ReviewVitamin E and neurodegenerative diseases
Introduction
Neurodegenerative diseases are defined by the progressive loss of specific neuronal cell populations and are associated with protein aggregates. A growing body of evidence suggests that oxidative stress plays a key role in the pathophysiology of neurodegenerative disorders (Evans, 1993, Jenner, 1994, Knight, 1997). Reactive oxygen species (ROS), comprising superoxide anions, hydroxyradicals and hydrogen peroxide, are produced as a result of normal and aberrant cellular reactions (Coyle and Puttfarcken, 1993, Halliwell, 1992). ROS are known to cause cell damage by way of three main mechanisms: lipid peroxidation, protein oxidation and DNA oxidation. Therefore, cells have developed several defense and repair mechanisms to deal with oxidative stress: antioxidants represent the first line of defense and comprise enzymes such as superoxide dismutase, catalase, glutathione peroxidase and small molecules, as vitamins E and C, which are able to neutralise ROS and can be regenerated by the cellular antioxidant network (Halliwell, 1999). The role of vitamin E in the central nervous system (CNS) has not fully elucidated, but it acts protecting cell membranes from oxidative damage by neutralising the effects of peroxide and oxygen free radicals. In addition to its antioxidant properties, tocopherol can act as an anti-inflammatory agent, which may also be neuroprotective, and can regulate specific enzymes, thus changing the properties of membranes (Martin et al., 1999).
Evidence suggests that the cellular free radical scavenger systems lose efficiency with aging and that the age-associated increase in oxidative stress plays a major role in neurodegenerative processes. The CNS is especially vulnerable to free radical damage because it has a high oxygen consumption rate, an abundant lipid content and a relative deficit in antioxidant systems, compared with other tissues (Coyle and Puttfarcken, 1993, Smith et al., 2000).
It is still unclear whether oxidative stress is the primary initiating event associated with neurodegeneration or a secondary effect related to other pathological pathways, but a growing body of evidence implicates it as being involved in the propagation of cellular injury (Jenner, 2003).
The appealing feature of the oxidative stress hypothesis for neurodegenerative diseases is that cumulative oxidative damage over time could account for the late life onset and the slowly progressive nature of these disorders. Since vitamin E is the only lipid-soluble, chain-breaking antioxidant in biological membranes (Burton et al., 1983, Ingold et al., 1987), it is reasonable to propose that vitamin E may play a role in the treatment of some of these diseases.
Although the consequences of oxidative damage have been implicated in many neurodegenerative disorders, this review will focus on Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis and ataxia with vitamin E deficiency.
Section snippets
Alzheimer’s disease (AD)
AD is the most common neurodegenerative disease associated with aging; actually, it affects nearly 20–30 million people worldwide (Selkoe, 2005) and is present in almost half of individuals over the age of 85 (Puglielli et al., 2003). AD may have a genetic component (familial), where the onset of symptoms occurs relatively early in life (40s–50s); or may be sporadic (late-onset), where symptoms occur in individuals older than 60s (Law et al., 2001).
AD is clinically characterized by memory
Parkinson’s disease (PD)
PD is a chronic progressive neurodegenerative disease clinically characterized by bradykinesia, postural instability and tremor (Samii et al., 2004). Histopathologically, PD brains show intraneuronal deposition of alpha synuclein proteins (Lewy bodies) and irreversible loss of nigrostriatal dopaminergic neurons (Mark, 2001).
Amyotrophic lateral sclerosis (ALS)
ALS is a neurodegenerative disorder characterized by the selective death of upper and lower motor neurons, leading to profound muscle weakness and death, mostly by respiratory failure. The etiology of most ALS cases remains unknown, but 2% of instances are due to mutations in Cu/Zn superoxide dismutase (SOD1) (Rosen et al., 1993). The identification of sod1 (the gene encoding SOD1 protein) as a causative gene in ALS allowed the generation of multiple lines of transgenic mice, which exhibit a
Ataxia with vitamin E deficiency (AVED)
Mutations of the α-tocopherol transfer protein (α-TTP) gene, located on chromosome 8q, lead to reduced α-tocopherol concentrations in plasma and tissues, which lead ultimately to a severe syndrome named ataxia with vitamin E deficiency (AVED) (Ben Hamida et al., 1993). These patients show loss of neurons, symptoms of retinal atrophy, massive accumulation of lipofuscin in neurons including dorsal root ganglions, and retinitis pigmentosa (Yokota et al., 2000). The symptoms of AVED are similar to
Conclusion
Two relevant questions can be posed from this study. (1) What can be the basis for the contradictory results obtained by different clinical trials? (2) Should we abandon the idea that α-tocopherol may help protect against neurodegenerative diseases, or should we improve the trial conditions?
Although biochemical, cellular, and molecular biology data about α-tocopherol have increased dramatically, many molecular phenomena are still far from being fully elucidated.
The clinical intervention studies
Acknowledgements
Research in the authors’ laboratory is supported by grants from PRIN no. 2006065711_002.
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