Understanding and Augmenting Collateral Blood Flow During Ischemic Stroke

Stroke refers to brain damage and dysfunction that occurs due to the obstruction of blood flow to brain tissue. Stroke is one of the leading causes of death and disability worldwide, accounting for 10% of all deaths (Grysiewicz et al., 2008; Donnan et al., 2008). Risk of stroke is affected by a number of modifiable and non-modifiable risk factors. Age is the primary non-modifiable risk factor, while modifiable risk factors include chronic hypertension, diabetes, smoking, cholesterol and lack of exercise (Simons et al., 1998; Knuiman & Vu, 1996; Iso et al., 1989; Wadley et al., 2007). Ischemic stroke, the rapid development of a neurological deficit due to the disruption of blood supply to a specific region of the brain, is the most common cause of stroke. Usually caused by the blockage of an artery or vein by an embolus or blood clot, an ischemic stroke is a major cerebrovascular trauma with a mortality rate of 25% after one month (Donnan et al., 2008; Hossmann, 2006). Ischemic strokes are differentiated from transient ischemic attacks by neurological symptoms lasting for more than 24 hours (Albers et al., 2002). Death and extent of disability due to ischemic stroke is largely defined by location of the occlusion and corresponding size and location of the infarct. Brain injury following ischemic stroke results from an “ischemic cascade” of pathological events triggered by reduced blood flow. Disturbed ion homeostasis, excitotoxity, elevation of intracellular calcium concentrations, peri-infarct depolarisations, free radical generation, lipid peroxidation and protein synthesis dysfunction are all triggered by reduced blood flow and contribute to necrotic and apoptotic processes in ischemic tissue and expansion of the infarct (Dirnagl et al., 1999 and Hossmann et al., 2006). Notably, necrotic cell death tends to be fast and irreversible in the core or infarct of the stroke area, where blood flow falls below ~20% of baseline perfusion and results in energy failure in resident neurons (Hossman, 2006). However, in “penumbral” regions surrounding the core, partial blood flow is maintained and tissue is considered functionally silent but structurally intact. Importantly, damage in the penumbra is reversible, though this reversibility is time-limited (Hakim, 1987). Because pathophysiology in the penumbra evolves over hours and days after ischemic onset, it is believed that early treatments that restore blood flow or reduce brain damage can reduce damage and improve outcome (Green, 2008). Although hundreds to thousands of prospective treatments to salvage ischemic tissue or halt the pathological ischemic cascade have been identified, few have successfully been translated to clinical practice (Ginsberg , 2008; Wahlgren & Ahmed, 2005). In fact, only thrombolytic drugs have thus far produced significant positive

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