-six studies reached synthesis. eCAS was associated with higher
good functional outcome compared with the no-stenting approach (OR=1.52,
95% CI 1.19 to 1.95), despite a significantly increased risk of sICH
(OR=1.97, 95% CI 1.23 to 3.15), and higher successful recanalization
rate (OR=1.91, 95% CI 1.29 to 2.85). Restenosis rate was lower in the
eCAS group than in the no-stenting group (2% vs 9%, p=0.001).
Recanalization rate was higher in retrograde than antegrade eCAS
(OR=0.51, 95% CI 0.28 to 0.93). Intraprocedural antiplatelets during
eCAS were associated with higher rate of good functional outcome (60% vs
46%, p=0.016) and lower rate of sICH (7% vs 11%; p=0.08) compared with
glycoprotein IIb/IIIa inhibitors.
Conclusions
In observational studies, eCAS seems to be associated with higher good
functional outcome than no-stenting in patients with acute ischemic
stroke due to tandem occlusion, despite the higher risk of sICH.
Dedicated trials are needed to confirm these results.
Data availability statement
All data relevant to the study are included in the article or uploaded as supplementary information. Not applicable.
