Pathophysiology and treatment of focal cerebral ischemia

Abstract

This article examines the pathophysiology of lesions caused by focal cerebral ischemia. Ischemia due to middle cerebral artery occlusion encompasses a densely ischemic focus and a less densely ischemic penumbral zone. Cells in the focus are usually doomed unless reperfusion is quickly instituted. In contrast, although the penumbra contains cells "at risk," these may remain viable for at least 4 to 8 hours. Cells in the penumbra may be salvaged by reperfusion or by drugs that prevent an extension of the infarction into the penumbral zone. Factors responsible for such an extension probably include acidosis, edema, K+/Ca++ transients, and inhibition of protein synthesis. Central to any discussion of the pathophysiology of ischemic lesions is energy depletion. This is because failure to maintain cellular adenosine triphosphate (ATP) levels leads to degradation of macromolecules of key importance to membrane and cytoskeletal integrity, to loss of ion homeostasis, involving cellular accumulation of Ca++, Na+, and Cl-, with osmotically obligated water, and to production of metabolic acids with a resulting decrease in intra- and extracellular pH. In all probability, loss of cellular calcium homeostasis plays an important role in the pathogenesis of ischemic cell damage. The resulting rise in the free cytosolic intracellular calcium concentration (Ca++) depends on both the loss of calcium pump function (due to ATP depletion), and the rise in membrane permeability to calcium. In ischemia, calcium influx occurs via multiple pathways. Some of the most important routes depend on activation of receptors by glutamate and associated excitatory amino acids released from depolarized presynaptic endings. However, ischemia also interfers with the intracellular sequestration and binding of calcium, thereby contributing to the rise in intracellular Ca++. A second key event in the ischemic tissue is activation of anaerobic glucolysis. The main reason for this activation is inhibition of mitochondrial metabolism by lack of oxygen; however, other factors probably contribute. For example, there is a complex interplay between loss of cellular calcium homeostasis and acidosis. On the one hand, a rise in intracellular Ca++ is apt to cause mitochondrial accumulation of calcium. This must interfere with ATP production and enhance anaerobic glucolysis. On the other hand, acidosis must interfere with calcium binding, thereby contributing to the rise in intracellular Ca++.

Correlation of early reduction in the apparent diffusion coefficient of water with blood flow reduction during middle cerebral artery occlusion in rats

“…In general, the mean ADC values in ischemic regions were substantially lower in the 90-min occlusion group than in the 30-min group. For the 90-min group, the ADC 15 area corresponded best with the CBF 30 and CBF 35 areas (Fig. 5 and Table 1) and was significantly smaller than the CBF 50 area (54 ± 13% versus 73 ± 20%; P < 0.05).…”

“…CBF rates were estimated with a method that corrects for the "wash-out" volume of blood in the arterial and venous catheters (25). The percent of ischemic hemisphere with CBF rates less than 15,20,25,30,35,40, and 50 m1/100 g/min (CBF 15 , CBF 20 , CBF 25 , CBF 30 , CBF 35 , CBF 40 , and CBF 50 ) was determined for three sections from within the 2-mm thick slice of the MR images. Reported results are the mean of the three measurements.…”

Transdermal Glyceryl Trinitrate Lowers Blood Pressure and Maintains Cerebral Blood Flow in Recent Stroke

“…A CBF filter was then used to determine the number of pixels within the ROI matching prespecified CBF values for "core" (Ͻ10 mL/min per 100 g), "penumbra" (10 to 19 mL/min per 100 g), and "oligemia" (20 to 36 mL/min per 100 g). [17][18][19][20] Matching ROIs were sited on pretreatment and posttreatment scans to ensure consistency, and the areas (in pixels) of reduced CBF were compared.…”

Therapeutic neutralization of CD95-ligand and TNF attenuates brain damage in stroke

“…injected with anti-TNF and anti-CD95L antibodies (50 mg each) 30 min after occlusion of MCA ± a time point which would reflect later time points in humans, since the basal metabolic rate in humans is lower than in rodents. 32 This led to a significant Figure 2 Ischemic brain damage is reduced in gld, tnf 7/7 and gld/tnf 7/7 mice. (a) mortality within 24 h after occlusion of the middle cerebral artery (MCA) in wild-type (n=14), gld (n=17), tnf 7/7 (n=13), and gld/tnf 7/7 (n=15) mice.…”