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Nitric oxide donors as neuroprotective agents after an ischemic stroke-related inflammatory reaction.

Godínez-Rubí M, Rojas-Mayorquín AE, Ortuño-Sahagún D - Oxid Med Cell Longev (2013)

Bottom Line: Therefore, reducing oxidative stress (OS) and downregulating the inflammatory response are options that merit consideration as potential therapeutic targets for ischemic stroke.Consequently, agents capable of modulating both elements will constitute promising therapeutic solutions because clinically effective neuroprotectants have not yet been discovered and no specific therapy for stroke is available to date.In the present paper, we focus on the role of NOD as possible neuroprotective therapeutic agents for ischemia/reperfusion treatment.

View Article: PubMed Central - PubMed

Affiliation: Laboratorio de Desarrollo y Regeneración Neural, Instituto de Neurobiología, Departamento de Biología Celular y Molecular, CUCBA, Universidad de Guadalajara, camino Ing. R. Padilla Sánchez, 2100, Las Agujas, 44600 Zapopan, JAL, Mexico.

ABSTRACT
Cerebral ischemia initiates a cascade of detrimental events including glutamate-associated excitotoxicity, intracellular calcium accumulation, formation of Reactive oxygen species (ROS), membrane lipid degradation, and DNA damage, which lead to the disruption of cellular homeostasis and structural damage of ischemic brain tissue. Cerebral ischemia also triggers acute inflammation, which exacerbates primary brain damage. Therefore, reducing oxidative stress (OS) and downregulating the inflammatory response are options that merit consideration as potential therapeutic targets for ischemic stroke. Consequently, agents capable of modulating both elements will constitute promising therapeutic solutions because clinically effective neuroprotectants have not yet been discovered and no specific therapy for stroke is available to date. Because of their ability to modulate both oxidative stress and the inflammatory response, much attention has been focused on the role of nitric oxide donors (NOD) as neuroprotective agents in the pathophysiology of cerebral ischemia-reperfusion injury. Given their short therapeutic window, NOD appears to be appropriate for use during neurosurgical procedures involving transient arterial occlusions, or in very early treatment of acute ischemic stroke, and also possibly as complementary treatment for neurodegenerative diseases such as Parkinson or Alzheimer, where oxidative stress is an important promoter of damage. In the present paper, we focus on the role of NOD as possible neuroprotective therapeutic agents for ischemia/reperfusion treatment.

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Related in: MedlinePlus

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.
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fig1: 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.

Mentions: Finally, it should be taken into account that the cytoprotective and physiological effects of NO described (e.g., vasodilatation, neurotransmission, endothelial protection) require extremely small concentrations (pico- to nanomolar), while harmful effects take place at higher concentrations, particularly under OS [93]. In culture and in intracerebral application, the NOD concentrations usually administered fall within the micro- to millimolar range. Thus, direct contact of NOD with neurons in culture or intraparenchymally coupled with the high concentration of these could be mimicking overactivation of nNOS or iNOS during the postischemic reperfusion period or in other neurodegenerative disorders [83]. Figure 1 depicts the signaling pathways involved in the neurotoxic effects of NO.


Nitric oxide donors as neuroprotective agents after an ischemic stroke-related inflammatory reaction.

Godínez-Rubí M, Rojas-Mayorquín AE, Ortuño-Sahagún D - Oxid Med Cell Longev (2013)

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.
© Copyright Policy - open-access
Related In: Results  -  Collection

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fig1: 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.
Mentions: Finally, it should be taken into account that the cytoprotective and physiological effects of NO described (e.g., vasodilatation, neurotransmission, endothelial protection) require extremely small concentrations (pico- to nanomolar), while harmful effects take place at higher concentrations, particularly under OS [93]. In culture and in intracerebral application, the NOD concentrations usually administered fall within the micro- to millimolar range. Thus, direct contact of NOD with neurons in culture or intraparenchymally coupled with the high concentration of these could be mimicking overactivation of nNOS or iNOS during the postischemic reperfusion period or in other neurodegenerative disorders [83]. Figure 1 depicts the signaling pathways involved in the neurotoxic effects of NO.

Bottom Line: Therefore, reducing oxidative stress (OS) and downregulating the inflammatory response are options that merit consideration as potential therapeutic targets for ischemic stroke.Consequently, agents capable of modulating both elements will constitute promising therapeutic solutions because clinically effective neuroprotectants have not yet been discovered and no specific therapy for stroke is available to date.In the present paper, we focus on the role of NOD as possible neuroprotective therapeutic agents for ischemia/reperfusion treatment.

View Article: PubMed Central - PubMed

Affiliation: Laboratorio de Desarrollo y Regeneración Neural, Instituto de Neurobiología, Departamento de Biología Celular y Molecular, CUCBA, Universidad de Guadalajara, camino Ing. R. Padilla Sánchez, 2100, Las Agujas, 44600 Zapopan, JAL, Mexico.

ABSTRACT
Cerebral ischemia initiates a cascade of detrimental events including glutamate-associated excitotoxicity, intracellular calcium accumulation, formation of Reactive oxygen species (ROS), membrane lipid degradation, and DNA damage, which lead to the disruption of cellular homeostasis and structural damage of ischemic brain tissue. Cerebral ischemia also triggers acute inflammation, which exacerbates primary brain damage. Therefore, reducing oxidative stress (OS) and downregulating the inflammatory response are options that merit consideration as potential therapeutic targets for ischemic stroke. Consequently, agents capable of modulating both elements will constitute promising therapeutic solutions because clinically effective neuroprotectants have not yet been discovered and no specific therapy for stroke is available to date. Because of their ability to modulate both oxidative stress and the inflammatory response, much attention has been focused on the role of nitric oxide donors (NOD) as neuroprotective agents in the pathophysiology of cerebral ischemia-reperfusion injury. Given their short therapeutic window, NOD appears to be appropriate for use during neurosurgical procedures involving transient arterial occlusions, or in very early treatment of acute ischemic stroke, and also possibly as complementary treatment for neurodegenerative diseases such as Parkinson or Alzheimer, where oxidative stress is an important promoter of damage. In the present paper, we focus on the role of NOD as possible neuroprotective therapeutic agents for ischemia/reperfusion treatment.

Show MeSH
Related in: MedlinePlus