Hyperoxia

Tissue hypoxia plays a critical role in the primary and secondary events leading to cell death after ischemic stroke 215 therefore, increasing brain oxygenation has long been considered a logical stroke treatment strategy. Theoretically, oxygen should be an excellent drug for treating stroke since it has distinct advantages over pharmaceutical agents it easily diffuses across the blood-brain barrier, has multiple beneficial biochemical, molecular, and hemodynamic effects, it is well tolerated,...

Stroke Neuroprotective Clinical Trials Lessons from Past Failures

Various classes of neuroprotective agents have been tested in humans, with some showing promising phase II results. However, with the exception of the National Institute of Neurological Disorders and Stroke (NINDS) rt-PA trial 115 , none has been proven efficacious on the basis of a positive phase III trial. Notable failures include trials of the lipid peroxidation inhibitor tirilazad mesylate 116 , the ICAM-1 antibody enlimomab 61 , the calcium channel blocker nimodipine 117 , the...

Identifying the Ischemic Penumbra

As discussed above, although irreversible cell death begins within minutes after stroke onset within regions of maximally reduced blood flow (the infarct core), for several hours there exists a surrounding penumbra of ischemic but noninfarcted tissue that is potentially salvageable 134-137 . The concept of an ischemic penumbra provides a rationale for the use of neuroprotective drugs and reperfusion techniques to improve outcome after acute ischemic stroke. However, the extent of penumbral...

Excitotoxicity and Ionic Imbalance

Ischemic stroke results in impaired cellular energy metabolism and failure of energy-dependent processes such as the sodium-potassium ATPase. Loss of energy stores results in ionic imbalance, neurotrans-mitter release, and inhibition of the reuptake of excitatory neurotransmitters such as glutamate. Glutamate binding to ionotropic N-methyl-D-aspartate (NMDA) and acid (AMPA) receptors promotes excessive calcium influx that triggers a wide array of downstream phospholipases and proteases, which...

Mechanisms of Ischemic Cell Death

Mechanisms Ischemic Cell Injury

Ischemic stroke compromises blood flow and energy supply to the brain, which triggers at least five fundamental mechanisms that lead to cell death excito-toxicity and ionic imbalance, oxidative nitrative stress, inflammation, apoptosis, and peri-infarct depolarization Fig. 1.1 . These pathophysiological processes evolve in a series of complex spatial and temporal events spread out over hours or even days Major pathways implicated in ischemic cell death excitotoxicity, ionic imbalance, oxidative...

Apoptosis

Apoptosis, or programmed cell death 30 , is characterized histologically by cells positive for dUTP nick end labeling TUNEL that exhibit DNA laddering. Necrotic cells, in contrast, show mitochondrial and nuclear swelling, dissolution of organelles, nuclear chromatin condensation, followed by rupture of nuclear and cytoplasmic membranes, and the degradation of DNA by random enzymatic cuts. Cell type, cell age, and brain location render cells more or less resistant to apoptosis or necrosis. Mild...

Contributors

Neuroradiology Division Massachusetts General Hospital Harvard Medical School Boston, Mass., USA Neuroradiology Division Massachusetts General Hospital and Harvard Medical School Boston, Mass., USA Faculty of Medicine Hacettepe University Neuroradiology Division Massachusetts General Hospital Harvard Medical School Boston, Mass., USA Neuroradiology Division Massachusetts General Hospital and Harvard Medical School Boston, Mass., USA Interventional Neuroradiology and Endovascular Neurosugery...

Grey Matter Versus White Matter Ischemia

In addition to the size of the stroke, its location, and the relative involvement of gray versus white matter are key determinants of outcome. For example, small white matter strokes often cause extensive neurologic deficits by interrupting the passage of large axonal bundles such as those within the internal capsule. Blood flow in white matter is lower than in gray matter, and white matter ischemia is typically severe, with rapid cell swelling and tissue edema because there is little...