Reactive oxygen species (ROS) such as superoxide and hydroxyl radicals are known to mediate reperfu-sion-related tissue damage in several organ systems including the brain, heart, and kidneys . Oxygen free radicals are normally produced by the mitochondria during electron transport, and, after ischemia, high levels of intracellular Ca2+, Na+, and
ADP stimulate excessive mitochondrial oxygen radical production. Oxygen radical production may be especially harmful to the injured brain because levels of endogenous antioxidant enzymes [including superoxide dismutase (SOD), catalase, glutathione], and antioxidant vitamins (e.g.,alpha-tocopherol,and ascorbic acid) are normally not high enough to match excess radical formation. After ischemia-reperfusion, enhanced production of ROS overwhelms endogenous scavenging mechanisms and directly damages lipids, proteins, nucleic acids, and carbohydrates. Importantly, oxygen radicals and oxidative stress facilitate mitochondrial transition pore (MTP) formation,which dissipates the proton motive force required for oxidative phosphorylation and ATP generation . As a result, mitochondria release apoptosis-related proteins and other constituents within the inner and outer mitochondrial membranes . Upon reperfusion and renewed tissue oxygenation, dysfunctional mitochondria may generate oxidative stress and MTP formation. Oxygen radicals are also produced during enzymatic conversions such as the cyclooxygenase-dependent conversion of arachidonic acid to prostanoids and degradation of hypoxanthine, especially upon reperfusion. Furthermore, free radicals are also generated during the inflammatory response after ischemia (see below). Not surprisingly then, oxidative stress, excitotoxicity, energy failure, and ionic imbalances are inextricably linked and contribute to ischemic cell death.
Oxidative and nitrative stresses are modulated by enzyme systems such as SOD and the nitric oxide synthase (NOS) family. The important role of SOD in cerebral ischemia is demonstrated in studies showing that mice with enhanced SOD expression show reduced injury after cerebral ischemia whereas those with a deficiency show increased injury [20-23]. Similarly, in the case of NOS, stroke-induced injury is attenuated in mice with deficient expression of the neuronal and inducible NOS isoforms [24,25]. NOS activation during ischemia increases the generation of NO production, which combines with superoxide to produce peroxynitrite, a potent oxidant . The generation of NO and oxidative stress is also linked to DNA damage and activation of poly(ADP-ribose)
polymerase-1 (PARP-1), a nuclear enzyme that facilitates DNA repair and regulates transcription . PARP-1 catalyzes the transformation of b-nicoti-namide adenine dinucleotide (NAD+) into nicotinamide and poly(ADP-ribose). In response to DNA strand breaks, PARP-1 activity becomes excessive and depletes the cell of NAD+ and possibly ATP. Inhibiting PARP-1 activity or deleting the parp-1 gene reduces apoptotic and necrotic cell death [28, 29], pointing to the possible relevance of this enzyme as a target for stroke therapy.
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