Mechanisms, challenges and opportunities in stroke

'Stroke' refers to an umbrella of conditions caused by the occlusion or haemorrhage of blood vessels that supply the brain. Risk factors include elevated blood pressure and homocysteine levels, diabetes, atherosclerosis and genetic factors.In the core of the affected brain region, blood flow deficits, low ATP levels and energy stores, ionic disruption and metabolic failure are most severe, and cell death progresses within minutes. The ischaemic penumbra that surrounds the anoxic core suffers milder insults, and cells in this region can be rescued by rapid treatment.Three main mechanisms contribute to cell death during stroke — excitotoxicity and ionic imbalance, oxidative/nitrosative stress and apoptotic-like cell death.Proteolysis of the neurovascular matrix by plasminogen activator and metalloproteinases is linked with stroke-related haemorrhage and oedema, and anoikis. Therapeutic modulation of these proteases might ameliorate these indications.Inflammatory cascades are triggered by ischaemic injury, in both the occluded blood vessels and brain parenchyma. Effects of inflammation are both detrimental (for example, exacerbation of oedema) and potentially beneficial.Thrombolytic therapy — lysing of clots in the occluded blood vessels to reperfuse affected brain regions — is the current standard for treatment of stroke. Reperfusion injury and cell death might be minimized through co-administration of neuroprotectants.The neurovascular unit — a conceptual model comprised of cerebral endothelial cells, astrocytes, neurons and the extracellular matrix — provides a framework for developing treatments based on an integrative and dynamic view of evolving tissue damage.Targeting more than one mechanism/cellular pathway to develop combination therapies might prove more effective than current treatments. Potentially useful variables include preconditioning with non-damaging hypoxic/ischaemic challenges and hypothermia.