Consequences of Oxidative Damage Following Stroke

Lipid Peroxidation

Phospholipids are major constituents of neuronal membranes, which account for 20% to 25% of the dry weight of the adult brain (53). Phosphatidylcholine and phosphatidylethanolamine comprise >60% of the membrane phospholipids, especially in brain cells. Fatty acids are incorporated into the phosphatidylcholine by combining diacylglycerols, which contain high amounts of such fatty acids as arachidonic and stearic acids. MCAO significantly increases lipid peroxidation in the ischemic hemisphere (54) by hydroxyl radicals and nitrogen dioxide, both of which are generated from ONOO- (55). Lipid peroxidation has many deleterious consequences. Oxidized cell membranes lead to structural compromise, altered permeability, and fluidity, leading to further calcium entry into the cell. Free radicals can cause disruption of membrane-bound receptors and inactivate, and even damage, proteins involved in ion transport (56 ).

Oxidative DNA Damage

Free radicals can directly damage nucleic acids, causing injury to nuclear DNA, thereby leading to oxidative DNA lesions (ODLs) and DNA strand breaks. Following focal cerebral ischemia, ODLs have been observed mainly in neurons, as well as in astrocytes. They are thought to be caused by hydroxyl radicals and NO (57). Although ODLs are thought to eventually cause neuronal cell death (58), ODLs can be repaired to some degree through nucleotide [nucleotide excision repair (NER)] and base excision repair (BER) (59). Ischemia can trigger NER and BER activity and might represent an important endogenous mechanism in protecting the brain against ischemia-induced oxidative injury (60). If not repaired promptly, ODLs and strand breaks have the potential to trigger various intracellular-signaling pathways and result in brain cell death (58). Not only can such damage interfere with DNA synthesis and gene transcription, but it might also activate poly(ADP-ribose) polymerase-1 (PARP-1) (58,61 ). Although involved in DNA repair, PARP-1 appears to be detrimental in the setting of brain ischemia (62,63 ). It is not entirely clear why a repair enzyme might exacerbate ischemic injury, but PARP-1 can deplete ATP and NAD +, leading to further compromises in the cell's energy stores (61,64,65). PARP-1 also appears to mediate caspase-independent apoptosis by facilitating mitochondrial release of apoptosis-inducing factor (AIF) (66,67 ).

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