Use the labels in the right column to find what you want. Or you can go thru them one by one, there are only 34,264 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.
Duke researchers developed an injectable scaffold that helped stroke-damaged brains grow new blood vessels, support nerve regrowth, and recover movement in mice. The treatment appears to work partly by recruiting the body’s own immune cells, including neutrophils that may switch from damaging to helpful under the right conditions.
Do you really think anyone in stroke is competent enough to get stroke testing going? I don't, everything in stroke IS A COMPLETE FUCKING FAILURE!
Prove me wrong; failure is defined as not getting to 100% recovery!
Don't try your tyranny of low expectations on me. Here;
oc1dean@gmail.com, I'll print it verbatim with my reply. Have at it, or
are you afraid to engage with a stroke-addled survivor?
Of course your competent? doctor can inform these researchers of earlier protocols they already created on these.
The combined function of 3D-printed collagen/silk fibroin (3D-CS) scaffolds with injury-preconditioned exosomes obtained from human umbilical cord mesenchymal stem cells (hUCMSCs) in traumatic brain injury repair remains unclear. Here, we demonstrate that exosomes produced from hUCMSCs preconditioned with brain trauma extracts have a neuroprotective effect on a craniocerebral trauma model in beagles. Notably, injury-preconditioned exosomes generated by hUCMSCs combined with 3D-CS scaffolds markedly promoted neuroregeneration and angiogenesis after TBI. Injury-preconditioned exosomes combined with 3D-CS scaffolds also alleviated both the proinflammatory factor-induced apoptosis and nerve apoptosis induced by injury in vivo. We further showed that the joint action of injury-preconditioned exosomes combined with 3D-C/S scaffold-induced neurorepair ultimately promoted the recovery of neurological dysfunction after traumatic brain injury. In summary, this study reveals the cofunction of injury-preconditioned exosomes and 3D-CS scaffolds in response to traumatic brain injury and suggests a potential therapeutic strategy.
Visual Abstract
The combined function of 3D-printed collagen/silk fibroin (3D-CS) scaffolds with injury-preconditioned exosomes obtained from human umbilical cord mesenchymal stem cells (hUCMSCs) in traumatic brain injury repair remains unclear. Here, we...
Do you really think anyone in stroke is competent enough to get human testing going? I don't, everything in stroke IS A COMPLETE FUCKING FAILURE! Prove me wrong; failure is defined as not getting to 100% recovery! Don't try your tyranny of low expectations on me. Here; oc1dean@gmail.com, I'll print it verbatim with my reply. Have at it, or are you afraid to engage with a stroke-addled survivor?
Of course your competent? doctor can inform these researchers of earlier work.
When someone has a stroke caused by a blood clot, doctors can quickly restore blood flow. However, they can’t easily replace the brain tissue that gets lost. Recovering this tissue usually means relying on rehab to help the remaining brain circuits adapt.
A team of biomedical engineers at Duke University has built an injectable biomaterial that could change stroke recovery.
Rebuilding the Brain’s Neighborhood
The research team isn’t attempting to rebuild the brain directly. Instead, they are setting up a scaffolding system to let the body do the work for them. They achieve this system using tiny hydrogel microparticles called MAPS. When the material is injected into the cavity caused by a stroke, it creates a porous structure for cells to grow on.
“Once brain tissue has been lost, restoring blood flow is no longer enough,” said Tatiana Segura, the Robert Plonsey Distinguished Professor of Biomedical Engineering at Duke. “Our goal is to engineer the injured space so that immune, vascular, and neural repair processes can begin to work together.”
The team attached specific signals to these particles so that the body’s immune cells could help. These signals come from astrocytes, which are star-shaped cells in the brain.
“We are not simply placing a material into the brain,” Segura added. “We are engineering a local environment that can coordinate several parts of the repair response.”
Surprising Helpers
The team found that certain signaling molecules attracted helpful immune cells, including the most common type of white blood cell: neutrophils. Usually, neutrophils cause inflammation right after a stroke. However, that wasn’t the case in this scenario.
“This result changes how we think about neutrophils after stroke,” said Shangjing Xin, lead scientist of the study and a postdoctoral fellow in the Segura Laboratory. “Their role appears to depend on when they arrive, where they are located, and the signals they receive from their surroundings. Our study demonstrates a potential engineering strategy to recruit and retain these cells at the right time.”
In mouse tests, this treated scaffold helped grow new blood vessels and improved movement. By eight weeks, the mice performed like healthy controls on a coordination test.
Right now, the work is still preclinical. The team is looking at using human cells next to make it scalable.
“You do not restore an ecosystem simply by containing the initial damage. You have to create the conditions that allow life to return. That is how we think about the stroke cavity,” Segura said. “The material is not intended to reproduce the brain itself, but to create an environment where the body’s own cells can enter, communicate and participate in rebuilding vascularized tissue.”
You don't understand ONE GODDAMN THING ABOUT SURVIVOR MOTIVATION, DO YOU?
You create EXACT 100% recovery protocols and your survivor will be motivated
to do the millions of reps needed because they are looking forward to
100% recovery. GET THERE!
This
parallel, randomized controlled trial examined intrinsic motivation,
adherence and motor function improvement demonstrated by two groups of
subjects that performed a 12-week, home-based upper extremity
rehabilitation program. Seventeen subjects played scaffolded games,
presenting eight to twelve discrete levels of increasing difficulty.
Sixteen subjects performed the same activities controlled by success
algorithms that modify game difficulty incrementally.
Methods
33
persons 20–80 years of age, at least 6 months post stroke with moderate
to mild hemiparesis were randomized using a random number generator
into the two groups. They were tested using the Action Research Arm
Test, Upper Extremity Fugl Meyer Assessment, Stroke Impact Scale and
Intrinsic Motivation Inventory pre and post training. Adherence was
measured using timestamps generated by the gaming system. Subjects had
the Home Virtual Rehabilitation System (Qiu in J Neuroeng Rehabil 17:
1–10, 2020) placed in their homes and were taught to perform
rehabilitation games using it. Subjects were instructed to train twenty
minutes per day but were allowed to train as much as they chose.
Subjects trained for 12 weeks without appointments and received
intermittent support from study staff. Group outcomes were compared
using ANOVA. Correlations between subject demographics and adherence, as
well as motor outcome, were evaluated using Pearson Correlation
Coefficients.
Results
There
were 5 dropouts and no adverse events. The main effect of time was
statistically significant for four of the five clinical outcome
measures. There were no significant training group by time interactions.
Measures of adherence did not differ significantly between groups. The
combined groups improved their UEFMA scores on average by 5.85 (95% CI
4.73–6.98). 21 subjects from both groups demonstrating improvements in
UEFMA scores of at least 5 points, exceeding the minimal clinically
important difference of 4.25. IMI scores were stable pre to post
training.
Conclusions
Scaffolding
challenges during game based rehabilitation did not elicit higher
levels of adherence when compared to algorithm control of game
difficulty. Both sparsely supervised programs of game-based treatment in
the home were sufficient to elicit statistically significant,
clinically meaningful improvements in motor function and activities of
daily living.
Trial registration: Clinical Trials.gov—NCT03985761, Registered June 14, 2019.
This
parallel, randomized controlled trial examined intrinsic motivation,
adherence and motor function improvement demonstrated by two groups of
subjects that performed a 12-week, home-based upper extremity
rehabilitation program. Seventeen subjects played scaffolded games,
presenting eight to twelve discrete levels of increasing difficulty.
Sixteen subjects performed the same activities controlled by success
algorithms that modify game difficulty incrementally.
Methods
33
persons 20–80 years of age, at least 6 months post stroke with moderate
to mild hemiparesis were randomized using a random number generator
into the two groups. They were tested using the Action Research Arm
Test, Upper Extremity Fugl Meyer Assessment, Stroke Impact Scale and
Intrinsic Motivation Inventory pre and post training. Adherence was
measured using timestamps generated by the gaming system. Subjects had
the Home Virtual Rehabilitation System (Qiu in J Neuroeng Rehabil 17:
1–10, 2020) placed in their homes and were taught to perform
rehabilitation games using it. Subjects were instructed to train twenty
minutes per day but were allowed to train as much as they chose.
Subjects trained for 12 weeks without appointments and received
intermittent support from study staff. Group outcomes were compared
using ANOVA. Correlations between subject demographics and adherence, as
well as motor outcome, were evaluated using Pearson Correlation
Coefficients.
Results
There
were 5 dropouts and no adverse events. The main effect of time was
statistically significant for four of the five clinical outcome
measures. There were no significant training group by time interactions.
Measures of adherence did not differ significantly between groups. The
combined groups improved their UEFMA scores on average by 5.85 (95% CI
4.73–6.98). 21 subjects from both groups demonstrating improvements in
UEFMA scores of at least 5 points, exceeding the minimal clinically
important difference of 4.25. IMI scores were stable pre to post
training.
Conclusions
Scaffolding
challenges during game based rehabilitation did not elicit higher
levels of adherence when compared to algorithm control of game
difficulty. Both sparsely supervised programs of game-based treatment in
the home were sufficient to elicit statistically significant,
clinically meaningful improvements in motor function and activities of
daily living.
Trial registration: Clinical Trials.gov—NCT03985761, Registered June 14, 2019.
Introduction
Despite
decades of research attempting to remediate upper extremity impairments
following stroke, a rehabilitation approach that elicits substantial
improvements in function that do not decay over time has not been
developed [2].
This points to a need for opportunities for persons with residual
impairments following stroke to work on their arm and hand function away
from the clinical environment with relative independence [3].
The use of traditional and technology-supported home-based
rehabilitation programs has increased steadily in the last two decades
and was further accelerated by the COVID–19 pandemic [4].
Short term and directly supervised telerehabilitation programs produce
outcomes comparable to those of clinic-based treatments [5, 6].
Longer programs and sparsely supervised programs have not been studied
as well, and outcomes are less consistent. In general, adherence to
programs of activity designed to improve or maintain motor function
following a stroke is relatively low [7].
Multiple barriers to consistent performance of motor function training
activities exist, including low motivation as well as a lack of interest
in, or enjoyment of, training activities [8].
Multiple authors have proposed that game-based rehabilitation
activities may help overcome these barriers and provide a solution to
low adherence to home based rehabilitation programs [9,10,11].
This said, the published evidence presents a range of adherence rates
to gamified, home based rehabilitation, suggesting that simply
presenting a rehabilitation activity as a game might not result in
across the board improvements in adherence [9, 12,13,14,15,16,17].
Multiple factors have been identified as possible causes for varied
adherence to technology supported rehabilitation interventions in the
home [9, 18, 19].
The
gaming industry utilizes a wide variety of gaming mechanics, processes
that govern the way a game flows, information is presented, and player
success or failure is communicated. This influences the frequency with
which players pick up a game and play it, as well as the amount of time
they play a game after initiating [20].
This study focused on scaffolding, a very common gaming mechanism that
presents a relatively easy version of a game, followed by gradually
ascending levels of difficulty as a participant succeeds [21].
This affords the participant immediate initial feelings of
self-efficacy and then proceeds to challenge them. Appropriate levels of
challenge [22] and feelings of self-efficacy [23] are both associated with higher levels of motivation, as is the clear knowledge of results feedback [22]
a participant receives when they are presented with a new challenge
after they succeed or they are required to repeat a level if they fail.
This
study utilized a parallel randomized clinical trial to examine the
adherence levels of subjects with stroke performing a 12-week,
home-based upper extremity rehabilitation program incorporating
simulations that used scaffolding to that of a control group of subjects
that performed the same activities controlled by success algorithms
that increase and decrease game difficulty incrementally and
undetectably [24, 25].
Our overall study question focused on autonomous adherence to the
training program by setting the subjects up with the system and having
them perform their training without direct supervision or appointments.
The primary analysis focused on the impact of scaffolding on adherence,
by tracking total treatment time using system-collected measurement of
actual game play frequency. Secondary analyses examined (1) the effect
of scaffolding on motivation by analyzing pre and post training
Intrinsic Motivation Inventory scores and (2) the effectiveness of the
training programs using clinical measures of upper extremity function
and self-reported measures of hand function and activities of daily
living.
We
introduce the main pathological mechanisms of current brain injuries,
pointing out the prospect for the application of electrospun nanofiber
scaffolds compared to current clinical treatment strategies.
•
We
discuss brain regeneration methods that combine electrospun scaffolds
with physical cues, biochemical cues (cells, growth factors, and other
biomolecules), external stimuli, and support materials that populate the
scaffold lumen.
•
We
review recent research advances in the role of electrospun biomaterials
in brain injury as anti-inflammatory, inhibiting glial scarring, and
promoting cellular differentiation into neurons.
•
We
point out the challenges facing the effective treatment of brain
injury, aiming to provide insights into the development of repairing
scaffolds for brain function recovery from the perspective of clinical
treatment.
Abstract
Patients
with brain injury can suffer disability and accompanying complications.
Current clinical treatments have significant limitations to successful
repair due to the complexity of the pathological processes and the
inhibitory microenvironment that follows brain injury. Here, we conclude
recent research progresses in engineering strategies based on
electrospun nanofibers for promoting neural repair and functional
recovery after brain injury. Firstly, we introduce the main pathological
mechanisms of current brain injuries, pointing out the prospect of the
application of electrospun nanofiber scaffolds compared to current
clinical treatment strategies. We then discuss the repair strategies
combining the structure and the morphology of nanofiber scaffolds with
load therapeutic factors such as cells, drugs and growth factors. All of
these strategies show potential for improving the repair of brain
injury. Finally, we point out the challenges facing the effective
treatment of brain injury, aiming to provide insights into the
development of repairing scaffolds for brain function recovery from the
perspective of clinical treatment.
The
central nervous system (CNS) plays a vital part in health and
well-being, and the brain is the most vulnerable organ of the CNS [1].
Brain interposes input from the external environment and processes
information to support operational repair. Currently, brain injury is
one of the most serious public health problems, which mainly includes
traumatic brain injury (TBI), ischemic brain injury (IS), hemorrhagic
brain injury, etc. In the acute stage, the clinical treatment of brain
injury is mainly surgical. However, the brain has a limited regenerative
capacity [2,3],
and tissue damage or neurological damage caused by disease or traumatic
brain injury is permanent, leading to cognitive, motor, and
neurological dysfunction, among others. In response, most current
clinical treatment strategies are based on drug therapy to reduce
further tissue loss and/or alleviate other symptoms such as
inflammation, coupled with postoperative maintenance of motor function
through rehabilitation, etc. However, these approaches often result in
poor outcomes due to narrow time windows and the limited penetration of
the blood-brain barrier (BBB) and blood-cerebrospinal fluid barrier
(BCSFB) with conventional oral or intravenous therapeutic agents [4,5]. The BBB prevents the entry of potentially harmful substances to the brain from the blood [6] while the BCSFB controls the transfer of molecules from the blood to the cerebrospinal fluid before entering the brain [7], [8], [9].
These subtle mechanisms control the homeostatic state within the brain
but also limit the passage of various therapeutic molecules. Thus, after
a systemic administration (e.g., intravenous injection) of therapeutic
cells or molecules, only moderate concentrations of these therapeutic
drugs can reach the brain, resulting in unsatisfactory treatment
outcomes. In this case, high or frequent doses of therapeutic agents are
often necessary to achieve the desired therapeutic effect, which may
exacerbate systemic toxicity [10].
For example, the use of N-acetylcysteine (NAC) drugs for TBI requires
an increased systemic dose, which can lead to adverse effects such as
increased blood pressure [11],
and the use of chemotherapeutic drugs to treat brain tumors can cause
toxicity to cells throughout the body upon entering the circulation [12,13].
To
resolve this paradox, the most often used methods include disruption of
the BBB and invasive drug delivery to maximize drug concentrations at
the target site while minimizing drug exposure to surrounding tissues.
Disruption of the BBB was proposed in the 1960s [14] and can be achieved with hypertonic solutions such as mannitol, drugs, or focused ultrasound [15].
Additionally, an invasive procedure to create a hole a few millimeters
into the skull allows therapeutic drugs to be injected directly into the
brain through this channel. Unfortunately, these invasive strategies
not only can induce further neuronal damage and inflammatory responses,
but also ignore the balance of the internal environment in the brain
tissue. For example, drugs that increase the permeability of the BBB,
such as histamine, tend to induce inflammatory effects due to sudden
changes in the chemical composition of the internal environment [16].
Thus, to avoid these adverse influences, developing sophisticated brain
tissue engineering strategies show great promise to repair and further
regenerate brain tissues at the site of damage through reconstructing
the cellular microenvironment, ultimately achieving functional
reconstruction [17].
The brain consists of interconnected neurons that interact with the extracellular matrix (ECM) to form a complex network [18].
Cell loss following nerve injury can adversely affect brain function by
disrupting the connectivity and signaling between neurons. In addition,
progressive degeneration usually activates astrocytes, microglia, or
macrophages and oligodendrocyte precursor cells, which facilitate the
formation of glial scarring and leads to the formation of desmoplastic
cavities in the lesion site [19,20].
Cell therapy is expected to replace apoptotic neurons and/or prevent
further degradation by introducing exogenous cells, promoting the
expression of relevant trophic factors, guiding axon growth and
promoting angiogenesis [21].
In the process of tissue regeneration, neurotrophic factors can promote
the survival of neurons and the establishment of connections between
neurons to achieve the re-establishment of functional neural networks.
Common trophic factors include glial cell line-derived neurotrophic
factor (GDNF) and brain-derived neurotrophic factor (BDNF). In animal
models of Parkinson's disease (PD) [22], [23], [24], Huntington's disease [25,26],
and TBI, increasing the expression of these neurotrophic factors can
accelerate the promotion of cell survival and integration [27], so as to realize tissue regeneration.
The
creation of a microenvironment for cells growth is essential not only
in promoting normal cell growth to reduce inflammation, supporting the
survival of neurons (endogenous or derived from exogenous cells), and
reconstructing the vascular network at the site of injury, but also in
avoiding further damaging tissue surrounding lesion site as the support
structure [28,29].
Thereby it can be good support for drug therapy and cell therapy.
Electrospun nanofiber scaffolds are well received in various tissue
engineering [30], especially in neural tissues [31], [32], [33],
due to special properties that simulate the structure of the ECM.
Electrospun nanofibers scaffolds can guide axons extension of neurons
and modulate the phenotype and function of cells associated with brain
injury. Different cues can be combined or integrated with electrospun
nanofibers [34],
involving physical cues like gradient structures and fiber diameters,
biochemical cues like growth factors, exogenous cells like stem cells [35], and other support materials like hydrogels or nanoparticles [30].
In
this review, we firstly discuss the mechanisms of several common brain
injuries including TBI, ischemic brain injury, and hemorrhagic brain
injury, and then summarize the recent development of the
functionalization of electrospun nanofiber scaffolds. Afterwards, we
discuss the recent and representative development in the application of
electrospun nanofiber scaffolds in brain injury repair. In the end, we
raise the prospect for the future development direction of combining
electrospun nanofiber scaffolds with other tools, aiming to improve the
treatment efficacy for treating brain injury.
2. Pathologies of Different Types of Brain Injuries
Brain
injuries can be caused by different reasons, such as external shocks,
near-drowning, cerebrovascular diseases, and brain surgery [36],
leading to TBI, IS, hemorrhagic stroke, and so on. Current clinical
treatment strategies mainly include clinical surgery (e.g., blood
drainage), pharmacological treatment (e.g., recombinant tissue
plasminogen activator (rtPA)), and physical therapy (e.g.,
electrotherapy and ultrasound), all of which are very limited to prevent
the onset of sequelae [37].
Understanding the pathologies after brain injury is important to
explore new treatment strategies for providing brain injury patients
with a better quality of life.
2.1. Traumatic brain injury
TBI
involves brain tissue damage and dysfunction, which is caused by a
series of sharp or blunt mechanical external forces, usually resulting
from traffic accidents, falls, sports injuries, and criminal violence.
TBI includes primary injury caused by the direct action of mechanical
external forces and secondary injury triggered minutes or hours later [38].
Depending on the degree of the injury, primary injury can manifest as
increased intracranial pressure, nerve damage, vascular damage, tissue
swelling, and hypoxic damage [39].
Then, secondary brain injury can be immediately triggered through the
four main mechanisms of cellular excitotoxicity, neuroinflammatory
cytokines, oxidative stress, and apoptosis [40,41].
Cellular excitotoxicity, primarily caused by the massive release of glutamate, is a form of secondary damage [42].
The damage caused to axons by mechanical forces leads to extravasation
of glutamate into the ECM, resulting in the swelling of neurons and
astrocytes through the inward flow of sodium and calcium ions [38].
In addition, the high intracellular calcium levels can activate a range
of catabolic enzymes capable of disrupting both cellular and
mitochondrial membranes as well as the cytoskeleton and can also cause
DNA fragmentation, ultimately leading to cell death [43].
At the same time, intracellular calcium overload leads to the opening
of mitochondrial permeability transition pores, significantly affecting
the function of the mitochondria and preventing them from producing
adenosine triphosphate to meet metabolic demands [44].
Glutamate also contributes to the production of reactive oxygen species
(ROS), which can cause damage to critical cellular components like DNA
and lipid membranes [38,40].
Cytokines
are biologically active proteins that are secreted by immune and
certain non-immune cells. These regulate cell growth and differentiation
as well as affect and regulate immune response by binding to
corresponding receptors. Cytokines secreted by immune cells include
interleukins, interferons, and chemokines, which can be involved in the
neuroinflammatory response [40,45].
After TBI occurs, inflammatory cells such as activated microglia,
neutrophils, and macrophages produce a variety of pro-inflammatory
mediators to promote neuroinflammation [46], thereby accelerating brain edema, disruption of the BBB, and cell death, while resulting in secondary post-traumatic injury.
Oxidative
stress is the imbalance between oxidation and anti-oxidation in the
body, and a tendency toward oxidation results in an excess of free ROS,
which damages the molecules that makeup DNA, proteins, and lipids,
ultimately leading to apoptosis and tissue necrosis [47].
As the inflammatory response of microglia gradually increases, the
upregulation of NADPH oxidase 2 (NOX2) in phagocytes occurs for several
days, catalyzing the production of large amounts of ROS that
significantly contribute to oxidative stress injury and neuronal death.
Furthermore, other major sources of ROS include oxidation products from
hemoglobin and products from the activation of NOX2 by bradykinin, etc [48].
Apoptosis
of neurons is initiated by a variety of pathways, among which the main
one being the initiation of mitochondrial dysfunction through the
cysteine-aspartate protease (caspase)-dependent pathway [49].
A series of different caspases are activated by proteolytic cleavage to
form a complex that causes the release of cytochrome C, a molecule that
can induce apoptosis. Beyond that, some caspase-independent pathways
may also regulate cell death. For example, mitochondria can cause
chromatin condensation at peripheral nucleus and the fragmentation of
DNA through the release of apoptosis-inducing factor (AIF) [40].
2.2. Ischemic stroke
Stroke is the second leading reason of death worldwide and can cause long-term disability [50].
Resulting in brain damage due to clogged or ruptured vessels in the
brain, stroke is characterized as a group of diseases that include IS
and hemorrhagic stroke (intracerebral hemorrhage (ICH) and subarachnoid
hemorrhage (SAH)), with IS dominating the morbidity of strokes overall [50].
The development of IS involves a variety of factors, such as genetic
factors, type of diet, and lifestyle. The pathogenesis of IS is complex
and is usually caused by cerebral thrombosis and cerebral embolism,
accompanied by atherosclerotic plaque destruction, with thrombosis being
the main clinical pathogenesis [51]. Atherosclerosis, caused by damage to the endothelium [52],
leads to the occlusion of the arteries in the brain, eventually
resulting in reduced cerebral blood flow and consequent cerebral
ischemia [53].
The release of damage-associated molecular patterns (DAMPs) from
neurons in the central ischemic area activates the immune response,
followed by the release of TNF-α, IL-1β, and other inflammatory factors
from astrocytes and microglia, as well as the upregulation of ICAM-1
expression in vascular endothelial cells, which can then trigger an
inflammatory response and irreversible neuronal death, as shown in Fig. 2.
The
area surrounding the infarct core, known as the penumbra, is a
potentially salvageable area of the brain that remains metabolically
active and returns to normal function after continuing to receive an
adequate blood supply [54].
Thus, the penumbra, which typically accounts for half of the brain
volume damaged after a stroke, provides an opportunity for treatment.
Neuronal death in the penumbra is much slower than in the infarct core
and may take several days to occur, so at least some neurons of the
penumbra may be salvageable if there is a timely therapeutic
intervention to restore blood [55].
However, if treatment is not timely, neurons in the penumbra will
suffer from apoptosis through mitochondrial dysfunction, oxidative
stress, and autophagy [56,57].
On one hand, the dysregulated sodium-potassium pumps of neurons in the
penumbra result in the release of large amounts of glutamate into the
synaptic gap, causing excitatory amino acid toxicity in the cells.
Simultaneously, one part of the glutamates binds to
α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors
to facilitate
inward flow [58],
ultimately inducing apoptosis through membrane potential imbalance, DNA
damage, and mitochondrial dysfunction. The dysfunctional mitochondria
release apoptosis proteins, from the caspase-dependent and independent
apoptosis pathways to exert apoptosis [59].
Another part of glutamates binds to N-methyl-d-aspartic acid (NMDA)
receptors and then releases ROS and RNS to trigger an oxidative stress
response leading to apoptosis. While, on the other hand, the expression
of LC-3, beclin 1, and other related autophagy proteins are up-regulated
in the neurons of the penumbra, which causes the over-activation of the
cellular autophagic response, leading to cell death through degradation
of the nucleus. The relevant signaling pathways are also described in Fig. 2. In addition, oxidative stress in cells can also induce cellular autophagy [60].
2.3. Hemorrhagic stroke
Hemorrhagic strokes account for 15% of all strokes, and can cause the most damage and mortality [61].
There are two types of hemorrhagic strokes, ICH and SAH, of which ICH
is twice as common. In addition, most survivors of ICH exhibit various
sequelae symptoms, causing significant inconvenience in daily life [62].
A variety of factors can contribute to the development of ICH,
involving the angiorrhexis at different locations in the brain due to
chronic hypertension, cerebral amyloid angiopathy (CAA), arteriovenous
malformations, or systemic diseases [63].
Brain injury after ICH is similar to TBI, mainly consisting of primary injury and secondary injury [64].
Primary injury is caused by hemorrhage, and involves mechanical damage
triggered by the effect of the hematoma mass on the surrounding tissues
during the hyperacute phase of ICH, where blood rapidly accumulates at
the brain parenchyma within minutes, causing damage to normal tissue
structures and increasing pressure to the cranial cavity [65].
High intracranial pressure decreases cerebral blood flow and can even
cause displacement of brain tissue, resulting in brain herniation. In
addition, mechanical compression from the hematoma as well as blood
clots including some toxic substances can cause the death of neurons and
damage of the BBB, ultimately inducing cerebral edema [65].
Secondary injury is caused by the pathological response to the
hematoma, and it occurs as the body responds to the hematoma and high
intracranial pressure in a series of ways, the mechanisms of which
involve inflammation, oxidative stress, cellular excitotoxicity, and
cytotoxicity [63]. The main signaling pathways are shown in Fig. 3.
After the occurrence of ICH, the blood released by a ruptured blood
vessel enters the brain tissue and triggers an immune response in the
brain. The activated immune system accelerates the infiltration of
surrounding inflammatory cells into the lesion site in brain, triggering
inflammation by releasing inflammatory factors. Meanwhile, excess
glutamate released by damaged neurons can lead to the inward flow of
and eventually resulting in cellular edema. Meanwhile, stimuli such as
high mobility group protein 1(HMGB1) generated by dead neurons can bind
to TLR4 receptors, thereby activating microglia [63].
In addition, hemoglobin (Hb) produced by the breakdown of released red
blood cells from the blood can be degraded to heme, which in turn is
broken down by heme oxygenase-1 and heme oxygenase-2 to iron [66,67],
carbon monoxide, and biliverdin. The excess iron is then removed from
the cells via efflux transporters (FPNs) and deposited in brain tissue,
where it releases numerous ROS through the Fenton reaction, inducing
oxidative stress and inflammation [64].
At the same time, fibrinogen released from the blood can cause
inflammation by activating microglia, leading to neuronal death. After
hematoma production, the coagulation system can limit the expansion of
the hematoma by activating and releasing thrombin, which likewise causes
microglial activation and increases the release of inflammatory
cytokines [68].
Ruptured intracranial aneurysms are the main cause of most non-traumatic cases of SAH [69]. Other causative factors include cerebral venous thrombosis, cerebrovascular malformations, pituitary apoplexy, and so on [70].
The pathogenesis of aneurysmal subarachnoid hemorrhage (aSAH) can be
divided into two phases: early-type brain injury within the first 72
hours and delayed cerebral ischemia (DCI) within 3-14 days after initial
bleeding [71].
The blood released by a ruptured blood vessel enters into the
subarachnoid space, causing intracranial macro-physiological changes,
such as increased intracranial pressure (ICP) [72],
decreased cerebral perfusion pressure (CPP), and cerebral blood flow
(CBF), thus triggering whole-brain ischemia. Eventually, whole-brain
ischemic and released blood in the subarachnoid space can induce
neuroinflammation, oxidative stress, BBB disruption, brain edema, and
the death of neurons through different mechanisms [71]. DCI is the main complication of aSAH [73].
Among the listed various etiological factors, vasospasm is the main
pathogenesis and is caused by luminal narrowing due to the strong
contraction of smooth muscle in the vessel wall that results in reduced
blood flow within the brain tissue. At present, there is an abundance of
showing that oxygen-containing hemoglobin (OxyHb) plays a vital role in
causing vasospasm [74],
with contributing related mechanisms that include oxidative stress,
inflammation, decreased nitric oxide (NO) levels, and increased
endothelin (ET) levels, among others [71].
