Neurodegenerative diseases including Alzheimer's Disease (AD), Parkinson's disease (PD), Huntington's disease (HD) and amyotrophic lateral sclerosis (ALS) share in common both aging as a major risk factor and oxidative stress as an important pathophysiological mechanism.
Interestingly, an involvement of oxidative stress has been suggested in accelerated aging processes such as progeria and Werner syndromes, which are also associated with neurodegenerative processes.
Collectively, there is enough evidence to suggest that oxidative damage plays an important role in brain dysfunction seen in dementias, especially in AD.
The potential implication of antioxidant patterns also displays in this disease: while scientists found high peripheral levels of biomarkers of oxidative damage to DNA, lipids and proteins paralleling a dramatic decrease in levels and activities of several enzymatic and non-enzymatic antioxidants, only some antioxidants appear to be specifically associated to particular biomolecular damage.
This is, for instance, the case of lutein, lycopene, a- and b-carotene, whose plasma levels have been found to be inversely related to the lymphocyte DNA content of an oxidized base, 8-hydroxy-2-deoxyguanosine, in AD patients.
This observation might be of relevance in AD prevention or in slowing disease progression, since lycopene has been shown to exert protective effects against oxidative DNA damage and since supplementation with xanthophylls and lycopene was able to decrease the amount of biomarkers of DNA and lipid oxidation in humans.
The critical question is whether oxidative stress is a consequence rather than a causative step in the development of neurodegenerative processes.
It can be, at least, partially answered with the observation that subjects with mild cognitive impairment (MCI), a condition frequently associated with AD, have increased plasma, urine and CSF levels of 8,12-iso-iPF2a-VI - a sensitive marker of in vivo lipid peroxidation; compared to healthy subjects.
These results, together with the report of increased levels of cerebral biomarkers of oxidative damage in the early AD stage compared to the most advanced one as well as the observation of broad and dramatic antioxidant depletion noted in MCI and AD subjects support the hypothesis that oxidative damage occurs as one of the earliest pathophysiological events in AD.
An early stage of AD, MCI, precedes AD by several years.
A large number of studies found an association between high dietary antioxidant intake and with a decreased risk for AD.
However, intervention trials demonstrated no major benefit with antioxidant supplementation in the treatment of AD.
It is possible that when the clinical symptoms of AD appear a large proportion of neuronal cells might already be destroyed and therefore the intervention with antioxidants could be too late.
Several lines of evidence support a role for oxidative stress in atherogenesis.
Epidemiological studies suggest that low levels of antioxidants are associated with increased risk for CVD, while high vitamin E plasma levels have been shown to be associated with the absence of atherosclerosis in octogenarians.
After brain injury by ischemic or hemorrhagic stroke or trauma, the production of ROS may increase, sometimes drastically, leading to tissue damage via several different cellular molecular pathways, including complex cascades of metabolic events that involve glutamate and its transporter proteins, NMDA receptors, nitric oxide synthases, etc.
Scientists showed that plasma levels of vitamin C - but not of vitamin E, ubiquinol-10 and uric acid - were inversely correlated with the size of the brain lesion in patients with brain hemorrhage or head trauma.
In addition, plasma vitamin C levels were lower in jugular compared with peripheral blood samples in a small subset of patients.
Independent of dietary intake, lipid profile, smoking habit and vitamin supplementation only plasma levels of vitamin C and of lutein, but not of other antioxidants, were shown to be associated with functional outcome in patients with neurological impairment due to ischemic stroke of recent onset.
In these individuals, lipid peroxidation was shown to be significantly higher compared to controls.
In classic experiments, it was shown that under conditions of oxidative stress, until all vitamin C is consumed there is neither a significant loss of other antioxidants nor an increase in lipid peroxidation in human plasma.
The protection against free radicals exhibited by vitamin C was confirmed even in the presence of bleomycin-detectable free iron, an effect that might be of relevance in brain injury when iron is released by damaged cells.
Two recent intervention studies showed that short-term and long-term vitamin C supplementation increases the resistance of plasma to lipid peroxidation both in healthy humans and in stroke patients.
Antioxidant micronutrients have been postulated to exert protective effects against coronary heart disease (CHD).
A meta-analysis has indicated that the relative risk reduction of ischemic heart disease in high consumers of fruit and vegetables may be in the order of 15%.
Vitamin E is thought to prevent atherosclerotic disease not only by its antioxidant effects, but also through its inhibitory effects upon smooth muscle proliferation and platelet adhesion.
In supplementation studies in humans, a-tocopherol decreases lipid peroxidation and platelet aggregation and adhesion and is anti-inflammatory in nature.
Of 11 studies evaluating the effects of various combinations of antioxidants including a-tocopherol, ascorbic acid and b-carotene on cardiovascular events, 4 showed a benefit with regards to the primary endpoint.
Randomized, controlled trials of specific antioxidant supplements, however, have failed to demonstrate a consistent or significant effect of any single vitamin or combinations of vitamins on incidence of or on death from CVD.
In scientific study 30 elderly patients were studied with CHF due, in half of the cases, to ischemic heart disease.
The sample population, once again, was rigorously controlled for several potential oxidative stress-related confounding variables, including comorbidity, drug therapy, antioxidant vitamin supplementation, dietary intake, smoking habit, lipid profile, and degree of physical activity.
Independently of the ischemic origin of the failure, the left ventricular ejection fraction (the ratio of the volume of blood the heart empties during systole to the volume of blood in the heart at the end of the diastole, expressed as a percentage of the total diastolic blood volume in the heart and normally ranging between 60% and 80%) significantly and directly correlated with plasma levels of vitamin A, vitamin E, lutein and lycopene - but not with other carotenoids.
This observation is substantiated by the synergistic action and quenching activity of lutein and lycopene and by their potential ability to neutralize free radicals implicated as a cause of endothelial dysfunction in heart disease.
In our study a simultaneous inverse correlation was found between ejection fraction and malondialdehyde, a marker of lipid peroxidation.
Recently, an inverse correlation between ejection fraction and plasma levels of a more sensitive and specific biomarker of lipid peroxidation (8,12-isoprostane F2a-VI, one of the most abundant F2 -isoprostanes produced in vivo in humans) was also found in another group of patients with moderate and moderately severe CHF of ischemic origin (Polidori et al., not yet published data).
It is, therefore, interesting to note that the relationship between the antioxidant pattern observed in CHF and the heart functionality might be, once again, mediated by and intimately linked to the pathophysiological step of lipid peroxidation.