The reason why β-carotene may exert dual activity, namely antioxidant or pro-carcinogenic has been debated for quite a long time. The first hypothesis is that at high concentrations, β-carotene stimulates free radical production, whereas at lower concentrations β-carotene exerts antioxidant activity [90,91]. Furthermore, in the presence of cigarette smoke-derived free radicals β-carotene is cleaved into many derivatives which are very unstable and may trigger further oxidation [92-95]. A recent corollary to this theory is the evidence that β-carotene, either alone or in combination with cigarette smoke condensate, repressed HO-1 expression both in rat fibroblasts and human lung cancer cells [96]. The reduced expression of HO-1 accounted for a reduced production of CO and BR both of which have a marked antiproliferative effects [96-100]. Vitamin E has also been shown to act at the immune system level; in fact, supplementation with this vitamin can increase production of antibodies and enhance cell-mediated immunity in both experimental animals and in humans [101].
Neurodegenerative diseases, such as Parkinson's disease (PD), Alzheimer's disease (AD), and amyotrophic lateral sclerosis (ALS), as well as multiple slerosis (MS), are triggered, at least in part, by oxidative and nitrosative stress and also sustained by inflammatory cytokine production [11,70,102-104]. Similarly, autoimmunity mainly contributes to the pathogenesis of MS, characterized by central and peripheral loss of nerve myelin [105,106]. Although the specific sources of the damaging ROS and the affected target structures differ between the neuronal pathologies, the following general features can be defined. Increased levels of oxidation-altered metabolites are found in post-mortem tissues in many of the neurodegenerative diseases listed above [107-113]. An oxidative stress response and compensatory defense reactions can be seen in the affected neural cells; further, disturbances of the mitochondrial metabolism are observed, which may account for an increased leakage of ROS originating from the respiratory chain [11,70,104,114]. However, in addition to the direct induction of oxidative stress, metabolic disorders underlying every single disease can also indirectly generate an oxidative microenvironment, for example via the induction of a local immune response [115,116]. On this basis, antioxidant and antinflammatory drugs, such as polyphenols and non-steroidal antinflammatory drugs (NSAIDs), have been proposed in the treatment of different neurodegenerative diseases [117-119]. However, both polyphenols and NSAIDs gave rise to some problems when used in clinical setting. Due to their scarce bioavailability, only a negligible amount of polyphenols reaches brain tissue and the concentrations achieved are much lower than those efficacious in vitro [3]. As far as NSAIDs, ad hoc designed clinical trials with a large number of patients, clearly demonstrated that these drugs do not have any significant effect in slowing cognitive decline in patients suffering from mild-to-moderate AD [120,121]. Similar disappointing results have been obtained in the treatment of ALS, a systemic motor neuron disease that affects corticospinal and corticobulbar tracts, ventral horn motor neurons and motor cranial nerve nuclei [122,123]. Approximately 10% of cases are familial and have been linked to point mutation in the gene encoding for Cu/Zn superoxide dismutase (SOD) [124]. Mice transgenic for mutated SOD1 develop symptoms and pathologies similar to those in human ALS. Mutant SOD1 toxicity is mediated by damage to mitochondria in motor neurons, and this may trigger the functional decline of motor neurons and the onset of ALS in mice [125]. Unfortunately, although the role played by free radical to the pathogenesis of ALS has been demonstrated, antioxidants did not have any effect to prevent or slow down its progression. Desnuelle et al., clearly demonstrated that alpha-tocopherol, given together with riluzole, did not affect the survival and motor functions in ALS patients respect to the group treated with riluzole alone [126]. Novel compound, such as AEOL-10150 (Aeolus), structurally related to the SOD catalytic site, is under phase I clinical investigation, but further clinical trials will be necessary to evaluate the real efficacy of this compound for the therapy of ALS [127,128].