Stroke Pathophysiology and Pharmacology (Dr.Sadana)

What are the 2 types of brain edema?

1. Cytotoxic edema (early onset in minutes) 2. Vasogenic edema (late onset hours--> days)

What is the pathophysiologic of an ischemic stroke?

1. Occlusion of an intracranial vessel by an embolus often affecting the large intracranial vessels 2. Thrombosis of an intracranial vessel, typically affecting the small penetrating arteries that arise from the major intracranial arteries 3. Hypoperfusion caused by flow- limiting stenosis of a major extracranial (e.g., internal carotid) or intracranial vessel, often producing "watershed" ischemia- border zone infarcts. Watershed means receiving partial circulation by multiple vessels

What are the types of ischemic stroke?

1. Thrombotic: -Large vessels (major cerebral arteries) -Small vessels (Called Lacunar stroke) -Venous occlusion--> blood backs up behind occlusion, causes edema and tissue infarction 2. Embolic: -Artery to artery -Cardioembolic

What is streptokinase?

A protein (but not an enzyme in itself, Not a protease) synthesized by streptococci that combines with the proactivator plasminogen. This enzymatic complex catalyzes the conversion of inactive plasminogen to active plasmin It forms a complex with plasminogen that releases plasmin. SK produces significant fibrinogenolysis along with clot fibrinolysis Allergic reactions occur in ∼5% of patients treated with streptokinase. These may manifest as a rash, fever, chills, and rigors. Although anaphylactic reactions can occur, these are rare. Transient hypotension is common with streptokinase and has been attributed to plasmin-mediated release of bradykinin

What is cytotoxic edema?

ATP depletion with subsequent lactate accumulation due to anaerobic metabolism and accumulation of intracellular sodium and water, leading to cytotoxic edema and eventual cell lysis. Occurs within minutes.

How does a stroke cause disruption of ionic gradients?

ATP is used for maintenance of transmembrane ion gradients. With energy failure, these gradients are dissipated. Na+/K+-ATPase, which accounts for approximately 2/3 of neuronal energy expenditure fails to maintain high intracellular K+ conc As a consequence, K+leaks from cells and depolarizes adjacent cells, activating voltage-gated ion channels, Ca2+ influx, and neurotransmitter release.

What is a transient ischemic attack?

Abbreviated TIA is transient episode of neurological dysfunction caused by focal brain, spinal cord, or retinal ischemia, without acute infarction. Have ischemia but no infarction (no cell death) TIA is a risk factor for acute ischemic stroke. Precedes acute ischemic stroke in some cases

If you have a stroke in the middle cerebral artery what is effected?

Face, hand, arms, tongue

How does a stroke cause inflammation?

Cerebral ischemia triggers an inflammatory response that involves both resident and blood-borne cells of the innate immune system. Includes astrocytes and microglia, neutrophils, lymphocytes, and monocytes. Inflammation begins within blood vessels as a response to occlusion and is amplified by cell death within brain parenchyma. Adaptive immune responses may emerge later in the course. Molecular mediators of ischemia-induced inflammation include adhesion molecules, cytokines, chemokines, and proteases. Although the early inflammatory response to ischemia is thought to provoke secondary injury, subsequent inflammatory events may be neuroprotective or contribute to tissue repair.

What are the survival/repair mechanisms after a stroke?

Collateral Circulation Inhibitory Neurotransmitters Transcription hypoxia response Neurogenesis Angiogenesis Ischemic tolerance

What are the signs of a stroke?

F=Face: Facial drooping A=Arm: Arm weakness S=Speech: Speech difficulties T=Time: Time to call 911!!! Other Signs: -inability to speak -loss of vision -vertigo, or falling Ischemic stroke is not usually painful, but patients may complain of headache, and with hemorrhagic stroke, it can be very severe. Neurologic dysfunction and hemiparesis (inability to move on one side of the body) are common.

What are the injury mechanisms of a stroke?

Energy Failure--> mitochondrial dysfunction Disruption of Ionic Gradients Calcium Dysregulation Excitotoxicity Oxidative and Nitrosative injury Cell death cascade Inflammation Brain Edema Happens basically in this order (over minutes--> weeks)

What is tenecteplase?

Genetically engineered TPA Longer half-life Easy to use More fibrin specific than t-PA: produces less fibrinogen degradation Improved safety profile compared to t-PA

What is an hemorrhagic stroke? and what are the types?

Hemorrhagic stroke is a result of bleeding into the brain and other spaces within the CNS Can be caused by hypertension or aneurism Hemorrhagic stroke is more lethal than ischemic Types: 1. Intracerebral Hemorrhage (ICH) - bleeding in the brain parenchyma. HTN is the biggest cause 2. Sub Arachnoid Hemorrhage (SAH) - bleeding in the subarachnoid space due to aneurysm rupture

How does energy failure occur in a stroke?

High energy demands dependent on oxidation Reduction of blood flow interferes with the delivery of —oxygen and glucose—causing ATP levels to fall. Glycolysis keeps up only for a little bit Ultimately neuronal cell death occurs.

What are stroke risk factors?

Hypertension (most important!) Dyslipidemia Atrial fibrillation Other cardiac diseases (myocardial infarct, etc) Embolism or vasospasm Intracranial hemorrhage Loss of perfusion secondary to cardiac arrest Asymptomatic carotid stenosis History of TIA Age (doubling per decade >55) Gender (men > women) Family history Ethnic group (African American>Hispanic>Caucasian) Diabetes Smoking Chronic alcoholism Obesity Postmenopausal hormone therapy Low birth weight: < 2500g (doubles risk!)

What is alteplase?

Intrinsic compound Recombinant DNA manufacture Non-antigenic Short half-life Higher fibrin specificity than fibrinogen. Which facilitates localization of plasmin generation on fibrin surface. Expensive Adverse effects - bleeding (especially intracranially), angioedema

What is angiogenesis?

Ischemia also stimulates the sprouting of existing blood vessels to enhance local blood supply This process takes at least several days, it probably has little impact in the acute phase of stroke

What is ischemic tolerance?

Ischemia may protect against a subsequent ischemia events In this process, mild ischemia preconditions brain tissue so it is better able to survive more severe ischemia for a few days thereafter.

How does a stroke cause calcium dysregulation?

Ischemia-induced elevation of extracellular K+ causes membrane depolarization and triggers Ca2+ entry through voltage-gated Ca2+ channels and voltage-sensitive glutamate receptor-gated channels The rise in intracellular Na+ that results from loss of Na+/K+-ATPase activity causes the Na+/Ca2+ exchanger, which normally exports Ca2+ from cells against its concentration gradient, to operate in reverse and import Ca2+. In addition, Ca2+ induces further Ca2+ release from ER. As intracellular Ca2+ levels rise, the Ca2+-buffering capacity of organelles (mitochondria and ER) and Ca2+-binding proteins is overwhelmed. Catabolic proteases, lipases, and nucleases are activated, mitochondrial function is compromised, and cell death pathways are mobilized.

How do inhibitory neurotransmitters help in survival/repair?

Ischemic brain tissue is characterized by excessive excitation Mitigated early in the course of stroke by enhanced tonic inhibition mediated through extrasynaptic GABA-A receptors (inhibitory effect on transmission). Later, however, this inhibitory effect may be detrimental to recovery.

What are the cell death cascades of a stroke?

Ischemic cell death thought to occur most rapidly in the infarct core and more slowly in the penumbra and during reperfusion. Rapid cell death in the ischemic core is caused by necrosis However, it's slower and more regulated modes of cell death (apoptosis), may predominate in the penumbra and during reperfusion injury. The core expands over time Apoptosis may be triggered by extracellular (extrinsic pathway) or intracellular (intrinsic pathway) signals; may progress in a caspase dependent or caspase independent manner.

If you have a stroke in the anterior cerebral artery what is affected?

Legs, feet, arms, trunk

What is neurogenesis?

Long term mechanism New neurons and astrocytes continue to be produced in the adult brain in at least two regions: -hippocampal dentate gyrus - subventricular zone Make more neurons in the opposite hemisphere of damage and then those neurons will migrate to the infarct zone

What are the early cellular changes during a stroke?

Loss of function due to: -Rapid drop of tissue oxygen -Rapid drop in tissue glucose -Acidosis (change to anaerobic metabolism) But some good stuff still operative... -Residual ATP (energy) production -Ionic gradients across membranes still somewhat preserved

What is an ischemic stroke?

Most stroke cases are ischemic strokes Ischemic stroke is defined as an infarction of CNS tissue attributable to ischemia Based on neuropathologic, neuroimaging, and/or clinical evidence (ie, persistence of symptoms or findings) of permanent injury. Caused by a blockage in an artery that supplies blood to the brain It is characterized by the abrupt development of a focal neurological deficit that occurs due to inadequate blood supply to an area of the brain.

What is NIHSS?

National Institute of Health Stroke Scale The NIHSS is a 15-item neurologic examination stroke scale used to evaluate the effect of acute cerebral infarction on the levels of consciousness, language, neglect, visual- field loss, extraocular movement, motor strength, ataxia, dysarthria, and sensory loss.

What is urokinase?

Not fibrin specific Intrinsic compound--> Isolated from urine or renal cell cultures Non-antigenic Cleaves plasminogen

What regulates endogenous fibrinolysis?

PAI-1: inhibits tPA Alpha-2 antiplasmin: inhibits plasmin. Plasmin generated on the fibrin surface is relatively protected from inactivation by α2-antiplasmin. Plasmin degrades not only fibrin but also other proteins like fibrinogen and other clotting factors (alpha 2 anti-plasmin helps keep this in check)

What is fibrin specificity?

Plasminogen activators that preferentially activate fibrin- bound plasminogen are considered fibrin-specific. In contrast, nonspecific plasminogen activators do not discriminate between fibrin-bound and circulating plasminogen. Activation of circulating plasminogen results in the generation of unopposed plasmin that can trigger the systemic lytic state. Specific: -Alteplase -Reteplase -Tenecteplase Nonspecific agents: -streptokinase -anistreplase -urokinase

How does a stroke cause excitotoxicity?

Refers to the pathogenic effects of excitatory neurotransmitters, especially glutamate, on central neurons. Ischemia promotes excitotoxicity by stimulating depolarization-induced synaptic release of neuronal glutamate, releasing glutamate through reversal of astrocytic glutamate uptake, and activating voltage-sensitive glutamate receptor-gated channels. The receptors primarily involved in excitotoxicity are extrasynaptic NMDA ionotropic receptors. Influx of Ca2+ through NMDA receptor-coupled channels contributes to the Ca2+ dysregulation In addition, this route of Ca2+ entry is closely linked to the activation of neuronal nitric oxide synthase (NOS1), which generates nitric oxide (NO). Neuronally derived NO contributes to nitrosative injury. (This type of NO is not beneficial- not a vasodilator b/c its not produced in endothelial cells). Produced a free radical called peroxynitrite

What is t-PA vs streptokinase?

SK is not a protease and has no enzymatic activity; however, it forms a complex with plasminogen that releases plasmin. Unlike tPA, it does not bind preferentially to clot-associated fibrin and therefore binds equally to circulating and non- circulating plasminogen. Therefore, SK produces significant fibrinogenolysis along with clot fibrinolysis

How does a stroke cause oxidative and nitrostative injury?

Some of the toxic effects of ischemia are mediated through the production of ROS and RNS (nitrogen-containing species) These include superoxide anion (O -) and NO, which can combine to generate peroxynitrite (ONOO-). Their effects are include: -inhibiting mitochondrial enzymes and function -damaging DNA -activating ion channels -covalent modification of proteins -triggering cell death pathways

What is the transcriptional hypoxia response?

The cellular response to hypoxia is mediated partly by hypoxia-inducible protein-1 (HIF-1) -->it causes transcriptional activation of proteins that promote cell survival and tissue recovery. Causes production off: - Glycolytic enzymes - Erythropoietin (EPO) -VEGF--> makes new vessels EPO and VEGF also exert direct protective effects on ischemic cells (neuroprotective effect)

What is collateral circulation?

The first line of defense against ischemia is collateral circulation which, if adequate, can bypass an arterial occlusion. The cerebral circulation contains numerous collateral pathways, and the observation that patients with total occlusion of a major vessel may sometimes be asymptomatic indicates that these pathways can be clinically functional.

What is vasogenic edema?

The increased capillary permeability due to blood-brain barrier breakdown leads to greater passage of osmotic particles into the brain's extracellular space and results in an extracellular accumulation of water (vasogenic brain edema). Vasogenic edema is found primarily in the white matter. This has late onset: hours to days to weeks.

How is a stroke heterogenous?

Type of stroke Duration of ischemia Size of infarct area Impacted regions--> parts of the brain are more likely to clot than others (Internal carotid artery or Middle cerebral artery are more likely to clot) All of these parameters impact treatment strategies!

What is reperfusion injury?

Tissue damage caused when blood supply returns to the tissue after a period of ischemia or lack of oxygen Mostly caused by ROS production (decreased antioxidant response) and inflammatory response Unavoidable have to do revascularization

What is a penumbra?

Tissue that is ischemic but maintains membrane integrity is referred to as the ischemic penumbra because it usually surrounds the infarct core. This penumbra is potentially salvageable through therapeutic intervention

What is anistreplase?

is a complex of human plasminogen and bacterial streptokinase. not fibrin specific

What are the steps of t-PA causing clot lysis?

tPA binds to fibrin on the surface of the clot Activates fibrin-bound plasminogen Plasmin is cleaved from the plasminogen associated with the fibrin. Plasmin is a protease that is capable of breaking apart fibrin molecules, thereby dissolving the clot Fibrin molecules are broken apart by the plasmin and the clot dissolves However, it is important to note that plasmin also breaks down other circulating proteins, including fibrinogen.

What is a lacunar stroke?

thrombotic stroke in small vessels

If you have a stroke in the posterior cerebral artery what is effected?

tongue

What are the fibrinolytic drug options?

• Streptokinase (SK) • Anistreplase • Urokinase (UK) • t-PA drugs: Alteplase, Reteplase, Tenecteplase

What is reteplase?

• recombinant TPA derivative • Similar fibrin specificity as alteplase • Longer half-life than alteplase