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Stroke is classified as both a neurological and a cardiovascular disease, as it is a disruption in blood supply to the brain which causes the neurological abnormalities. There are two types of stroke; ischemic and hemorrhagic.
Ischemic strokes are caused by a reduction in the blood supply to an area of the brain, usually due to a blockage within a blood vessel, resulting in the initiation of an ischemic cascade. There are three main causes of ischemic stroke; cerebral thrombosis, where a blood clot forms in a major blood vessel within the brain, cerebral embolism, where a thrombus forms in a vessel outside the CNS and then travels to the brain, and thrombosis in capillaries within the brain parenchyma, termed a lucunar stroke.
Hemorrhagic strokes are caused by the rupture of a blood vessel and subsequent accumulation of blood. There are two types of hemorrhagic stroke; intracerebral hemorrhage, when a blood vessel within the brain tissue ruptures, and intracranial hemorrhage, where a blood vessel within the skull but outside of the brain parenchyma ruptures, either due to trauma or spontaneously (a cerebral aneurysm). Both types of hemorrhagic stroke cause an increase in intracranial pressure, which leads to compression and distortion of brain tissue. Additionally the compression may lead to loss of blood supply resulting in ischemia.
Numerous pathways are involved in the ischemic cascade. Depletion of oxygen and glucose within the brain prevents production of ATP. In the normal brain, extracellular levels of glutamate are kept low by glutamate transporters. The glutamate transporter is dependent on the concentration of Na+ across neuronal membranes, which is established by ATP-dependent ion pumps. Loss of ATP due to ischemia results in an altered Na+ concentration gradient. This reverses glutamate transporter function, allowing excessive glutamate release into the extracellular space. Glutamate acts on neuronal NMDA, AMPA and kainate receptors, causing elevated Ca2+ influx. Ca2+-mediated intracellular enzymatic activity is increased to pathological levels, leading to cell damage and death by necrosis and apoptosis. In addition, abnormal recruitment of inflammatory cells and excessive production of free radicals is seen immediately after stroke.
Following the initial cell loss, a process of repair and partial recovery can occur through plasticity within cortical connections. Neurons adjacent to the infarct show hyperexcitability with increased baseline neuronal firing frequency, diminished inhibitory postsynaptic potentials and prolonged excitatory postsynaptic potentials. Stroke produces long-lasting alterations in the network properties by facilitating the induction of synaptic plasticity. Axonal sprouting and neurogenesis occur in the ischemic border zone and angiogenesis is activated in contiguous regions. The degree of plasticity is associated with the level of functional recovery gained.
Coincident cardiovascular pathologies represent risk factors for stroke. Hypertension is a major underlying cause of the spontaneous rupture of blood vessels in hemorrhagic stroke. Atrial fibrillation, valvular heart disease, coronary artery disease, congestive heart failure, atherosclerosis and myocardial infarction are all major risk factors for ischemic stroke, especially those of embolic origin. Non-cardiovascular disease risk factors for stroke include diabetes, dietary factors (such as high salt and low protein intake), obesity and hypercholesterolemia.
Epidemiological evidence suggests that the existence of a genetic susceptibility to stroke. Three genes potentially involved in the stroke phenotype are atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and adrenomedullin, which are natriuretic or vasodilatory substances that also modulate the stability and proliferation of cardiovascular cells. Polymorphisms in these genes can confer susceptibility for or protection against stroke.
A common preventative drug for stroke is low-dose aspirin. Aspirin acts as an anticoagulant by inhibiting TXA2, which prevents platelet aggregation, thus lowers the risk of thrombus formation. Alteplase (rt-PA) was the first therapy successfully developed for acute stroke therapy. rt-PA is in fact tissue plasminogen activator (tPA), a serine protease that cleaves plasminogen to plasmin, an inhibitor of the clotting cascade. rt-PA is effective in degrading plasma proteins and blood clots.
Many novel pharmacological interventions for stroke are in the preclinical phase. 5-HT1A agonists inhibit excitatory neurotransmission during ischemic insult and may protect neurons from glutamate-mediated neuronal death. Caspase inhibitors have been investigated, as induction of apoptosis is a key element in delayed brain injury after stroke. Gangliosides have a neuroprotective effect through normalization of protein phosphorylation, increasing brain-derived neurotropic factor (BDNF) expression and blocking overstimulation of excitatory pathways. Free radical scavengers may protect against reactive oxygen species damage and calcium channel inhibitors prevent overactivation of intracellular enzymes triggered during the ischemic cascade. However, historically there has been little success in transferring preclinical successes into efficacious treatments in humans.