- Ischemic Stroke
- Neuroprotective Agents
What is a stroke?
A stroke is an interruption in blood supply to a part of the brain causing brain tissue damage. Stroke is a medical emergency and one of the leading causes of death and adult disability.
The three main types of strokes are:
- Hemorrhagic stroke: Blood vessel rupture in the brain that leads to bleeding and tissue damage.
- Ischemic stroke: Blockage of a blood vessel in the brain which interrupts blood supply to a part of the brain leading to cell death from lack of oxygen and nutrients.
- Transient ischemic attack: Brief blockage of blood supply to a part of the brain. Known as mini-strokes, transient ischemic attacks usually last just a few minutes, but are a warning sign for future ischemic strokes.
What is the mode of action for an ischemic stroke?
Currently, the only approved medical therapy for an ischemic stroke is with a medication known as tissue plasminogen activator. Tissue plasminogen activator is an enzyme that helps dissolve the blood clot blocking the blood vessel. The medication is usually administered intravenously within the first three hours after symptoms of an ischemic stroke.
What are neuroprotective agents?
Neuroprotective agents are medications that are being studied for use in ischemic stroke patients, to minimize damage and prevent further injury to partially damaged nerve cells (neurons). The target of neuroprotective agents is to improve functional recovery in ischemic stroke patients by reducing the impact of the stroke.
The neurons in the rim (penumbra) of the core ischemic region are less likely to suffer irreversible damage, and can revive with resumption of blood flow. Animal studies indicate that the penumbral neurons remain viable for about four hours after a stroke.
What are the uses of neuroprotective agents in stroke?
The research on the use of neuroprotective agents is with the aim of protecting the penumbral neurons from irreversible damage, and promoting neuronal healing. Neuroprotective agents may be useful in protecting penumbral neurons from two types of injury that can occur after a stroke:
Early ischemic injury
The loss of blood supply causes cellular injury by inducing excessive activation of certain cell mechanisms such as:
- Activation of excitatory amino acid receptors and release of neurotransmitters (chemicals that transmit signals between neurons)
- Accumulation of calcium in the cells
- Release of toxic products
Neuroprotective agents used for limiting early ischemic injury work by preventing the release of excitatory neurotransmitters, which may reduce the ischemic effects on the neurons in the penumbral region.
Resumption of blood flow after dissolution of the blood clot brings oxygen to the ischemic tissue, but it can also cause injury. Reperfusion injury may result because of the following reasons
- White cells in the blood can block small blood vessels which are affected by partial ischemia, and cause further ischemia.
- Leucocytes also release toxic products that can lead to formation of free radicals and inflammatory proteins (cytokines).
Neuroprotective agents used to prevent reperfusion injury work in the following ways
- Prevent the white cells from adhering to the blood vessel walls
- Limit formation of free radicals and cytokines
- Promote repair of the affected neurons
What are the neuroprotective agents that can be used for a stroke?
Although many neuroprotective agents are being studied for preventing neuronal injury from a stroke, there has been no positive results for efficacy in reducing stroke-related injury. As of 2020, the FDA had not approved any neuroprotective agent for use in stroke patients.
Following sections contain some of the neuroprotective agents that have been studied for efficacy in reducing neuronal injury from stroke.
Prevention of early ischemic injury
N-methyl-D-aspartate receptor antagonists
N-methyl-D-aspartate (NMDA) receptor antagonists are the most commonly studied neuroprotective agents for use in strokes. NMDA receptor antagonists are medications that bind to NMDA receptors on the neurons and block neurotransmitters from activating them. An agonist drug activates a cell’s receptors while an antagonist blocks their activity.
Cell receptors are protein molecules present in the cell membrane, which bind to specific neurotransmitters and activate the cells appropriately. NMDA receptors are a type of neuronal receptors that bind to certain excitatory neurotransmitters such as glutamate, and activate the neurons. Preventing the penumbral neuron activation may limit ischemic injury.
Following are some of the NMDA receptor antagonist drugs investigated for efficacy in minimizing early ischemic injury
- Dextrorphan: Clinical trials have not shown significant neuroprotective effects. Side effects that limit its use include:
- Sulfotel: Clinical trials indicated higher mortality in patients and trials were stopped prematurely.
- GV150526: No improvement was noted in three months and no further trials are planned.
- Magnesium: Studies found that it was safe and feasible to initiate magnesium sulfate treatment by paramedics to reduce the time to treatment. There was no improvement in disability outcomes over the three months of the study, however.
Non-NMDA receptor antagonists
Modulating the activity of certain non-NMDA receptors may also prevent the release of excitatory neurotransmitters. Following are some of the drugs that have been used in clinical trials in stroke patients.
- Nalmefene (Cervene): A narcotic receptor antagonist with minimal side effects, but no clinical benefit was found. No further trials are planned.
- Lubeluzole: Exact mechanism of action is not clear but may block sodium channels and prevent cellular activity. Clinical trials did not confirm efficacy that was observed in animal models, and research was abandoned.
- Clomethiazole: An agonist of gamma-aminobutyric acid (GABA), which is an inhibitory neurotransmitter. Clinical trials did not show significant improvement in functional outcomes at three months.
Some of the other drugs that were investigated in clinical trials before being discontinued for lack of efficacy were
- Calcium channel blockers: To prevent intracellular calcium build-up
- Potassium channel modulators: To decrease intracellular calcium
- Repinotan: Agonist for serotonin, an inhibitory neurotransmitter
- Tirilazad: Free radical scavenger to clear free radicals
- NXY-059: Free radical trapping agent
Other neuroprotective products for early ischemic injury which are being investigated include
- Albumin: A protein made by the liver, which has antioxidant properties and ability to increase blood flow to the penumbral region. The trial was stopped early because results were not promising.
- Hypothermia and caffeinol: A combination of caffeine and low-dose ethanol, along with mild hypothermia produced neuroprotective effects in animal models and is currently being evaluated.
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Prevention of reperfusion injury
Following are some of the neuroprotective agents being evaluated for use in reperfusion injury prevention:
Enlimomab is a monoclonal antibody produced in mice (murine), which can prevent the white cells from adhering to blood vessels and causing a block. Clinical trials with enlimomab produced worse outcomes than placebo in stroke patients. The adverse effects were possibly due to immune response to the murine antibody.
A human antileukocytic antibody, Hu23F2G did not produce an immune response in clinical trials, but there was no clinical benefit. No further studies are planned.
A clinical trial with minocycline, a tetracycline antibiotic, showed improvement in stroke outcome by reducing leukocyte infiltration. Minocycline also appears to reduce risks of cerebral hemorrhage resulting from clot dissolution.
Abciximab (ReoPro) is an antiplatelet antibody that inhibits platelet aggregation, preventing additional ischemia and clot formation. Clinical trial was discontinued because of high risks of cerebral hemorrhage.
Citicoline is a substance that helps in cell membrane’s biosynthesis and may reduce ischemic injury by stabilizing the neuronal membrane. Clinical trials have shown that citicoline is safe for stroke patients and prolonged use after the stroke may be effective in improving functional recovery.
Several studies have been conducted to investigate substances that can enhance neuronal healing after an ischemic stroke.
Fiblast is a fibroblastic growth factor, a type of protein that helps in wound healing and cell multiplication. Trials have been discontinued due to poor risk-to-benefit ratio.
Autologous mesenchymal stem cells
Autologous mesenchymal stem cells are produced in the bone marrow and important for tissue repair. Studies are in progress for feasibility and safety of using these stem cells in stroke patients.
After a stroke, the levels of a protein known as myelin-associated-glycoprotein (MAG) spontaneously increases in the penumbral region.
GSK249320 is a monoclonal antibody that blocks MAG. Animal studies have shown it might be safely used in stroke patients to promote neuronal healing.
Neuroprotective agents are medications that are being studied for use in some stroke patients, to minimize damage and prevent further injury to partially damaged nerve cells (neurons). The target of neuroprotective agents is to improve functional recovery in ischemic stroke patients by reducing the damage of the stroke.
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Related Disease Conditions
14 Warning Signs and Symptoms of a Stroke FAST
Stroke is a serious medical condition. If you think you or someone you know is having a stroke call 911 immediately. There are two main types of strokes, hemorrhagic and ischemic (the most common type). A hemorrhagic stroke occurs due to a blood vessel rupture in the brain. An ischemic stroke occurs when a blood clot becomes lodged in a blood vessel in the brain, which causes a loss of blood supply to the brain, possibly causing brain tissue death. FAST is an acronym that helps people identify stroke signs and symptoms so they can act fast and call 911. Face drooping, Arm weakness, and Speech difficulty are indicators that a person may be having a stroke and it is Time to seek emergency medical treatment. Additional signs and symptoms of stroke may include weakness, difficulty walking, blurred vision, dizziness, headache, confusion, difficulty speaking, and loss of sensation. Stroke is a major cause of death and disability in the U.S. Early identification and treatment of stroke helps reduce the risk of morbidity and mortality.
A stroke is an interruption of the blood supply to part of the brain caused by either a blood clot (ischemic) or bleeding (hemorrhagic). Symptoms of a stroke may include weakness, numbness, double vision or vision loss, confusion, vertigo, difficulty speaking, or understanding speech. A physical exam, imaging tests, neurological exam, and blood tests may be used to diagnose a stroke. Treatment may include administration of clot-busting drugs, supportive care, and in some instances, neurosurgery. The risk of stroke can be reduced by controlling high blood pressure, high cholesterol, diabetes, and stopping smoking.
Transient Ischemic Attack (TIA, Mini-Stroke)
When a portion of the brain loses blood supply, through a blood clot or embolus, a transient ischemic attack (TIA, mini-stroke) may occur. If the symptoms do not resolve, a stroke most likely has occurred. Learn the symptoms, risk factors, and treatment for a transient ischemic attack.
Stroke vs. Mini-Stroke (TIA) Differences
A stroke occurs when a blood clot or artery ruptures within the brain. The rupture or clot causes brain cell damage or death. A mini-stroke (TIA, transient ischemic attack) is caused by brain cells that become dysfunctional over a short period. Stroke and mini-stroke warning signs of stroke and mini-stroke are the same, and include, speech problems, weakness, numbness, and facial droop. Side effects of stroke may be permanent and you may never regain full function of the parts of the body affected. Mini-stroke side effects usually resolve within minutes to a couple of days. A transient ischemic attack (mini-stroke) is a precursor for stroke because 40% of individuals who have a mini-stroke will have a stroke within a year. Treatment of stroke depends upon the type and parts of the body affected.
What Is the Difference Between Ischemic Stroke and Hemorrhagic Stroke?
A stroke is a serious medical event that can have lasting consequences. Learn more about the two primary types of strokes and how to recognize the symptoms.
How Can You Tell the Difference Between Bell's Palsy and a Stroke?
Bell's palsy and stroke have similar symptoms, but they are two very different conditions. Learn more about what makes them different, recognize each's symptoms, and how to treat both.
Heart Attack vs. Stroke Symptoms, Differences, and Similarities
Heart attack usually is caused by a clot that stops blood flow supplying oxygen to an area of heart muscle, which results in heart muscle death. Stroke or "brain attack" is caused by a loss of blood supply to the brain (usually a blood clot) or by hemorrhagic stroke (bleeding within the brain), which results in brain tissue death. Both heart attack and stroke usually come on suddenly, produce similar symptoms, can be disabling, and can be fatal. The classic symptoms and warning signs of heart attack are different. Classic heart attack warning signs are chest pain or discomfort, shortness of breath, pain that radiates to the shoulders, back, arms, belly, jaw, or teeth, sweating, fainting, and nausea and vomiting. Moreover, woman having a heart attack may have additional symptoms like abdominal pain or discomfort, dizziness, clammy skin, and moderate to severe fatigue. The classic symptoms and warning signs that a person is having a stroke are confusion or loss of consciousness, sudden severe headache, speech problems, problems seeing out of one or both eyes, and numbness or weakness of only one side of the body. Moreover, a woman having a stroke may have additional warning symptom and signs like shortness of breath, disorientation, agitation, behavioral changes, weakness, nausea, vomiting, seizures, and hiccups. Recognition of stroke symptoms is vital for emergency treatment. The acronym "FAST" stands for recognition of Facial drooping, Arm weakness, Speech difficulty, and a Time for action. If you experience the symptoms heart attack or stroke (FAST) or see them develop in another person, then contact 911 immediately.
Stroke vs Aneurysm (Differences and Similarities)
A stroke or "brain attack" is caused because blood flow to an area of the brain has been cut off by a blood clot or by a weakened or damaged blood vessel (for example, head trauma). The damaged area of the brain dies, which results in loss of function like speech capabilities, muscle movement, or muscles of an extremity like an arm or leg is reduced or lost completely. An aneurysm is a weakness in an artery wall. This weakness in the wall causes the artery to widen or balloon out, and then they rupture or break open.
Migraine and Stroke
Migraine headache is a type of headache in which the exact cause is not known; however, they may be inherited, and certain foods and environmental factors can trigger and may contribute them. A stroke (brain attack) happens when a blood vessel in the brain leaks, bursts, or becomes blocked, which can be caused by many other health problems. Both migraines and strokes can can cause severe head pain (migraine pain usually is only on one side of the head). Migraine aura symptoms may mimic or feel like a stroke or mini-stroke (transient ischemic attack, TIA) because they have similar symptoms and signs like severe headache, numbness in the legs, feet, arms, hands, or face, nausea, vomiting, and dizziness. Other migraine aura symptoms include vision problems like flashing lights or blind spots in one eye. The main difference between migraine headache and stroke symptoms and signs is that a migraine headaches usually come on gradually while a stroke symptoms come on suddenly and unexpectedly.
Can Drinking Water Help Prevent a Stroke?
Many studies have proven that proper hydration at the time of a stroke is linked to better stroke recovery. It is possible that dehydration causes blood to be thicker. Viscous blood causes the body to retain sodium and increases blood pressure. Drinking enough water regularly prevents dehydration. This may play a role in keeping the blood less viscous, which in turn prevents a stroke.
Is CADASIL a Terminal Illness?
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a genetic disorder that affects the small arteries in the brain, leading to stroke-like episodes, cognitive decline, and other symptoms. It can be life-threatening in some cases, but symptoms, severity, and progression of the disease varies. The exact mortality rate for people with CADASIL is not known, but a person with CADASIL on average lives for 61 years.
How Can You Prevent a Stroke From Happening?
Strokes occur due to the obstruction of blood flow to the brain. Some irreversible factors, such as age and family history, are likely to increase the risk of stroke. These factors cannot be modified. However, many such preventable or modifiable factors can help prevent strokes.
Aneurysm vs Stroke: Which Is Worse?
What is the difference between an aneurysm and a stroke?
How Do You Detect Brain Damage?
Brain damage, also known as brain injury or neurological injury, is an injury to the brain that affects its ability to function properly. There are several tests used to detect brain damage, including medical history, physical examination, neurological examination, neuroimaging, neuropsychological testing, and other specialized tests. Brain damage can be subtle and may not always be detectable. Sometimes the effects of brain damage may not become apparent until later in life.
Types of Strokes
A stroke, also called cerebrovascular accident (CVA), occurs when the blood supply is cut off or reduced to a part of the brain. There are five main types of strokes, and the causes and clinical presentation of each of them vary
Treatment & Diagnosis
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- Stroke Treatment
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Medications & Supplements
Prevention & Wellness
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