Materiały źródłowe

• #1 Pathophysiology and Treatment of Stroke: Present Status and Future Perspectives

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7589849/

  Stroke is defined as an abrupt neurological outburst caused by impaired perfusion through the blood vessels to the brain. […] Ischemic stroke is caused by deficient blood and oxygen supply to the brain; hemorrhagic stroke is caused by bleeding or leaky blood vessels. […] Ischemic occlusions contribute to around 85% of casualties in stroke patients, with the remainder due to intracerebral bleeding. Ischemic occlusion generates thrombotic and embolic conditions in the brain. […] In thrombosis, the blood flow is affected by narrowing of vessels due to atherosclerosis. […] In an embolic stroke, decreased blood flow to the brain region causes an embolism; the blood flow to the brain reduces, causing severe stress and untimely cell death (necrosis). […] Other key events contributing to stroke pathology are inflammation, energy failure, loss of homeostasis, acidosis, increased intracellular calcium levels, excitotoxicity, free radical-mediated toxicity, cytokine-mediated cytotoxicity, complement activation, impairment of the blood-brain barrier, activation of glial cells, oxidative stress and infiltration of leukocytes.

• #1 Stroke Mechanisms

  http://neuroanatomy.ca/stroke/mechanisms.html

  A stroke occurs when there is interruption of the blood supply to a particular area of the brain, ultimately leading to cell injury and cell death. Strokes can be classified as either: ischemic or hemorrhagic. […] Ischemic strokes are the most common, accounting for up to 80% of strokes, and occur when there is an occlusion of a blood vessel impairing the flow of blood to the brain. Ischemic strokes are divided into: [A] Thrombotic [B] Embolic [C] Systemic Hypoprofusion. […] In thrombotic stroke, a thrombus or clot gradually builds up in the artery, eventually occluding it and disturbing blood flow to tissue downstream from the thrombus. […] Three primary influences predispose to the formation of thrombi, the so-called Virchow Triad: Endothelial Injury, Stasis or Turbulent Blood Flow, Hypercoagulability.

• #1 Stroke Mechanisms

  http://neuroanatomy.ca/stroke/mechanisms.html

  In an embolic stroke, a piece of material (or embolus) travels from a distant location and lodges in the blood vessel, occluding it. […] Because the blockage arrives from another location, the onset of embolic strokes is usually quicker than that of thrombotic strokes. […] In systemic hypoperfusion, blood flow is decreased to all areas of the body. […] Although less common (~15% of strokes), hemorrhagic (or bleeding) strokes can be much more serious. This is because in addition to the interruption of blood supply to the target tissue, the hemorrhage (bleed) can also cause increasing intracranial pressure which can physically impinge on brain tissue, further impairing perfusion of the cerebrum.

• #1 Stroke | CVA | Cerebrovascular Accident | MedlinePlus

  https://medlineplus.gov/stroke.html

  A stroke happens when there is a loss of blood flow to part of the brain. Your brain cells cannot get the oxygen and nutrients they need from blood, and they start to die within a few minutes. This can cause lasting brain damage, long-term disability, or even death. […] Ischemic stroke is caused by a blood clot that blocks or plugs a blood vessel in the brain. This is the most common type; about 80% of strokes are ischemic. […] Hemorrhagic stroke is caused by a blood vessel that breaks and bleeds into the brain. […] Certain factors can raise your risk of a stroke. The major risk factors include: High blood pressure. This is the primary risk factor for a stroke. […] Atrial fibrillation and other heart diseases can cause blood clots that lead to stroke. […] Stroke rehabilitation can help you relearn skills you lost because of the damage. The goal is to help you become as independent as possible and to have the best possible quality of life. […] Prevention of another stroke is also important, since having a stroke increases the risk of getting another one. Prevention may include heart-healthy lifestyle changes and medicines.

• #1 Lacunar stroke: mechanisms and therapeutic implications | Journal of Neurology, Neurosurgery & Psychiatry

  https://jnnp.bmj.com/content/92/8/823

  Lacunar stroke is a marker of cerebral small vessel disease and accounts for up to 25% of ischaemic stroke. […] In this narrative review, we provide an overview of potential lacunar stroke mechanisms and discuss therapeutic implications based on the underlying mechanism. […] These studies suggest that lacunar stroke is a heterogeneous disease with various mechanisms, including most commonly lipohyalinosis and less commonly atheromatous disease and cardioembolism, highlighting the importance of a careful review of brain and neurovascular imaging, a cardiac and systemic evaluation. […] A better understanding of pathomechanisms of neurological deterioration may lead to investigating the utility of novel treatment strategies and optimisation of short-term antithrombotic treatment strategies to reduce the risk of neurological deterioration and prevent long-term disability in patients with lacunar stroke.

• #1 Lacunar stroke: mechanisms and therapeutic implications | Journal of Neurology, Neurosurgery & Psychiatry

  https://jnnp.bmj.com/content/92/8/823

  There are several potential mechanisms described for the pathogenesis of lacunar stroke. […] Lipohyalinosis is defined as concentric hyaline thickening of the cerebral small vessels leading to occlusion of the small penetrating arteries and is one of the first and most common lacunar stroke mechanisms described and pathologically proven to cause lacunar stroke. […] Lipohyalinosis is thought to originate from hypertension-related hypertrophy and fibrinoid degeneration of the vessel walls as well as subintimal foam cells obliterating the lumen of small penetrating arteries, leading to small subcortical infarcts. […] In addition to lipohyalinosis, some studies hypothesised that endothelial dysfunction and impaired autoregulation as well as extravasation of blood products into the vessel wall resulting in perivascular oedema and damage to the neurovascular unit and surrounding brain tissue may be a contributing factor to the development of lacunar infarcts.

• #1 Hemorrhagic Stroke | American Stroke Association

  https://www.stroke.org/en/about-stroke/types-of-stroke/hemorrhagic-strokes-bleeds

  Hemorrhagic strokes make up about 13% of stroke cases. They occur when a weakened vessel ruptures and bleeds into the surrounding brain. The blood accumulates and compresses the surrounding brain tissue. […] The two types of hemorrhagic strokes are intracerebral hemorrhage (within the brain) or subarachnoid hemorrhage (between the inner and outer layers of the tissue covering the brain). […] A brain AVM contains abnormal “weakened” blood vessels that direct blood away from normal brain tissue. These abnormal and weak blood vessels dilate over time. Eventually, they may burst from the high pressure of blood flow from the arteries. […] The annual risk of a first-ever ICH from an unruptured brain AVM is ≈1%. The chance of a brain AVM bleeding is about 2% per year over 10 years. […] Each time blood leaks into the brain, normal brain tissue is damaged. This results in loss of normal function, which may be temporary or permanent. The chance of permanent brain damage is 20% to 30%. The risk of death related to each bleed is 10% to 15%.

• #1 Pathophysiology and Treatment of Stroke: Present Status and Future Perspectives

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7589849/

  Hemorrhagic stroke accounts for approximately 10-15% of all strokes and has a high mortality rate. […] It produces toxic effects in the vascular system, resulting in infarction. […] The main reasons for ICH are hypertension, disrupted vasculature, excessive use of anticoagulants and thrombolytic agents.

• #1 Hemorrhagic Stroke | American Stroke Association

  https://www.stroke.org/en/about-stroke/types-of-stroke/hemorrhagic-strokes-bleeds

  If an aneurysm ruptures, it may leak blood into the space around the brain. This is called a subarachnoid hemorrhage. […] Subarachnoid hemorrhage and intracerebral hemorrhage are two types of hemorrhagic stroke. The bleeding damages the brain and can lead to: Weakness or paralysis of an arm or leg, Trouble speaking or understanding language, Vision problems, Seizures, Death. […] After blood enters the brain and the space around it, direct damage to the brain tissue and brain function results. The amount of damage is usually related to the amount of blood. Damage is due to the increased pressure and swelling from bleeding directly into the brain tissue, or from local cellular damage to brain tissue from irritation of blood in the space between the brain and the skull.

• #1

  https://journals.lww.com/nrronline/fulltext/2021/16030/physiopathology_of_ischemic_stroke_and_its.5.aspx

  The reduction or cessation of blood flow in the brain may produce different levels of damage depending on the time elapsed, cell resistance and magnitude of the ischemia, and activates a very complex cascade of interrelated cellular and molecular events with a temporal overlapping profile that evolves over minutes, hours or days, inducing injury in all cell types and damage that can range from transient to irreversible (e.g., cell death). This event produces two different areas of damage: the ischemic core and the penumbra. In the ischemic core, blood flow is abruptly reduced and the cells are permanently injured and die rapidly by necrosis. The size of this area will depend primarily on the duration and magnitude of the ischemia and the location of the stroke. The penumbra is located around the ischemic core. This zone is perfused by collateral blood vessels which allow cells that are structurally intact but functionally weakened. These functionally impaired cells can be slowly incorporated into the ischemic stroke or saved.

• #1 Ischemic Stroke: Background, Anatomy, Pathophysiology

  https://emedicine.medscape.com/article/1916852-overview

  Acute ischemic strokes result from vascular occlusion secondary to thromboembolic disease (see Etiology). Ischemia causes cell hypoxia and depletion of cellular adenosine triphosphate (ATP). Without ATP, there is no longer the energy to maintain ionic gradients across the cell membrane and cell depolarization. Influx of sodium and calcium ions and passive inflow of water into the cell lead to cytotoxic edema. […] An acute vascular occlusion produces heterogeneous regions of ischemia in the affected vascular territory. Local blood flow is limited to any residual flow in the major arterial source plus the collateral supply, if any. Affected regions with cerebral blood flow of lower than 10 mL/100 g of tissue/min are referred to collectively as the core. These cells are presumed to die within minutes of stroke onset.

• #1 Ischemic Stroke: Background, Anatomy, Pathophysiology

  https://emedicine.medscape.com/article/1916852-overview

  Zones of decreased or marginal perfusion (cerebral blood flow 25 mL/100g of tissue/min) are collectively called the ischemic penumbra. Tissue in the penumbra can remain viable for several hours because of marginal tissue perfusion. […] On the cellular level, the ischemic neuron becomes depolarized as ATP is depleted and membrane ion-transport systems fail. Disruption of cellular metabolism also impairs normal sodium-potassium plasma membrane pumps, producing an intracellular increase in sodium, which in turns increases intracellular water content. This cellular swelling is referred to as cytotoxic edema and occurs very early in cerebral ischemia. […] Cerebral ischemia impairs the normal sodium-calcium exchange protein also found on cell plasma membranes. The resulting influx of calcium leads to the release of a number of neurotransmitters, including large quantities of glutamate, which in turn activates N-methyl-D-aspartate (NMDA) and other excitatory receptors on other neurons.

• #1 The Pathophysiology of Ischemic Stroke Studied by Radionuclide Imaging

  https://www.jneurology.com/articles/pthe-pathophysiology-of-ischemic-stroke-studied-by-radionuclide-imagingp.html

  The potential for postischemic recovery of functionally impaired cells is determined not only by the level of residual flow in the ischemic phase but also by the duration of the flow disturbance. […] The extent of the penumbra and its conversion into infarction is a dynamic process, and irreversible damage spreads from the core of ischemia to its border. […] The effect of the only approved conservative therapy for acute ischemic stroke was established also in imaging studies, in which reperfusion to penumbral tissue was followed by improvement in neurological deficits. […] Malignant brain infarcts develop in about 10 % of patients with ischemic stroke in the middle cerebral artery (MCA) territory. […] Microglia changes from a resting to an activated state in response to central nervous system insults that stimulate them to function as phagocytes.

• #1

  https://journals.lww.com/nrronline/fulltext/2021/16030/physiopathology_of_ischemic_stroke_and_its.5.aspx

  Ischemic cascade refers to several interrelated and overlapped pathological mechanisms that are activated after a few minutes of blood vessel occlusion and whose progress occurred on a different time scale. The first event of the ischemic cascade is the reduction of oxygen and glucose which leads to a failure to produce high-energy molecules to maintain the cellular homeostasis. This sets off several mechanisms that include ionic imbalance, excitotoxicity, calcium overload, cytotoxic and vasogenic edema, peri-infarct depolarization, oxidative and nitrosative stress, blood-brain barrier (BBB) disruption, inflammation, and apoptosis. […] Although after a stroke neuroprotective and neuroplastic mechanisms overlap, they can be differentiated as follows: after damage, all the cells activate a series of mechanisms against the harmful factors to avoid damage (neuroprotection). In the infarct core, these mechanisms exceed their capacity to protect and the cells die. In the penumbra this mechanism contributes to limit the expansion of the infarct core and include: 1) homeostatic regulation of ions and fluids, 2) free radical scavenging, 3) neurotransmitter re-uptake, 4) production and release of anti-inflammatory cytokines, 5) BBB and neurovascular unit repair, 6) isolation of the injury site through scar formation, and 7) phagocytosis and debris clearance. Neuroplasticity involves the activation of mechanisms to restore the homeostatic function of the tissue previously damaged through reorganization and compensation of structural and functional deficiencies and includes: 1) production and release of growth factors, 2) angiogenesis, gliogenesis, and neurogenesis, 3) reorganization of microvascular and neuronal networks, and 4) synaptic contact growth.

• #1 Understanding the Pathophysiology of Ischemic Stroke: The Basis of Current Therapies and Opportunity for New Ones

  https://www.mdpi.com/2218-273X/14/3/305

  Continuous blood supply is critical to the survival of the brain because the brain constantly requires oxygen and nutrients for proper functioning, relying on effective blood circulation. Once a major cerebral artery is blocked, the blood supply to the affected brain region is reduced. The diminished circulation causes energy disruption due to hypoxia and ischemia by interfering with ATP production. […] Excessive activation of NMDA receptors also contributes to the disruption of neuronal plasticity, affecting aging, memory, and learning, which leads to cognitive decline associated with stroke. […] Oxidative stress, a major mechanism in ischemic stroke, disrupts the oxidant–antioxidant balance, particularly in brain cells rich in polyunsaturated fatty acids. […] Mitochondria recognized as the cellular powerhouses, play a crucial role in maintaining cell energy homeostasis, making them integral players in ischemic neuronal death.

• #1 Ischemic Stroke: Background, Anatomy, Pathophysiology

  https://emedicine.medscape.com/article/1916852-overview

  These neurons then become depolarized, causing further calcium influx, further glutamate release, and local amplification of the initial ischemic insult. This massive calcium influx also activates various degradative enzymes, leading to the destruction of the cell membrane and other essential neuronal structures. […] Ischemia also directly results in dysfunction of the cerebral vasculature, with breakdown of the blood-brain barrier occurring within 4-6 hours after infarction. Following the barriers breakdown, proteins and water flood into the extracellular space, leading to vasogenic edema. This produces greater levels of brain swelling and mass effect that peak at 3-5 days and resolve over the next several weeks with resorption of water and proteins. […] Ultimately, the ischemic penumbra is consumed by these progressive insults, coalescing with the infarcted core, often within hours of the onset of the stroke.

• #1 Molecular Pathogenesis of Ischemic and Hemorrhagic Strokes: Background and Therapeutic Approaches

  https://www.mdpi.com/1422-0067/25/12/6297

  After cell death, stressors such as organelle swelling, plasma membrane disruption and cellular content leakage are responsible for neuronal damage. The fundamental processes that contribute most to the genesis of the pathological picture are inflammation, the secretion of excitatory amino acids, the increase in intracellular calcium levels and the production of prostaglandins, leukotrienes and reactive oxygen species, and these are potential targets of interest in therapeutic research. […] Brain ischemia and, to a more significant extent, brain reperfusion are also associated with producing free oxygen radicals. The significantly increased calcium concentration activates some calcium-dependent enzymes, such as nitric oxide synthase (NOS), which leads to cell damage following the formation of reactive oxygen species (ROS), such as peroxynitrite.

• #1 Molecular Pathogenesis of Ischemic and Hemorrhagic Strokes: Background and Therapeutic Approaches

  https://www.mdpi.com/1422-0067/25/12/6297

  After ischemic stroke, the brain insult results in apoptosis and necrosis, each of which drive an inflammatory response; this response is called neuroinflammation, and is characterized by the participation of numerous cytotypes, first with the activation of resident glial cells and then with the infiltration of leukocytes, monocytes and other immune cells in the brain, and the releasing of inflammatory agents. […] The role of different miRNAs in ischemic stroke’s pathogenesis is summarized in Table 2.

• #1 Understanding the Pathophysiology of Ischemic Stroke: The Basis of Current Therapies and Opportunity for New Ones

  https://www.mdpi.com/2218-273X/14/3/305

  The intense neuroinflammation during the acute phase of stroke is linked to blood–brain barrier (BBB) breakdown, neuronal injury, and poor outcomes. Neuronal death is the ultimate determinant of IS-induced morbidity and mortality, and the success of its management is determined by the extent to which it is prevented. […] Understanding the intricate interplay of these different cell death pathways in the context of ischemic stroke is crucial for developing targeted therapeutic interventions. […] Autophagy forms part of the cellular cascade of events triggered by oxygen and nutrient deprivation in IS. […] The protection of ischemic penumbra from post-stroke degeneration and damage is ensured using neuroprotective and, more recently, neuroreparative agents. These agents act primarily by targeting one or several aspects of the underlying pathophysiology of IS thus increasing the likelihood of developing effective add-on neuroprotective therapies.

• #1 Pathogenesis of seizures and epilepsy after stroke | Acta Epileptologica | Full Text

  https://aepi.biomedcentral.com/articles/10.1186/s42494-021-00068-8

  Studies have shown that hemosiderin deposition is closely related to the occurrence of early epileptic seizures after subarachnoid hemorrhage. […] In addition to the above mechanisms of early epileptic seizures, several other potential pathogenic mechanisms have been proposed, such as acute electrolyte disturbances (such as increased intracellular calcium and sodium concentrations) in the ischemic penumbra surrounding the stroke lesion, which lead to depolarization of neuronal membrane. […] In the later stages of stroke, the CNS is damaged, because the glial scar formed by reactive astrocytes can cause acquired epilepsies. […] BBB injury causes a flow of a large amount of blood-derived fluid to the extravascular space. […] About 30% of all epileptic syndromes are hereditary, and more than 500 genetic loci have been revealed to be associated with epilepsy in humans and mice. […] The pathogenesis of epilepsy after stroke has been studied in depth, with some mechanisms confirmed while others being new hypotheses that awaits confirmation.

• #1 A Review of Potential Mechanisms of Cryptogenic Stroke and a Recommended Approach to Diagnosis – touchNEUROLOGY

  https://touchneurology.com/stroke/journal-articles/a-review-of-potential-mechanisms-of-cryptogenic-stroke-and-a-recommended-approach-to-diagnosis/

  Cryptogenic strokes have no probable cause despite appropriate initial testing, and are common, representing at least 2030% of all ischaemic strokes. […] Multiple potential mechanisms have been proposed and include cardioembolic source, proximal arterial source, venous source (in the presence of a right-to-left shunt), and more rare causes, such as genetic syndromes associated with stroke. […] Determining the underlying mechanism is important, since cryptogenic strokes are associated with increased risk of recurrent stroke compared with strokes due to a defined mechanism. […] Numerous mechanisms have been proposed for cryptogenic stroke, including cardioembolism from occult atrial fibrillation, cardiac structural abnormalities, paroxysmal embolism, hypercoagulable or prothrombotic states, sub-stenotic large-vessel disease, aortic atherosclerotic disease and other non-atherosclerotic vasculopathies.

• #1 A Review of Potential Mechanisms of Cryptogenic Stroke and a Recommended Approach to Diagnosis – touchNEUROLOGY

  https://touchneurology.com/stroke/journal-articles/a-review-of-potential-mechanisms-of-cryptogenic-stroke-and-a-recommended-approach-to-diagnosis/

  Potential mechanisms of stroke in patients with a PFO include paroxysmal embolism from a venous source or embolization of thrombotic material formed on the PFO, or associated atrial septal aneurysm (redundant and mobile inter-atrial septal tissue). […] Aortic arch plaque is an important possible source of cryptogenic stroke. […] Complex plaque is defined as atherosclerotic plaque of 4 mm thickness and associated with ulcerations, mobile debris or superimposed thrombi. […] Recent advancements in imaging have allowed for better characterization of plaque composition. […] Other, non-atherosclerotic vasculopathies, such as arterial dissection, reversible cerebral vasoconstriction syndromes and vasculitis are among potential causes for cryptogenic stroke.

• #1 The Science of Stroke: Mechanisms in Search of Treatments

  https://pmc.ncbi.nlm.nih.gov/articles/PMC2957363/

  It is also crucial to expand the narrow repertoire of therapeutic opportunities for these devastating conditions. […] To accomplish this, novel approaches are required that expand upon our evolving mechanistic understanding of the fundamentals of cell survival and death processes as well as tissue repair. […] The future depends upon how successful we are in deciphering these mechanisms and bringing clarity to the complex interactions between the multiplicity of cell and tissue types within brain. […] Risk factors have profound effects on the structure and function of blood vessels, and on their interface with circulating blood. […] Many of the established risk factors alter vascular structure by promoting atherosclerosis and stiffening of arteries, and by inducing narrowing, thickening and tortuosity of arterioles and capillaries.

• #1 The Science of Stroke: Mechanisms in Search of Treatments

  https://pmc.ncbi.nlm.nih.gov/articles/PMC2957363/

  In brain, these morphological changes are often associated with reductions in resting cerebral blood flow (CBF) and marked alterations in CBF regulation. […] Thus, aging, hypertension, diabetes and hypercholesterolemia impair vital adaptive mechanisms that assure that the brain is adequately perfused. […] Some risk factors, like hypertension and diabetes, impair protective vascular mechanisms that keep CBF stable during reductions in blood pressure (cerebrovascular autoregulation), facilitating the occurrence of ischemia if intravascular pressure drops. […] These vascular alterations increase the brain’s vulnerability to ischemia after arterial occlusion because they compromise the development of collateral flow arising from adjacent non-ischemic vascular territories, which is vital to the survival of the ischemic perinfarct zone.

• #1 Molecular Pathogenesis of Ischemic and Hemorrhagic Strokes: Background and Therapeutic Approaches

  https://www.mdpi.com/1422-0067/25/12/6297

  Stroke represents one of the neurological diseases most responsible for death and permanent disability in the world. Different factors, such as thrombus, emboli and atherosclerosis, take part in the intricate pathophysiology of stroke. Comprehending the molecular processes involved in this mechanism is crucial to developing new, specific and efficient treatments. Some common mechanisms are excitotoxicity and calcium overload, oxidative stress and neuroinflammation. Furthermore, non-coding RNAs (ncRNAs) are critical in pathophysiology and recovery after cerebral ischemia. ncRNAs, particularly microRNAs, and long non-coding RNAs (lncRNAs) are essential for angiogenesis and neuroprotection, and they have been suggested to be therapeutic, diagnostic and prognostic tools in cerebrovascular diseases, including stroke.

• #1 Signaling pathways involved in ischemic stroke: molecular mechanisms and therapeutic interventions | Signal Transduction and Targeted Therapy

  https://www.nature.com/articles/s41392-022-01064-1

  Overall, these cellular dysfunctions are termed excitotoxicity and involve NMDARs, -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors, and kainite receptors. […] The protective effect of the PI3K/Akt signaling pathway on ischemic stroke has been reported both in in vitro neurons during hypoxia and in vivo against ischemic neuronal death, and PI3K/Akt signaling inhibition aggravates ischemia-induced neuronal death in experimental stroke animals. […] Mechanistically, the neuroprotective effect of Akt is related to the phosphorylation and inactivation of various downstream targets, including glycogen synthase kinase 3 beta (GSK3), pro-apoptotic B-cell lymphoma 2 (Bcl2)-associated BAD, c-Jun N-terminal kinase (JNK)/p38 activator ASK1, and apoptotic p53. […] The neuroprotective PI3K/Akt pathway induces the nuclear translocation of Nrf2, which in turn stimulates the production of various antioxidants.

• #1 Signaling pathways involved in ischemic stroke: molecular mechanisms and therapeutic interventions | Signal Transduction and Targeted Therapy

  https://www.nature.com/articles/s41392-022-01064-1

  Nrf2 is a crucial player against oxidative stress and mitochondrial dysfunction in ischemic brain injuries, possibly via the regulation of various downstream signaling pathways. […] The activated mitophagy pathway may alleviate oxidative stress-induced cell injuries by promoting the degradation of damaged mitochondria. […] Targeting these signals could potentially ameliorate the pathological changes and symptoms of ischemic stroke; however, the mechanisms remain to be elucidated.

• #1 Molecular Pathogenesis of Ischemic and Hemorrhagic Strokes: Background and Therapeutic Approaches

  https://www.mdpi.com/1422-0067/25/12/6297

  Ischemic stroke and hemorrhagic stroke share different pathophysiological mechanisms, such as oxidative stress and inflammation; among the other most important mechanisms in ischemic stroke are calcium overload and excitotoxicity. […] Given the diversity of the pathophysiological mechanisms involved, therapeutic strategies continually evolve in search of potential pharmacological targets. Therefore, this review focuses on the pathophysiology, molecular basis and potential therapeutic strategies for stroke, both those consolidated and newly evolving. […] The onset of ischemia is followed by a cascade of events producing or activating different components, disrupting the homeostatic balance within the brain and leading to cellular death. Among these, excitotoxicity, oxidative stress and the inflammatory response play vital roles.

• #1

  https://journals.lww.com/nrronline/fulltext/2021/16030/physiopathology_of_ischemic_stroke_and_its.5.aspx

  Memantine, an approved drug to treat patients with moderate to severe Alzheimers disease, showed pleiotropic effects in models of experimental stroke, suggesting that it participates in different regulatory pathways of neuroprotection and neuroplasticity. The protective role of memantine is expressed as the reduction of infarct volume and neurological deficits if the drug is applied immediately or a few minutes after artery occlusion, which suggests its utility in the acute phase as a complement to thrombolytic therapy and endovascular thrombectomy. Moreover, some results suggest that memantine decreases apoptosis, proteases, and BBB permeability, which can contribute to the protective effect. Long-term use (28 days, oral administration) showed neuroplastic effects such as reconfiguration of optical maps, significant increase of BDNF, angiogenesis, and functional recovery, decrease of astrogliosis, but no difference in the infarct size, which suggests that memantine could be useful in the chronic poststroke stage, which is a more realistic possibility.

• #1

  https://journals.lww.com/nrronline/fulltext/2025/01000/mechanism_of_inflammatory_response_and_therapeutic.7.aspx

  Stem cell therapy holds promise in stroke treatment owing to its regenerative and immunomodulatory properties. […] Various types of stem cells have shown potential in promoting tissue repair, reducing inflammation, and enhancing functional recovery after stroke. […] However, further research is needed to optimize the delivery methods, dosage, and timing of stem cell therapy in stroke treatment.

• #1 The Science of Stroke: Mechanisms in Search of Treatments

  https://pmc.ncbi.nlm.nih.gov/articles/PMC2957363/

  This review focuses on mechanisms and emerging concepts that drive the science of stroke in a therapeutic direction. […] Growing evidence has led to the realization that the biological processes underlying stroke are driven by the interaction of neurons, glia, vascular cells and matrix components, which actively participate in mechanisms of tissue injury and repair. […] As new targets are identified, new opportunities emerge that build on an appreciation of acute cellular events acting in a broader context of ongoing destructive, protective and reparative processes. […] The burden of disease is great and its magnitude widens as a role for blood vessels and stroke in vascular and non-vascular dementias becomes more clearly established. […] Hence, the disease burden is great. […] The estimated cost for stroke is 73.7 billion dollars in 2010 (USA) and projected to be 1.52 trillion dollars in 2050 (in 2005 dollars).

• #2 Stroke Mechanisms

  http://neuroanatomy.ca/stroke/mechanisms.html

  A stroke occurs when there is interruption of the blood supply to a particular area of the brain, ultimately leading to cell injury and cell death. Strokes can be classified as either: ischemic or hemorrhagic. […] Ischemic strokes are the most common, accounting for up to 80% of strokes, and occur when there is an occlusion of a blood vessel impairing the flow of blood to the brain. Ischemic strokes are divided into: [A] Thrombotic [B] Embolic [C] Systemic Hypoprofusion. […] In thrombotic stroke, a thrombus or clot gradually builds up in the artery, eventually occluding it and disturbing blood flow to tissue downstream from the thrombus. […] Three primary influences predispose to the formation of thrombi, the so-called Virchow Triad: Endothelial Injury, Stasis or Turbulent Blood Flow, Hypercoagulability.

• #2 Pathophysiology and Treatment of Stroke: Present Status and Future Perspectives

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7589849/

  Hemorrhagic stroke accounts for approximately 10-15% of all strokes and has a high mortality rate. […] It produces toxic effects in the vascular system, resulting in infarction. […] The main reasons for ICH are hypertension, disrupted vasculature, excessive use of anticoagulants and thrombolytic agents.

• #2 Stroke Mechanisms

  https://www.neuroanatomy.ca/stroke/mechanisms.html

  A stroke occurs when there is interruption of the blood supply to a particular area of the brain, ultimately leading to cell injury and cell death. Strokes can be classified as either: ischemic or hemorrhagic. […] Ischemic strokes are the most common, accounting for up to 80% of strokes, and occur when there is an occlusion of a blood vessel impairing the flow of blood to the brain. […] In thrombotic stroke, a thrombus or clot gradually builds up in the artery, eventually occluding it and disturbing blood flow to tissue downstream from the thrombus. […] Three primary influences predispose to the formation of thrombi, the so-called Virchow Triad: Endothelial Injury, Stasis or Turbulent Blood Flow, Hypercoagulability. […] In an embolic stroke, a piece of material (or embolus) travels from a distant location and lodges in the blood vessel, occluding it.

• #2 Stroke Mechanisms

  https://www.neuroanatomy.ca/stroke/mechanisms.html

  Because the blockage arrives from another location, the onset of embolic strokes is usually quicker than that of thrombotic strokes. […] In systemic hypoperfusion, blood flow is decreased to all areas of the body. […] Although less common (~15% of strokes), hemorrhagic (or bleeding) strokes can be much more serious. This is because in addition to the interruption of blood supply to the target tissue, the hemorrhage (bleed) can also cause increasing intracranial pressure which can physically impinge on brain tissue, further impairing perfusion of the cerebrum.

• #2 Lacunar stroke: mechanisms and therapeutic implications | Journal of Neurology, Neurosurgery & Psychiatry

  https://jnnp.bmj.com/content/92/8/823

  There are several potential mechanisms described for the pathogenesis of lacunar stroke. […] Lipohyalinosis is defined as concentric hyaline thickening of the cerebral small vessels leading to occlusion of the small penetrating arteries and is one of the first and most common lacunar stroke mechanisms described and pathologically proven to cause lacunar stroke. […] Lipohyalinosis is thought to originate from hypertension-related hypertrophy and fibrinoid degeneration of the vessel walls as well as subintimal foam cells obliterating the lumen of small penetrating arteries, leading to small subcortical infarcts. […] In addition to lipohyalinosis, some studies hypothesised that endothelial dysfunction and impaired autoregulation as well as extravasation of blood products into the vessel wall resulting in perivascular oedema and damage to the neurovascular unit and surrounding brain tissue may be a contributing factor to the development of lacunar infarcts.

• #2

  https://journals.lww.com/nrronline/fulltext/2021/16030/physiopathology_of_ischemic_stroke_and_its.5.aspx

  The reduction or cessation of blood flow in the brain may produce different levels of damage depending on the time elapsed, cell resistance and magnitude of the ischemia, and activates a very complex cascade of interrelated cellular and molecular events with a temporal overlapping profile that evolves over minutes, hours or days, inducing injury in all cell types and damage that can range from transient to irreversible (e.g., cell death). This event produces two different areas of damage: the ischemic core and the penumbra. In the ischemic core, blood flow is abruptly reduced and the cells are permanently injured and die rapidly by necrosis. The size of this area will depend primarily on the duration and magnitude of the ischemia and the location of the stroke. The penumbra is located around the ischemic core. This zone is perfused by collateral blood vessels which allow cells that are structurally intact but functionally weakened. These functionally impaired cells can be slowly incorporated into the ischemic stroke or saved.

• #2

  https://journals.lww.com/nrronline/fulltext/2021/16030/physiopathology_of_ischemic_stroke_and_its.5.aspx

  Ischemic cascade refers to several interrelated and overlapped pathological mechanisms that are activated after a few minutes of blood vessel occlusion and whose progress occurred on a different time scale. The first event of the ischemic cascade is the reduction of oxygen and glucose which leads to a failure to produce high-energy molecules to maintain the cellular homeostasis. This sets off several mechanisms that include ionic imbalance, excitotoxicity, calcium overload, cytotoxic and vasogenic edema, peri-infarct depolarization, oxidative and nitrosative stress, blood-brain barrier (BBB) disruption, inflammation, and apoptosis. […] Although after a stroke neuroprotective and neuroplastic mechanisms overlap, they can be differentiated as follows: after damage, all the cells activate a series of mechanisms against the harmful factors to avoid damage (neuroprotection). In the infarct core, these mechanisms exceed their capacity to protect and the cells die. In the penumbra this mechanism contributes to limit the expansion of the infarct core and include: 1) homeostatic regulation of ions and fluids, 2) free radical scavenging, 3) neurotransmitter re-uptake, 4) production and release of anti-inflammatory cytokines, 5) BBB and neurovascular unit repair, 6) isolation of the injury site through scar formation, and 7) phagocytosis and debris clearance. Neuroplasticity involves the activation of mechanisms to restore the homeostatic function of the tissue previously damaged through reorganization and compensation of structural and functional deficiencies and includes: 1) production and release of growth factors, 2) angiogenesis, gliogenesis, and neurogenesis, 3) reorganization of microvascular and neuronal networks, and 4) synaptic contact growth.

• #2 Signaling pathways involved in ischemic stroke: molecular mechanisms and therapeutic interventions | Signal Transduction and Targeted Therapy

  https://www.nature.com/articles/s41392-022-01064-1

  Various signaling pathways become activated in these pathological transitions, and their targeted regulation could serve as a potential therapeutic strategy. […] Given the complex pathophysiology of ischemic stroke, the accompanying injury and signaling mechanisms should be first identified and then further elucidated to develop targeted interventions. […] The present review describes various signaling pathways associated with ischemic stroke pathophysiology and categorizes the corresponding therapeutic approaches. […] As a hallmark of ischemic stroke, interrupted cerebral blood flow depletes the brain of oxygen and glucose, which leads to disrupted ATP synthesis and energy deficiency, as well as impaired ion homeostasis and acid-base imbalance. […] All these dysfunctions result in cerebral neuropathological changes, such as brain edema, neuroinflammation, and neural cell death, eventually underpinning severe neurological deficits.

• #2 Signaling pathways involved in ischemic stroke: molecular mechanisms and therapeutic interventions | Signal Transduction and Targeted Therapy

  https://www.nature.com/articles/s41392-022-01064-1

  Nrf2 is a crucial player against oxidative stress and mitochondrial dysfunction in ischemic brain injuries, possibly via the regulation of various downstream signaling pathways. […] The activated mitophagy pathway may alleviate oxidative stress-induced cell injuries by promoting the degradation of damaged mitochondria. […] Targeting these signals could potentially ameliorate the pathological changes and symptoms of ischemic stroke; however, the mechanisms remain to be elucidated.

• #3 Stroke Mechanisms

  http://neuroanatomy.ca/stroke/mechanisms.html

  In an embolic stroke, a piece of material (or embolus) travels from a distant location and lodges in the blood vessel, occluding it. […] Because the blockage arrives from another location, the onset of embolic strokes is usually quicker than that of thrombotic strokes. […] In systemic hypoperfusion, blood flow is decreased to all areas of the body. […] Although less common (~15% of strokes), hemorrhagic (or bleeding) strokes can be much more serious. This is because in addition to the interruption of blood supply to the target tissue, the hemorrhage (bleed) can also cause increasing intracranial pressure which can physically impinge on brain tissue, further impairing perfusion of the cerebrum.

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