4-hydroxy-2-nonenal and Central-Nervous-System-Diseases

Increasing lines of evidence suggest a key role of oxidative stress in neurodegenerative diseases. Alzheimer's disease, Parkinson's disease, myoclonus epilepsy of the Unverricht-Lundborg type, spinocerebellar degeneration, tardive dyskinesia and Down's syndrome have been associated with several mitochondrial alterations. Oxidative stress can decrease cellular bioenergetic capacity, which will then increase the generation of reactive oxygen species resulting in cellular damage and programmed cell death. First, this review examines the mechanisms of action of N-acetylcysteine (NAC), an antioxidant and a free radical-scavenging agent that increases intracellular GSH, at the cellular level. NAC can act as a precursor for glutathione synthesis as well as a stimulator of the cytosolic enzymes involved in glutathione regeneration. The chemical properties of NAC include redox interactions, particularly with other members of the group XIV elements (selenium, etc.) and ebselen, a lipid-soluble seleno-organic compound. Second, NAC has been shown to protect against oxidative stress-induced neuronal death in cultured granule neurons. Recent findings on the protective effect of NAC against 4-hydroxynonenal (HNE)-induced toxicity in cerebellar granule neurons are summarized. Finally, the protective pharmacokinetics of NAC in humans and the possible usefulness of NAC for the treatment of neurodegenerative diseases are discussed with reference to basic and clinical studies.

Topics: Acetylcysteine; Aldehydes; Central Nervous System Diseases; Cerebellum; Free Radical Scavengers; Humans; Neurodegenerative Diseases; Neurons; Reactive Oxygen Species

Hyperoxic cardiopulmonary resuscitation (CPR) is associated with an increase in neurologic dysfunction upon successful resuscitation with much of the damage attributable to an increase in reperfusion oxidant injury. We hypothesized that by contrast, hypoxic ventilation during resuscitation would improve neurologic outcome by reducing available substrate necessary for oxidant injury. Specifically, this study investigated the effects of 2 levels of hypoxic ventilation during resuscitation: F1O2 = 0.085, PaO2 = 26.6 +/- 3.4 mmHg, (HY8), and F1O2 = 0.12, PaO2 = 33.0 +/- 4.2 mmHg, (HY12), and normoxic resuscitation: F1O2 = 0.21, PaO2 = 60.6 +/- 17.0 mmHg, (N) on survival and neurological outcome following 9 min of normothermic cardiac arrest. Concentrations of malonaldehyde (MDA) and 4-hydroxynonenal (4-OH) in plasma and concentrations of glutathione (GSH) in erythrocyte lysates were measured to quantify possible radical damage. Physiological variables including arterial blood gases were followed for 24 h after resuscitation. Neurologic outcome was assessed using a standardized scoring system. Hypoxically (HY8) resuscitated dogs tended to have a greater neurologic deficit than normoxically resuscitated dogs and had reduced overall survival (16.9 +/- 8.9 h) compared to N dogs (24.0 +/- 0.0 h). Overall survival time correlated negatively (-0.693) and significantly (P = 0.0018) with plasma glucose concentration. Arterial plasma glucose concentrations were higher in the HY8 group compared to the N group immediately (HY8, 312 +/- 86 mg/dL; N, 196 +/- 82 mg/dL; P = 0.17) and 30 min (HY8, 331 +/- 109 mg/dL; N, 187 +/- 74 mg/dL; P = 0.077) following resuscitation. No statistically discernible differences in markers of oxidant injury were apparent among the 3 groups, but pooled data increased significantly with time for MDA and 4-OH. Pooled data for GSH showed a significant drop at 1 h following resuscitation and returned to normal by 6 h. Data from these markers suggested attendant oxidant injury in all groups. Thus, hypoxic ventilation at 2 depths of hypoxia during resuscitation failed to improve neurologic outcome beyond that achieved by ventilation with air, suggesting that normoxia rather than hyperoxia or hypoxia is the ideal target for arterial oxygenation during resuscitation.

Topics: Aldehydes; Animals; Blood Glucose; Brain Ischemia; Cardiopulmonary Resuscitation; Central Nervous System Diseases; Dogs; Erythrocytes; Glutathione; Heart Arrest; Male; Malondialdehyde; Neurologic Examination; Oxygen; Oxygen Inhalation Therapy; Reperfusion Injury; Respiration, Artificial