Free Radicals

ROS, although initially regarded primarily as potentially damaging by-products of oxidative cell metabolism, appear to be key mediators of cellular signaling and important modulators of cerebral vascular tone, particularly in endothelium-dependent responses (85). Under normal physiologic conditions, the rate and magnitude of oxidant formation is balanced by the rate of oxidant elimination. However, when ROS production is enhanced, the overproduction of oxidants overwhelms the cellular antioxidant capacity, resulting in oxidative stress and dys-regulation of physiologic processes. Free radicals may also react with and damage cell lipids, proteins, and nucleic acids. Increasing evidence suggests that an elevation of oxidative stress and associated oxidative damage are mediators of vascular injury in various cardiovascular pathologies. Several studies indicate a pathophysiologic role of oxidative stress in cerebral vasospasm ( 55 ).

A number of sources produce free radicals after SAH, but the principal process in vasospasm is probably the spontaneous oxidation of oxyhemoglobin to methemoglobin, leading to the production of superoxide (^O2 -) and hydroxyl (•OH) radicals (Fig. 3) (52). The iron in hemoglobin also catalyzes the formation of hydroxyl from hydrogen peroxide within the cerebral arterial wall via the Fenton and Haber-Weiss reactions. Additionally, the antioxidant capacity of the CSF is very limited, rendering the vulnerable cerebral arteries highly susceptible to free radical attack.

As discussed earlier, superoxide and other radicals react extremely efficiently with NO, resulting in loss of NO bioavailability and endothelial dysfunction. In addition to impairing NO-mediated responses, oxidative stress impairs neurovascular coupling and potassium channel-mediated vasodilation (86,87). Vasoconstrictor mechanisms may also be enhanced by oxi-dative stress. Rho kinase may predispose vessels to vasoconstriction or vasospasm through effects on calcium sensitization. Rho kinase activity may be increased as a consequence of loss of inhibitory effects of NO on rho kinase activity or by direct effects of ROS to promote the activity of rho kinase (88 ).

However, the effects of ROS signaling extend beyond the regulation of vascular tone. ROS play an essential role in propagating the signals of several growth factors, peptide hormones, and cytokines, such as platelet-derived growth factor, endothelin, angiotensin II, interleukin-1, and tumor necrosis factor (89). Evidence is emerging that redox processes markedly influence the balance of the activities between the various MAPK systems that appear to regulate vascular force generation, proliferation, and adaptive responses to injury (90,91 ).

The integrity of the blood-brain barrier can also be threatened by exposure of the endothelial cells to ROS-induced activation of matrix metalloproteinase-9 (MMP-9)(92). The development of cerebral vasospasm after SAH is preceded by increases in serum MMP-9 and vascular endothelial growth factor levels (93). Cell membrane lipid peroxidation and oxidative damage

Free Fez+/Fe3+ (Fenton catalysis)

Nucleic -? Apo ptosis


Auto-oxidation of hemoglobin contractile proteins structural or cytoskeletal proleins

Inflammation leukocyte myeloperoxidase

Free Radicals

Proteins contractile proteins

Inflammation leukocyte myeloperoxidase


Cell membrane Disruption and loss of ion homeostasis

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