Cerebral Ischemia-Hypoxia Induces Intravascular Coagulation and Autophagy
Hypoxia is a critical factor for cell death or survival in ischemic stroke, but the pathological consequences of combined ischemia-hypoxia are not fully understood. Here we examine this issue using a modifiedLevine/Vannucci procedure in adult mice that consists of unilateral common carotid artery occlusion and hypoxia with tightly regulated body temperature. At the cellular level , ischemia-hypoxia produced proinflammatory cytokines and simultaneously acti- vated both prosurvival (eg , synthesis of heat shock 70 protein , phosphorylation of ERK and AKT) and pro-apoptosis signaling pathways.
At the tissue level, ischemia-hypoxia caused persistent cerebral perfusion deficits even after release of the carotid artery occlusion. These changes were associated with both platelet deposition and fibrin accumulation within the cerebral circulation and would be expected to contribute to infarction. Complementary studies in fibrinogen-deficient mice revealed that the absence of fibrin and/or secondary fibrin-mediated inflammatory processes significantly attenuated brain damage. Together, these results suggest that ischemia-hypoxia is a powerful stimulus for
spontaneous coagulation leading to reperfusion deficits and autophagic/lysosomal cell death in brain.
Three interesting papers (13-15) point toward other features associated with venous congestion, small thrombi and iron deposition. In the first two, children with early cerebral infarction (13) and children following severe ischemic-anoxic events (14) showed increases in iron content in the basal ganglia, thalami and white matter. Iron deposition was also associated with periventricular gliosis (14). In fact, desferrioximine, an iron chelator, has been used to minimize the damage for patients undergoing cardiac resuscitation (16). These findings also may be consistent with the fact that some MS lesions show iron build up. It has not been shown yet but one might conjecture if the MS lesions with the highest iron content may represent ischemic tissue of lesions and may correspond with the lowest blood volume. Finally, an interesting case of venous congestion shown with SWI that was similar in appearance to a developmental venous anomaly, also in a child, shows that SWI may be able to detect small thrombosed veins. In this particular case, the child was treated and recovered and evidence of the problem on imaging disappeared at two months (15). So iron regulation appears to be disrupted in ischemic-anoxic insult. Could this be what is happening in MS as well?
(13) Cross et al (1990). MR evaluation of brain iron in children with cerebral infarction. AJNR 11; 341-348.
(14) Dietrich et al (1988). Iron accumulation in the basal ganglia following severe ischemic-anoxic insults in children. Radiology 168; 203-206.
(15) Amemiya et al (2008). Venous congestion associated with developmental venous anomaly: Findings on susceptibility weighted imaging. JMRI 28: 1506-1509.
(16) Gutteridge et al (1979). Inhibition of the iron-catalysed formation of hydroxyl radicals from superoxide and of lipid peroxidation by desferrioxamine. Biochem J 184; 469-472.
gibbledygook wrote:Excellent post, Cheer. As ever!
I still have lots of fibrin-munching supplements like lumbrokinase and serrapeptase though I haven't wanted to take any since the operation. I do remember that when I took them for a while back in 07 or 08 that I felt modestly better.
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