Nitric Oxide Donors as Neuroprotective Agents after an Ischemic Stroke-Related Inflammatory Reaction
Figure 1
In vitro and intracerebral effects of sodium nitroprusside and other nitric oxide donors (NOD) on neuronal survival. SNP is capable of releasing or producing diverse byproducts, such as nitric oxide (NO), iron, cyanide anions, hydroxyl radicals, and peroxynitrite. Collectively, these are all capable of inducing oxidative and nitrosative stress [1], with the possibility of modifying the structure and function of proteins, nucleic acids, and lipids by means of oxidation and nitrosylation. Iron, via the Fenton reaction, generates OH− that, together with ONOO− and other reactive species, damage membranes by lipid peroxidation [2] with decreased cellular viability. This effect is blocked by the addition of NO, oxyhemoglobin, and deferoxamine, which suggests the important role of iron and NO in this reaction. The oxidative stress (OS) produced by SNP increases the activation of MEK1/2 and its substrate ERK1/2 by phosphorylation [3]. Both effects are blocked by SOD, suggesting the participation of (O2−) in this reaction, probably in the form of ONOO−. Activation of ERK1/2 is associated with a reduction of Bcl2 and an increase in (Bax), and both conditions are associated with an activation of mitochondrial apoptotic pathways. Mitochondria are a target of SNP at different levels: SNP induces lipid peroxidation of its membrane with the subsequent activation of proapoptotic pathways via caspases. In addition, NO and CN− affect the functioning of the mitochondrial respiratory chain, thereby altering mitochondrial membrane potential, reducing ATP production and the generation of large amounts of reactive oxygen species [4]. The addition of ONOO− scavengers and SOD1 counteracts this effect. Also, SNP decreases Akt phosphorylation [5] and reduces the expression and function of SOD1 and catalase [6]. These actions decrease antioxidant responsiveness and the activation of neuronal survival pathways. OH−, hydroxyl radical; ONOO−, peroxynitrite; Akt, protein kinase B (PKB); Bax, Bcl-2-associated X protein; Bcl2, B-cell lymphoma 2; CN−, cyanide anion; ERK1/2, extracellular signal-regulated kinase 1/2; IL-1β, interleukin 1 beta; MEK1/2, mitogen-activated protein kinase kinase 1/2; MMP, mitochondrial membrane potential; NO, nitric oxide; ROS, reactive oxygen species; SNP, sodium nitroprusside; SOD1, superoxide dismutase (Cu-Zn); TNF-α, tumor necrosis factor alpha.
