Oxidative stress

About: Oxidative stress is a research topic. Over the lifetime, 86513 publications have been published within this topic receiving 3845790 citations. The topic is also known as: oxydative stress.

Mechanism of toxicity in rotenone models of Parkinson's disease.

Abstract: Exposure of rats to the pesticide and complex I inhibitor rotenone reproduces features of Parkinson's disease, including selective nigrostriatal dopaminergic degeneration and alpha-synuclein-positive cytoplasmic inclusions (Betarbet et al., 2000; Sherer et al., 2003). Here, we examined mechanisms of rotenone toxicity using three model systems. In SK-N-MC human neuroblastoma cells, rotenone (10 nm to 1 microm) caused dose-dependent ATP depletion, oxidative damage, and death. To determine the molecular site of action of rotenone, cells were transfected with the rotenone-insensitive single-subunit NADH dehydrogenase of Saccharomyces cerevisiae (NDI1), which incorporates into the mammalian ETC and acts as a "replacement" for endogenous complex I. In response to rotenone, NDI1-transfected cells did not show mitochondrial impairment, oxidative damage, or death, demonstrating that these effects of rotenone were caused by specific interactions at complex I. Although rotenone caused modest ATP depletion, equivalent ATP loss induced by 2-deoxyglucose was without toxicity, arguing that bioenergetic defects were not responsible for cell death. In contrast, reducing oxidative damage with antioxidants, or by NDI1 transfection, blocked cell death. To determine the relevance of rotenone-induced oxidative damage to dopaminergic neuronal death, we used a chronic midbrain slice culture model. In this system, rotenone caused oxidative damage and dopaminergic neuronal loss, effects blocked by alpha-tocopherol. Finally, brains from rotenone-treated animals demonstrated oxidative damage, most notably in midbrain and olfactory bulb, dopaminergic regions affected by Parkinson's disease. These results, using three models of increasing complexity, demonstrate the involvement of oxidative damage in rotenone toxicity and support the evaluation of antioxidant therapies for Parkinson's disease.

Oxidative Stress in Parkinson's Disease

Abstract: Parkinson's disease (PD) is a common adult-onset neurodegenerative disorder. Typically PD is a sporadic neurological disorder, and over time affected patients see their disability growing and their quality of life declining. Oxidative stress has been hypothesized to be linked to both the initiation and the progression of PD. Preclinical findings from both in vitro and in vivo experimental models of PD suggest that the neurodegenerative process starts with otherwise healthy neurons being hit by some etiological factors, which sets into motion a cascade of deleterious events. In these models initial molecular alterations in degenerating dopaminergic neurons include increased formation of reactive oxygen species, presumably originating from both inside and outside the mitochondria. In the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD, time-course experiments suggest that oxidative stress is an early event that may directly kill some of the dopaminergic neurons. In this model it seems that oxidative stress may play a greater role in the demise of dopaminergic neurons indirectly by activating intracellular, cell death-related, molecular pathways. As the neurodegenerative process evolves in the MPTP mouse model, indices of neuroinflammation develop, such as microglial activation. The latter increases the level of oxidative stress to which the neighboring compromised neurons are subjected to, thereby promoting their demise. However, these experimental studies have also shown that oxidative stress is not the sole deleterious factor implicated in the death of dopaminergic neurons. Should a similar multifactorial cascade underlie dopaminergic neuron degeneration in PD, then the optimal therapy for this disease may have to rely on a cocktail of agents, each targeting a different critical component of this hypothesized pathogenic cascade. If correct, this may be a reason why neuroprotective trials using a single agent, such as an antioxidant, have thus far generated disappointing results.

Onset of Maternal Arterial Blood Flow and Placental Oxidative Stress: A Possible Factor in Human Early Pregnancy Failure

Abstract: The aim was to measure changes in the oxygen tension within the human placenta associated with onset of the maternal arterial circulation at the end of the first trimester of pregnancy, and the impact on placental tissues. Using a multiparameter probe we established that the oxygen tension rises steeply from 50 mmHg at 12 weeks. This rise coincides with morphological changes in the uterine arteries that allow free flow of maternal blood into the placenta, and is associated with increases in the mRNA concentrations and activities of the antioxidant enzymes catalase, glutathione peroxidase, and manganese and copper/zinc superoxide dismutase within placental tissues. Between 8 to 9 weeks there is a sharp peak of expression of the inducible form of heat shock protein 70, formation of nitrotyrosine residues, and derangement of the mitochondrial cristae within the syncytiotrophoblast. We conclude that a burst of oxidative stress occurs in the normal placenta as the maternal circulation is established. We speculate that this may serve a physiological role in stimulating normal placental differentiation, but may also be a factor in the pathogenesis of pre-eclampsia and early pregnancy failure if antioxidant defenses are depleted.