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Neuroprotectants: Reactive Oxygen Species (ROS) Based
Introduction
Oxygen-free-radical-induced membrane lipid peroxidation (LP) is a highly validated secondary injury mechanism that occurs in focal and global cerebral ischemia and subarachnoid hemorrhage (SAH). It has been firmly established as a major contributor to multiple aspects of ischemic, postischemic, and posthemorrhagic pathophysiologic conditions caused by the oxidative damage to lipids and proteins of the neural cell membrane.
Sources of Reactive Oxygen Species in Cerebral Ischemia and SAH
Superoxide Radical
The primordial radical formed in most biologic processes is superoxide radical (O 2 − ). Within the ischemic nervous tissue, a number of sources of superoxide radical are operative within the first minutes and hours of the onset of ischemia, particularly after postischemic reperfusion. These sources include the arachidonic acid cascade (i.e., prostaglandin synthase and 5-lipoxygenase activity), enzymatic oxidation (i.e., monoamine oxidase) or autoxidation of biogenic amine neurotransmitters (e.g., dopamine), mitochondrial leak, xanthine oxidase activity, and the oxidation of extravasated hemoglobin. Over the first few postischemic hours and days, activated microglia and infiltrating neutrophils and macrophages provide additional sources of O 2 − .
Superoxide, which is formed by the single electron reduction of oxygen, may act as either an oxidant (electron acceptor) or reductant (electron donor). Although superoxide itself is reactive, its direct reactivity toward biologic substrates in aqueous environments is questioned. Moreover, once formed, superoxide undergoes spontaneous dismutation to form hydrogen peroxide (H 2 O 2 ) in a reaction that is markedly accelerated by the enzyme superoxide dismutase (SOD) (O 2 − + O 2 − + 2H + → H 2 O 2 + O 2 ).
In solution, superoxide actually exists in equilibrium with the hydroperoxyl radical formed by the protonation of superoxide (O 2 − + H + → HO 2 ). The pKa of this reaction is 4.8 and the relative concentrations of O 2 − and HO 2 depend on the H + concentration. Therefore, at a pH around 6.8 the ratio of O 2 − /HO 2 is 100/1, whereas at a pH of 5.8 the ratio is only 10/1. Thus under conditions of tissue acidosis of a magnitude known to occur within the ischemic nervous system, a significant amount of the O 2 − formed will exist as HO 2 . Furthermore, compared with O 2 − , HO 2 is considerably more lipid soluble and is a far more powerful oxidizing agent. Therefore, as the pH of a solution falls, and the equilibrium between O 2 − and HO 2 shifts toward greater formation of HO 2 , superoxide becomes more reactive, particularly toward lipids. In addition, whereas the dismutation of O 2 − to H 2 O 2 is exceedingly slow at neutral pH in the absence of SOD, HO 2 will dismutate to H 2 O 2 far more readily at acidic pH values because the rate constant for HO 2 dismutation is on the order of 10 8 times greater than that for O 2 − . Thus in an acidic environment, O 2 − is converted to the more reactive, more lipid-soluble HO 2 and its rate of dismutation to H 2 O 2 is greatly increased.
Iron and the Formation of Hydroxyl Radical and Iron–Oxygen Complexes
The central nervous system (CNS) is an extremely rich source of iron. Under normal circumstances, low-molecular-weight forms of redox-active iron in the brain are maintained at extremely low levels. Extracellularly, the iron transport protein transferrin tightly binds iron in the Fe 3+ form. Intracellularly, Fe 3+ is sequestered by the iron storage protein ferritin. Although both ferritin and transferrin have very high affinity for iron at neutral pH and effectively maintain iron in a noncatalytic state, both proteins readily give up their iron at pH values of 6.0 or less. The iron in ferritin can also be released by reductive mobilization by O 2 − . Therefore, within the ischemic CNS environment where pH is typically lowered and several sources of superoxide are active, conditions are favorable for the potential release of iron from storage proteins. Once iron is released from ferritin or transferrin, it can actively catalyze oxygen radical reactions.
The second source of catalytically active iron is hemoglobin. SAH or intracerebral hemorrhage (ICH) places hemoglobin in contact with nervous tissue. Although hemoglobin itself can stimulate oxygen radical reactions, it is more likely that iron released from hemoglobin is responsible for hemoglobin-mediated LP. Iron is released from hemoglobin by either H 2 O 2 or lipid hydroperoxides (LOOHs), and this release is further enhanced as the pH falls to 6.5 or below. Therefore, hemoglobin may catalyze oxygen radical formation and LP either directly or through the release of iron by H 2 O 2 , LOOH, and/or acidic pH.
Free iron or iron chelates participate in further free radical production at two levels: (1) the autoxidation of Fe 2+ provides an additional source of O 2 − (Fe 2+ + O 2 → Fe 3+ + O 2 − ) and (2) Fe 2+ is oxidized in the presence of H 2 O 2 to form hydroxyl radical (Fenton reaction, Fe 2+ + H 2 O 2 → Fe 3+ + OH + OH − ) or perhaps a ferryl ion (Fe 2+ + H 2 O 2 → Fe 3+ OH + OH − ). Both OH or Fe 3+ OH are extraordinarily potent initiators of LP.
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