Redox Control of Neuronal Damage during Brain Ischemia after Middle Cerebral Artery Occlusion in the Rat: Immunohistochemical and Hybridization Studies of Thioredoxin

Abstract

Thioredoxin (TRX) is a small, multifunctional protein with a redox-active site and multiple biological functions that include reducing activity for reactive oxygen intermediates. We assayed TRX and TRX mRNA by immunohistochemical methods and hybridization experiments in the rat brain after middle cerebral artery (MCA) occlusion. During ischemia, the immunoreactivity for TRX decreased; it disappeared after MCA occlusion in the ischemic regions. It rapidly decreased and nearly disappeared at 4 and 16 hours after MCA occlusion in the lateral striatum and frontoparietal cortex, respectively. On the other hand, in the perifocal ischemic region, the penumbra, TRX immunoreactivity began to increase 4 hours after MCA occlusion and continued to increase until 24 hours after occlusion. In hybridization experiments, TRX mRNA decreased and nearly disappeared 4 hours after MCA occlusion in the lateral striatum. In the frontoparietal cortex, it decreased until 24 hours after MCA occlusion. In the perifocal ischemic region, TRX mRNA began to increase 4 hours after MCA occlusion and continued to increase until 24 hours. Northern blot analysis showed that total TRX mRNA in the operated hemispheres was induced from 8 hours and increased until 24 hours after the surgical procedures. We previously reported that recombinant TRX promotes the in vitro survival of primary cultured neurons. We now suggest that TRX in the penumbra has neuroprotective functions and that decreased levels of TRX in the ischemic core modify neuronal damage during focal brain ischemia.

Overexpression of thioredoxin in transgenic mice attenuates focal ischemic brain damage

“…We have reported the proliferated astroglial induction of TRX in the CA1 region during transient forebrain ischemia (33). Recently we documented decreased TRX in the ischemic core and increased TRX in the penumbral ischemic region during permanent middle cerebral artery occlusion in rats (34). In combination, these findings indicate that TRX and the redox system modulated by TRX has a function in the cellular defense against oxidative stress in neurons as well as in other cell types and may play a role during brain injury.…”

Chronic elevation of plasma thioredoxin: Inhibition of chemotaxis and curtailment of life expectancy in AIDS

“…Several studies, for example, have already reported that injection of a bolus of Trx substantially prevents ischemic reperfusion injury (15)(16)(17)(18). These findings were previously ascribed to the reducing power of Trx and its ability to remove locally generated reactive oxygen intermediates.…”

“…It is induced by oxidative stress (8,11), is translocated into the nucleus in stressed cells (8,11), is chemotactic in vitro for eosinophils (7), and effectively blocks ischemic injury (15)(16)(17)(18). In addition, our recent studies show that Trx has potent in vitro and in vivo chemoattractant activity for murine neutrophils, monocytes, and lymphocytes (9).…”

Molecular Physiology of Preconditioning-Induced Brain Tolerance to Ischemia

“…Hypobaric hypoxia-induced preconditioning increased Trx-2 mRNA expression in the rat brain (355); the same procedure also markedly strengthened the increased levels of Trx-1 and Trx-2 produced by a subsequent, severe hypobaric hypoxia (395,396). It is also pertinent to mention that in rats subjected to MCAO, both Trx mRNA expression and protein levels rapidly decreased in the ischemic core (i.e., striatum and frontoparietal cortex), but increased in perifocal regions throughout the 4-to 24-h period after MCAO (403).…”