Acidosis-Induced Ischemic Brain Damage: Are Free Radicals Involved?

Abstract

Summary: Substantial evidence exists that reactive oxy gen species participate in the pathogenesis of brain dam age following both sustained and transient cerebral isch emia, adversely affecting the vascular endothelium and contributing to the formation of edema. One likely trig gering event for free radical damage is delocalization of protein-bound iron. The binding capacity for some iron binding proteins is highly pH sensitive and, consequently, the release of iron is enhanced by acidosis. In this study, we explored whether enhanced acidosis during ischemia triggers the production of reactive oxygen species. To that end, enhanced acidosis was produced by inducing ischemia in hyperglycemic rats, with normoglycemic ones serving as controls. Production of HzOz, estimated from the decrease in catalase activity after 3-amino-1,2,4-triazole (AT) administration, was measured in the cerebral cortex, caudoputamen, hippocampus, and sub stantia nigra (SN) after 15 min of ischemia followed by 5, 15, and 45 min of recovery, respectively (in substantia nigra after 45 min of recovery only). Free iron in cere brospinal fluid (CSF) was measured after ischemia and 45 min of recovery. Levels of total glutathione (aSH + OSSH) in cortex and hippocampus, and levels of Abbreviations used: AT, 3-amino-I,2,4-triazole; GSH, gluta thione; MeA, middle cerebral artery; PBS, phosphate-buffered saline; PEG, polyethylene glycol; SN, substantia nigra; SOD, superoxide dismutase; TBAR, thiobarbituriac acid-reactive. 587a-tocopherol in cortex, were also measured after 15 min of ischemia followed by 5, 15, and 45 min of recovery. The results confirm previous findings that brief ischemia in normoglycemic animals does not measurably increase H202 production in AT-injected animals. Ischemia under hyperglycemic conditions likewise failed to induce in creased H202 production. No difference in free iron in CSF was observed between animals subjected to isch emia under hyper-and normoglycemic conditions. The moderate decrease in total glutathione or a-tocopherol levels did not differ between normo-and hyperglycemic animals in any brain region or at any recovery time. Thus, the results failed to give positive evidence for free radical damage following brief periods of ischemia complicated by excessive acidosis. However, it is possible that free radical production is localized to a small subcellular com partment within the tissue, thereby escaping detection. Also, the results do not exclude the possibility that free radicals are pathogenetically important after ischemia of longer duration.

Acidosis has opposite effects on neuronal survival during hypoxia and reoxygenation

“…Furthermore, the pH optimum of the hydroxyl radical producing reaction between iron and ascorbic acid is close to pH 6 (Almaas et al 1997). On the other hand, Lundgren et al found no evidence for acidosis-induced free radical formation during cerebral ischemia in vivo (Lundgren et al 1991). In the present study, acidosis (during both ischemia and reoxygenation) increased the formation of isoprostanes by 50%.…”

“…On the other hand, Lundgren et al . found no evidence for acidosis‐induced free radical formation during cerebral ischemia in vivo (Lundgren et al . 1991).…”

Overexpression of thioredoxin in transgenic mice attenuates focal ischemic brain damage

“…The excitatory amino acids elevated cytosolic-free calcium (Ca 2ϩ ), and in pathological conditions, a Ca 2ϩ overload may occur, which can set off a cascade of events, such as phospholipase activation, potentially leading to free-radical production (3). The formation of oxygen-derived free radicals may occur in the electron transport chain, in metabolic processes such as free fatty acids, and in purine and nitric oxide (35)(36)(37)(38). These oxidants destroy or inactivate cellular and subcellular proteins and various enzymes.…”

Antioxidant defense of the brain: a role for astrocytes

“…Prolonged ischemia increases extracellular glutamate concentration enough to cause oxidative stress by excitotoxic mechanisms . However, brief ischemia without reoxygenation does not increase production of superoxide (Nelson et al 1992) or hydrogen peroxide (Lundgren et al 1991), and it initially diminishes formation of hydroxyl radical (Globus et al 1995). Reperfusion of the transiently ischemic region accelerates formation of the reactive oxygen species that cause mitochondrial dysfunction, DNA fragmentation, and cell death (Kuroda et al 1996;Murakami et al 1997).…”