Cellular and Molecular Mechanisms Underlying Perturbed Energy Metabolism and Neuronal Degeneration in Alzheimer's and Parkinson's Diseases

There is growing evidence that oxidative stress and mitochondrial respiratory failure with attendant decrease in energy output are implicated in nigral neuronal death in Parkinson disease (PD). It is not known, however, which cellular elements (neurons or glial cells) are major targets of oxygen-mediated damage. 4-Hydroxy-2-nonenal (HNE) was shown earlier to react with proteins to form stable adducts that can be used as markers of oxidative stress-induced cellular damage. We report here results of immunochemical studies using polyclonal antibodies directed against HNE-protein conjugates to label the site of oxidative damage in control subjects (ages 18-99 years) and seven patients that died of PD (ages 57-78 years). All the nigral melanized neurons in one of the midbrain sections were counted and classified into three groups according to the intensity of immunostaining for HNE-modified proteins--i.e., no staining, weak staining, and intensely positive staining. On average, 58% of nigral neurons were positively stained for HNE-modified proteins in PD; in contrast only 9% of nigral neurons were positive in the control subjects; the difference was statistically significant (Mann-Whitney U test; P < 0.01). In contrast to the substantia nigra, the oculomotor neurons in the same midbrain sections showed no or only weak staining for HNE-modified proteins in both PD and control subjects; young control subjects did not show any immunostaining; however, aged control subjects showed weak staining in the oculomotor nucleus, suggesting age-related accumulation of HNE-modified proteins in the neuron. Our results indicate the presence of oxidative stress within nigral neurons in PD, and this oxidative stress may contribute to nigral cell death.

Current concepts of the cause of Parkinson's disease (PD) suggest a role for both genetic and environmental influences. Common to a variety of potential causes of nigral cell degeneration in PD is the involvement of oxidative stress. Postmortem analysis shows increased levels of iron, decreased complex I activity, and a decrease in reduced glutathione (GSH) levels. The decrease in GSH levels may be a particularly important component of the cascade of events leading to cell death because it occurs in the presymptomatic stage of PD and may directly induce nigral cell degeneration or render neurons susceptible to the actions of toxins. There is evidence suggesting that oxidative stress might originate in glial cells rather than in neurons, and alterations in glial function may be an important contributor to the pathologic process that occurs in PD. Oxidative damage occurs in the brain in PD, as shown by increased lipid peroxidation and DNA damage in the substantia nigra. Increased protein oxidation is also apparent, but this occurs in many areas of the brain and raises the specter of a more widespread pathologic process occurring in PD to which the substantia nigra is particularly vulnerable. The inability of the substantia nigra to handle damaged or mutant (eg, alpha-synuclein) proteins may lead to their aggregation and deposition and to the formation of Lewy bodies. Indeed, Lewy bodies stain for both alpha-synuclein and nitrated proteins. Current evidence enables us to hypothesize that a failure to process structurally modified proteins in regions of the brain exhibiting oxidative stress is a cause of both familial and sporadic PD.

Stroke, an age-related disorder involving degeneration of neurons resulting from cerebral ischemia, is a major cause of disability and mortality. Although dietary restriction (DR) extends lifespan and reduces levels of cellular oxidative stress in several different organ systems including the brain, the impact of DR on ischemic brain injury is unknown. We report that maintenance of adult rats on a DR regimen resulted in reduced brain damage and improved behavioral outcome in a middle cerebral artery occlusion-reperfusion (MCAO-R) stroke model. Administration of 2-deoxyglucose (2-DG), a nonmetabolizable analogue of glucose, to rats fed ad libitum resulted in reduced ischemic brain damage and improved behavioral outcome following MCAO-R. 2-DG protected cultured hippocampal neurons against chemical hypoxia, demonstrating a direct protective action on neurons. DR and 2-DG administration resulted in an increase in the level of the stress protein heat-shock protein 70 (HSP-70) in striatal cells in vivo, and 2-DG treatment induced HSP-70 in cultured neurons suggesting involvement of a preconditioning stress response in the neuroprotective actions of DR and 2-DG. The neuroprotective effect of DR and 2-DG in this focal cerebral ischemia model suggests that outcome following stroke may be improved in individuals who follow a regimen of reduced food intake. Copyright 1999 Wiley-Liss, Inc.