Stroke and cardiac arrest are major causes of death and disability, affect millions of individuals around the world and are responsible for the leading health care costs of all diseases.


TYPES OF STROKE
A stroke occurs when blood vessels carrying oxygen and other nutrients to a specific part of the brain suddenly burst or become blocked. When blood fails to get through to the affected parts of the brain, the oxygen supply is cut off, and brain cells begin to die.
Strokes fall into two major categories, based on whether the disrupted blood supply is caused by a blocked blood vessel (occlusive or ischemic stroke) or a hemorrhage (hemorrhagic stroke) (see figure below).

Eighty percent of strokes are ischemic and includes thrombotic and embolic stroke. In thrombotic stroke a blood clot (thrombus) forms inside a large artery such as the internal carotid artery, the proximal and intracranial vertebral arteries, or the basilar artery. Small arteries (diameter<200 µm) that branch from a large intracerebral artery, produces lacunes, small infarcts with specific and restricted syndromes. Typical locations include the basal ganglia, thalamus, internal capsule, pons, and cerebellum.
Embolic stroke is also caused by a clot; however, the clot originates somewhere else than the brain (e.g. left ventricle of the atrium, extracranial arteries) and gets wedged in medium-sized branching arteries. Patients typically have a history of coronary disease, atrial fibrillation, rheumatic heart disease, prosthetic valve, myocardial infarction or cancer.

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STROKE SYNDROMES
The injury results in stroke syndromes including vertigo, sensory loss, nystagmus, anopia, facial numbness, ataxia, dysphagia, dysarthria, ophtalamoplegia, hemiparesis, arm and leg paralysis, amnesia, color anomia, abulia, alexia, urinary incontinence or coma depending on the arterial territory involved.
An ischemic attack is often preceded by a transient ischemic attack (TIA) with clinical symptoms typically lasting less than one hour.

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RISK FACTORS
Several factors may play role in the development of stroke such as environmental factors (e.g. smoking, alcohol consumption, oral contraceptives, diet etc.), comorbidities (e.g. hypertension, coronary heart disease, atrial fibrillation, aneurysm, arteriovenous malformation, atherosclerosis, diabetes mellitus etc.) and genetic factors (e.g. age, race etc.).

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STROKE OUTCOME AND PATHOGENESIS
Each source of stroke is associated with different infarct mechanisms and size, ranging from the lacunar strokes of small vessel disease to the large wedge-shaped cortical and subcortical infarctions of embolic stroke.
Extremely brief (1-2 minutes) ischemic period results not only in neuronal survival but activation of mechanisms that make the neurons resistant to subsequent more severe ischemic episodes (ischemic tolerance or preconditioning).
Longer period of ischemic insult followed by reperfusion generally results in partial or complete restoration of oxidative metabolism, ATP synthesis, and repolarization of the neruonal membrane and followed by a complex cascade of molecular events results in cell death. Because survival is rare after prolonged cardiac arrest, most resuscitated patients have been exposed to less than 30 minutes of global ischemia.

After cardiac arrest (global ischemic animnal model) cell types and brain areas show differences between in their vulnerability. The hippocampal pyramidal cells of CA1, pyramidal neocortical neurons (layers 3, 5, and 6), Purkinje cells, and striatal neurons have the highest vulnerability.
In the hippocampus, the pyramidal neurons in area CA1 and some neurons in the hilus are most vulnerable, whereas most of the CA3 pyramidal neurons survive and the granular cells in dentate gyrus are resistant to ischemic damage. Ischemic cell death becomes manifested first in the hilar neurons, but the cell death in CA1 occurs with a delay of 1 to 2 days. At a week after ischemia complete ablation of the CA1 pyramidal cell layer can be observed..
There are also differences between cell types in their vulnerability. Neurons are more sensitive exposed to ischemia than glial cells because they have higher energy demands and only they produce glutamate.

After ischemic (thrombotic or embolic) stroke (focal ischemic animal model), selective vulnerability of specific neuronal populations has not been observed. The core of the area supplied by the occluded vessel undergoes pan-necrosis, and the penumbra sustains varying degrees of injury. The severity and duration of ischemia is affected by the collateral blood flow, clot propagation, spontaneous clot lysis and local vascular response. The area surrounding the ischemic core (penumbra) is characterized as an area of reduced cerebral blood flow that leads to electrical quiescence, but a site where ionic gradients are not irreversibly disturbed. If the blood supply is not restored and the tissue protected metabolically within 6 hours, the penumbral area deteriorates and contributes to the centrifugal enlargement of the ischemic core.
Middle cerebral artery occlusion in rodent models leads to cell death in striatum and different cortical areas (see figure on the right). Secondary neuronal damage can develop in remote brain regions, such as substantia nigra and thalamus.

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CELLULAR MECHANISMS OF STROKE
ATP depletion

ATP content is briefly preserved through the reaction of phosphocreatine and ADP catalysed by creatine kinase as well as through anaerobic glycolysis. The latter activity results in a marked and persistent increase in tissue lactate (5-14 times increase) leads to decrease of local pH. Lactic acidosis is more severe in patients who are hyperglycemic. Within 5 minutes of induction of ischemia ATP concentration reaches values less than 10 % of normal levels after global ischemia, 20-30 % in the core, and 50 % in the penumbra after focal ischemia.
ATP depletion causes neuronal membrane depolarization, which opens voltage-gated calcium and natrium channels and release of excitatory amino acids neurotransmitters such as glutamate.

Calcium overload

ATP depletion also results in cessation of energy-dependent mechanisms located in the mitochondrial, endoplasmic reticulum (sarcoplasmic/endoplasmic reticulum calcium-ATPase; SERCA), and plasma membrane to remove Ca2+ from the cytosol. Also disturbance of mitochondrial calcium-uptake and release mechanism of Ca2+ uniporter and 3Na+/Ca2+, H+/Ca2+ exchanger leading to net increase of mitochondrial Ca2+ concentration. Mitochondrial calcium overload further stimulates intramitochondrial reactive oxygen species (ROS) production which overwhelms endogenous protective mechanisms. Because of the absence of mitochondrial DNA-protecting proteins, the low efficiency reparation mechanisms and the proximity of the respiration chain, mtDNA is a privileged target for ROS. Finally, combination of increased mitochondrial calcium concentration and oxidative stress causes opening of the mitochondrial permeability transition pores. For further information, click on menu Oxidative stress and Mitochondria.

Protease activation

Release of calcium from mitochondria stimulates calcium-dependent enzymes such as proteases, nucleases and phospholipases. In the ischemic brain both intracellular and extracellular proteases are activated. These proteases cause site-specific cleavage of target proteins. The effect on the target protein may be activation, altered regulation of function, or loss of function. The two family of intracellular proteases that received the most attention after cerebral ischemia are calpains and caspases. Extracellular serine proteases and matrix metalloproteases also implicated in ischemic injury.

Calpains are Ca2+-dependent cytosolic cysteine proteases and they participate in a variety of cellular processes including remodeling of cytosceletal/membrane attachments, signal transduction pathways and apoptosis. Several calpain substrate including microtubule-associated protein 2, tubulin, and eukaryotic initiation factors 4E and 4G are degraded after reperfusion.

Caspases comprise a substrate-specific cystein proteases involved in inflammation and apoptosis. Caspases cleave proteins at specific sites adjacent to aspartate residues. Caspases are constitutively expressed as proenzymes that are activated either by autoproteolysis or cleavage by other caspases. Currently 14 members have been identified and can be classified based upon their structural and functional homology. Caspase-1 (interleukin 1-converting enzyme) is involved in triggering inflammation through activation of interleukin-1beta. Other caspases are specifically involved in the initiation and execution phases of apoptosis.


Cell death

Caspase-3 is considered an effector caspase involved in the execution phase of apoptosis downstream of the MPT. Caspase-3 can be activated by two major pathways. The extrinsic or death-receptor dependent route includes the activation of caspase-8 by Fas receptor or TNF-R and translocation of BID, a pro-apoptotic protein to mitochondria. The intrinsic or mitochondrial route includes cytochrome-c and apoptotic protease activating factor-1 (Apaf-1) release from the mitochondria leading to the activation of caspase-9, and then caspase-3.
Activation of caspase-3 promotes apoptotic cell death through proteolitic cleavage of downstream target proteins such as poly-(ADP-ribose) polymerase (PARP) and the inhibitor of caspase-activated DNase (ICAD) causing oligonucleosomal fragmentation of the DNA. PARP is involved in DNA damage surveillance and DNA repair. The obligatory triggers of PARP-1 activation are nicks and breaks in double-stranded DNA. Once activated, PARP-1 transfers between 50 and 200 molecules of ADP-ribose to target nuclear proteins including histones and topoisomerases. Excessive activation of PARP-1 may deplete the entire cell of its substrate nicotinamid adenine dinucleotide (NAD+). NAD+ depletion in mitochondria causes pronounced slowing of glycolysis, electron transport and ATP formation, leading to energy failure and necrotic cell death. For further information, click on menu Mirochondria.

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STROKE THERAPY
In the acute phase of ischemic stroke, antiplatelet (aspirin) or anticoagulant (tPA) treatments reduce the risk of recurrence, but carry a risk of hemorrhagic transformation, the most critical complication of thrombolytics.
Measures for stroke prevention include the correction of arterial hypertension, dyslipidemia, hyperglycemia and insulin resistance, the use of antiplatelet medications, the normalization of body mass, and physical exercise.
Effective antihypertensive treatment such as the ACE-inhibitor ramipril is highly beneficial for the reduction of stroke in diabetic patients. Antihypercholesteronemic medications (statins) reduced stroke risk and have neuroprotective properties for the acute ischemic brain in hypercholesterolemic and in normocholesterolemic individuals, also in subjects with diabetes mellitus. Statins have multiple effects beyond lowering the cholesterol level such as interfering with platelet aggregation and have anti-inflammatory and antioxidative properties, promoting stabilization of atherosclerotic plaques and improve blood flow to the ischemic brain.

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Links
American Heart Association
The PARP link