Vitamin E and neurodegenerative diseases

Vitamin E and neurodegenerative diseases

Available online at www.sciencedirect.com Molecular Aspects of Medicine 28 (2007) 591–606 www.elsevier.com/locate/mam Review Vitamin E and neurodeg...

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Available online at www.sciencedirect.com

Molecular Aspects of Medicine 28 (2007) 591–606 www.elsevier.com/locate/mam

Review

Vitamin E and neurodegenerative diseases Roberta Ricciarelli *, Francesca Argellati, Maria A. Pronzato, Cinzia Domenicotti Department of Experimental Medicine, via L.B. Alberti 2, 16132 Genoa, Italy Received 7 December 2006; revised 3 January 2007; accepted 3 January 2007

Abstract Vitamin E is essential for neurological function. This fact, together with a growing body of evidence indicating that neurodegenerative processes are associated with oxidative stress, lead to the convincing idea that several neurological disorders may be prevented and/or cured by the antioxidant properties of vitamin E. In this review, some aspects related to the role of vitamin E against Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis and ataxia with vitamin E deficiency will be presented. Ó 2007 Elsevier Ltd. All rights reserved. Keywords: Vitamin E; Neurodegenerative disease; Oxidative stress; AD; PD; ALS; AVED

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Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Alzheimer’s disease (AD) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. The oxidative hypothesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. The role of vitamin E in AD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Parkinson’s disease (PD) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. The oxidative hypothesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. The role of vitamin E in PD . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Corresponding author. Tel.: +39 010 3538831; fax: +39 010 3538836. E-mail address: [email protected] (R. Ricciarelli).

0098-2997/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.mam.2007.01.004

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Amyotrophic lateral sclerosis (ALS) . . . . Ataxia with vitamin E deficiency (AVED) Conclusion . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . .

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1. 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.

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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. 2. 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 dysfunction, loss of lexical access, spatial and temporal disorientation and impairment of judgment. Histopathologically, AD brain shows synaptic loss, neuronal loss (mostly in the cerebral cortex, in the hippocampus and in the amigdala), extracellular deposition of b-amyloid (Ab) protein in senile plaques, and intraneuronal precipitation of hyperphosphorylated tau protein forming neurofibrillary tangles (NFT) (Tanzi and Bertram, 2001). Aggregated Ab is composed of small peptides with 39–43 aminoacid residues produced from a large precursor protein (APP), and plays a pivotal role in the neuronal dysfunction and death; among different subtypes of Ab, Ab1–40 is the most predominant form accounting for more than 90% of the total Ab, whereas amyloid Ab1–42 is the most toxic form. Intracellular NFT are, at their core, formed by a hyper-phosphorylated form of the microtubule-associated protein named tau (Grundke-Iqbal et al., 1986); tau phosphorylation is thought to cause a destabilization of microtubular dynamics in the adult neurons, resulting in neuronal dysfunction (Alonso et al., 1996). 2.1. The oxidative hypothesis The exact biochemical mechanism of the pathogenesis of AD is still unknown, but much attention is given to the role of the massive loss of the neurotransmitter acetylcholine and to the possible implication of oxidative stress in its development. In AD, a ‘‘two hit’’ hypothesis has been postulated in which either oxidative stress or alterations of mitotic signaling serve as initiators and are also crucial to propagate disease pathogenesis (Longo and Massa, 2004; Zhu et al., 2004). Age is a risk factor for AD and several studies show logarithmic age-dependent increases in oxidized proteins, lipids and DNA in AD patients (Floyd and Hensley, 2002). Oxidative injury may play a role in Ab deposition and the complex relationships between this event, excitoxicity, calcium dysregulation and ROS generation in AD have been recently summarized (Canevari et al., 2004; Mattson, 2004). Oxidizing conditions cause protein cross-linking and aggregation of Ab peptides (Dyrks et al., 1993) and also contribute to aggregation of tau (Troncoso et al., 1993) and

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other cytoskeletal proteins. Behl and coll. have demonstrated that Ab aggregates, upon interaction with the neuronal cell membrane, induce a sequence of events that leads to the intracellular accumulation of ROS (Behl et al., 1994). In addition to the direct induction of oxidative stress, Ab can also indirectly generate an oxidative microenvironment mediated by the local immune response; indeed, cellular and soluble mediators of inflammation are found in post-mortem AD tissue (McGeer et al., 2000). It is worthy to mention a quite recent alternative hypothesis that considers Ab as a protective consequence with many physiological roles, some of which include redox-active metal sequestration (Smith et al., 1997) and SOD-like activity (Curtain et al., 2001). Several markers of oxidative damage to DNA, lipids and proteins have been widely studied in AD (Markesbery and Carney, 1999). A significant increase of 8hydroxy-2 0 -deoxyguanosine (8-OHdG) in nuclear DNA (nDNA) and mitochondrial DNA (mtDMA) was found in the parietal cortex of AD patients. These levels were much higher in mtDNA than in nDNA, showing an elevated susceptibility of mitochondria to oxidative stress (Mecocci et al., 1994); elevated levels of 8-OHdG were also detected in lymphocyte DNA from AD donors (Mecocci et al., 1998; Nunomura et al., 2001). In AD brains, lipid peroxidation has been quantitatively assessed by measuring thiobarbituric acid-reactive substances (TBARS), 4-hydroxy-2-nonenal (HNE), malondialdehyde (MDA), lipid hydroperoxides, and isoprostanes. TBARS were found to be increased in AD frontal and temporal cortices (Lovell et al., 1995; Subbarao et al., 1990) and several reports showed an increase in free HNE in multiple AD brain regions including cerebellum, amigdala and hippocampus (Markesbery, 1997; Markesbery and Lovell, 1998; Zarkovic et al., 2003). Regarding protein oxidation, Smith and coll. found that brain carbonyl levels increase with age, but no difference was observed between aged and AD brains (Smith et al., 1991). On the other hand, it has also been demonstrated that, consistently with the regional pattern of AD histopathology, protein carbonyls are significantly increased in both hippocampus and inferior parietal lobule (Hensley et al., 1995). Elderly subjects with mild cognitive impairment (MCI) and AD subjects show lower levels of vitamin A, vitamin C, vitamin E, uric acid, alpha-carotene and lower activities of plasma and erythrocyte superoxide dismutase (SOD) as well as glutathione peroxidase (Rinaldi et al., 2003). These findings suggest that subjects developing MCI and AD may have an antioxidant enzymatic activity inadequate to counteract the hyperproduction of free radicals. Therefore, antioxidant therapies for both prevention and treatment of neurodegenerative diseases currently appear to be a promising field of research. 2.2. The role of vitamin E in AD Vitamin E has been frequently tested in vitro, in animal studies and in epidemiological and clinical trials.

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In culture of embryonic hippocampal neurons, a-tocopherol can modulate the Ab-induced oxidative damage of creatine kinase, which is significantly impaired in brain of AD patients (Yatin et al., 1999). Moreover, when Ab25-35 is administered in the hippocampus of rats previously treated with vitamin E, neuronal damage and lipoperoxidation are efficiently prevented (Montiel et al., 2006). In vitro exposure of neuronal cells to vitamin E also decreases Ab induced lipid peroxidation and oxidative stress and suppresses inflammation-signalling cascades (Butterfield et al., 2002). Sung and coll. investigated the vitamin E mediated effects in the young transgenic mouse model of AD (Tg2576), finding that early vitamin E supplementation significantly reduces Ab levels and deposition. Conversely, mice receiving vitamin E supplementation at a later age do not show any significant difference in either markers when compared with placebo (Sung et al., 2004). Yokota and coll. have recently generated the a-tocopherol transfer protein knockout (Ttpa/) mouse, which shows marked lipid peroxidation due to lack of atocopherol, and is therefore considered as a model for chronic oxidative stress (Yokota et al., 2001). The double-mutants obtained by crossing of AD transgenic mice (Tg2576) with Ttpa/ mice showed earlier and more severe cognitive dysfunction and increased Ab deposits in the brain (Nishida et al., 2006). In line with these results, a different study demonstrated that the focal neurotoxicity associated with the senile plaques is partially reversed by antioxidant therapies. In fact, both Ginkgo biloba extract and vitamin E oral administration reduced the oxidative stress in APPswe/PS1d9 transgenic mice. Both treatments also led to a progressive reversal of the structural changes in dystrophic neurites (Garcia-Alloza et al., 2006). In a recent investigation, the gene chip technology was utilised to establish the impact of chronic vitamin E deficiency on hippocampal gene expression. The study, conducted on male rats fed a vitamin E deficient diet for 9 months, indicated that the vitamin strongly affects the expression of an array of genes directly or indirectly involved in the clearance of Ab (Rota et al., 2005). In line with this observation, another interesting work demonstrated that microglial cells isolated from adult animals are not able to degrade extracellular material very efficiently, and that this can be partially overcome by tocopherol supplementation (Stolzing et al., 2006). The protective activity of vitamin E against AD, underscored by results gained from animal studies, suggested the need of epidemiological and clinical trials. Perkins and coll. analyzed the association between the level of serum antioxidants (vitamins E, C, A, carotenoids, selenium) and memory performance in an elderly, multiethnic sample of 4809 subjects. After adjustment for age, education, income and vascular risk factors, they found a decreased serum level of vitamin E consistently associated with memory deficit. Serum levels of other antioxidants (vitamins A and C, b-carotene, and selenium) did not correlate with memory performance (Perkins et al., 1999). In another study, 2889 elderly subjects were asked to complete a food questionnaire; dietary or supplementary intake of vitamin E correlated with less cognitive

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decline with age. Little evidence of association with vitamin C or carotene was found (Morris et al., 2002). Data from the Rotterdam study, a prospective cohort study among elderly, have been analyzed to examine the influence of diet on the risk of dementia (Engelhart et al., 2002). High dietary intake of vitamin E and C was associated with lower risk of AD, and the correlation was most pronounced among current smokers subjects. The association did not vary by education or apolipoprotein E (ApoE) genotype. Whereas epidemiological studies have indicated a putative role of vitamin E in preventing cognitive impairment, intervention trials have produced contradictory results. The Alzheimer’s Disease Cooperative Study completed a multicenter clinical trial of vitamin E and selegiline supplementation of patients with moderate AD (Sano et al., 1997). Selegiline is a monoamine oxidase B inhibitor with antioxidant properties, at least in some experimental model systems. The primary objective of this study was to determine whether vitamin E or selegiline could slow functional decline. A total of 341 patients with moderately severe disease were enrolled in a double-blind, placebo-controlled, trial. Patients were randomly assigned to receive either vitamin E (2000 IU/d), selegiline (10 mg/d), both selegiline and vitamin E, or placebo. The primary outcome measure was the time to reach anyone of the following endpoints: institutionalization, loss of basic activities of daily living, severe dementia, or death. The risk of reaching the primary outcome was significantly reduced by vitamin E treatment, selegiline treatment, and combined treatment. There was no evidence of additional improvement with combined treatment over each treatment alone. The effect of vitamin E on each of the individual endpoints making up the primary outcome measure was also examined. Compared with the placebo group, the vitamin E group had a favorable hazard ratio and a prolonged time to event for all endpoints. However, no significant benefit was shown with cognitive tests. In a more recent double-blind study, 769 subjects with MCI were randomly assigned to receive 2000 IU of vitamin E daily, 10 mg of donepezil daily, or placebo for three years. Donepezil therapy was associated with a lower rate of progression to AD only during the first 12 months of treatment. In this study, vitamin E therapy had no benefits (Petersen et al., 2005).

3. 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). 3.1. The oxidative hypothesis The mechanisms of cell death in PD have not yet been fully elucidated, but increased oxidative stress, abnormal mitochondrial function and excitotoxicity are

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considered as the most likely initiators or mediators of neuronal damage (Abou-Sleiman et al., 2006). The evidence of an involvement of free radicals in PD comes from the observation that oxidation of dopamine yields potentially toxic semiquinones, and that the accelerated metabolism of dopamine by monoamine-oxidase-B may induce an excessive formation of hydrogen peroxide, superoxide anions and hydroxyradicals (Dexter et al., 1989; Fahn and Cohen, 1992; Jenner, 1991; Lei et al., 1992). Further evidence for the role of oxidative stress in PD patients comes from the selective toxicity against the substantia nigra of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which induces Parkinson’s like symptoms in primates. MPTP acts through its metabolite MPP+, which inhibits Complex I of the mitochondrial respiratory chain and acts by increasing the vulnerability of cells to oxidative stress (Lee et al., 2000). Mitochondrial complex I defects have been also found in muscle (Penn et al., 1995) and platelets (Blake et al., 1997) of PD patients. As for other neurodegenerative diseases, a fundamental molecular pathway to PD development is the abnormal folding, function and metabolism of proteins such as alpha synuclein and parkin, which are simultaneously source and target of oxidative and nitrative stresses (Bossy-Wetzel et al., 2004). Increased protein carbonyls were detected in the substantia nigra, basal ganglia, frontal cortex and cerebellum (Alam et al., 1997) and another evidence for oxidative damage to proteins is the increased expression of neural heme-oxygenase-1 (Castellani et al., 1996). A marked enhancement of 8-OHdG in caudatum and substantia nigra (Beal, 1995) and also in the serum and cerebrospinal fluids (CSF) of PD patients has been described (Kikuchi et al., 2002). Migliore and coll. found that patients with untreated PD show an increase in chromosomal, primary DNA damage and oxidative DNA damage in peripheral blood lymphocytes (Migliore et al., 2002). Moreover, lipid peroxidation markers as MDA and cholesterol lipid hydroperoxides are increased in parkinsonian substantia nigra (Dexter et al., 1989) and lipoprotein oxidation is found in CSF and plasma of PD patients (Dexter et al., 1994). Glutathione (GSH) is an important intracellular antioxidant; of particular note, in support to the oxidative hypothesis for the pathogenesis of PD, is the finding of a significant GSH decrease in PD patients (Li et al., 1997). Recent studies show that neurons from PD affected brains accumulate mitochondrial DNA deletions that cause impaired cellular respiration (Savitt et al., 2006). The putative role of mitochondrial dysfunction and oxidative stress in PD pathogenesis has lead to trials of antioxidant and promitochondrial compounds, including coenzyme Q10, vitamin E and creatine (Weber and Ernst, 2006). 3.2. The role of vitamin E in PD Using in vitro and in vivo experimental models, studies have demonstrated both vitamin E-mediated protection and lack of protection. In the MPTP-induced PD mouse model (C57/B1), vitamin E deficiency increased MPTP toxicity, measured

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in terms of lethality and dopamine metabolite depletion in the substantia nigra (Odunze et al., 1990). Subsequent studies have reported that MPTP-induced depletion of striatal dopamine could not be attenuated by pre-treatment of mice with a daily oral administration of a-tocopherol (48 mg/kg) (Chi et al., 1992; Gong et al., 1991). Moreover, in a very recent study, MPTP-induced neurodegeneration in Ttpa/ mice was not worsened by genetic vitamin E deficiency (Ren et al., 2006). The reason for the conflicting findings on vitamin E protection in vivo is unknown but it may be related to the high acute dose of a-tocopherol administered and the ability of MPTP to compromise the blood–brain barrier, enabling a pronounced delivery of vitamin E from the plasma to the brain (Adams and Wang, 1994; Perry et al., 1985). Because it is difficult to increase GSH concentration in the brain (Zeevalk et al., 2006), and vitamin C is not altered in PD, vitamin E (readily augmented with oral supplements) was selected in the late 1980s for the first clinical trial of neuroprotection in PD, the DATATOP study (1989). DATATOP (Deprenyl and tocopherol antioxidative therapy of parkinsonism) was a placebo-controlled clinical trial designed to test the hypothesis that long-term treatment of patients with early Parkinson’s disease with deprenyl 10 mg/d and/or a-tocopherol 2000 IU/d may extend the time until disability requires therapy with levodopa (primary end point). At 28 US and Canadian sites, 800 eligible patients in the early stages of untreated Parkinson’s disease were enrolled in DATATOP and randomized to receive deprenyl, tocopherol, deprenyl and tocopherol, or placebo treatments. After a follow-up of 14 ± 6 months, there was no beneficial effect of tocopherol or any interaction between tocopherol and deprenyl. Conversely, the beneficial and still unexplained effects of deprenyl significantly delayed the onset of disability requiring levodopa therapy (Parkinson Study Group, 1993). On the other hand, it was previously shown that high-dose a-tocopherol, in association with ascorbic acid, may delay the progression of PD by an average of 2.5 years versus the time required in the placebo group (Fahn, 1992). In this study, the patients that had been diagnosed with PD were assigned to receive both a-tocopherol (3200 IU) and ascorbate (3000 mg) daily and were compared with a control population. More recently, Zhang and coworkers reported that a diet rich in vitamin E reduces the risk of developing PD. The researchers showed that the protective effects were not observed neither taking vitamin E supplements, nor with dietary vitamin C or carotenoids (Zhang et al., 2002). Other studies have shown contradictory results about dietary intake of vitamin E, vitamin C and carotenoids and their efficacy to prevent PD progression (Etminan et al., 2005; Pham and Plakogiannis, 2005; Weber and Ernst, 2006). Experimental evidence has illustrated that oxidative stress is responsible for damage in the substantia nigra and subsequent PD development; vitamin E is considered to protect against oxidative damage, due to its antioxidants properties. However, based on the available literature, there are many disputes about the efficacy of a-tocopherol in the prevention and/or treatment of PD.

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4. 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 transgene dose-dependent ALS-like pathology (Bruijn et al., 1998; Ripps et al., 1995; Wong et al., 1995). Interestingly, recent data from mutant SOD1 mice showed that motor neurons do not die following a cell-autonomous insult (Clement et al., 2003). While normal motor neurons surrounded by mutant SOD1-expressing cells are prone to die, those harboring an ALS-linked SOD1 mutation, placed in a wild-type background, are not (Clement et al., 2003), suggesting that the cellular environment of motor neurons is crucial to activate the pathological process. On the other hand, increasing experimental evidences support the idea that mitochondria are key players in ALS pathogenesis (see review in Dupuis et al., 2004). Mitochondria constitute a primary site of intracellular production of ROS, and therefore a major source of oxidative stress. In turn, oxidative damage to mitochondrial components may impair the normal function of mitochondria (Lenaz et al., 2002), corroborating the hypothesis that oxidative stress may be either directly or indirectly linked to the pathogenesis of ALS. In 1996, data from SOD1 transgenic mice showed that vitamin E intake slowed the onset and the progression of the disease (Gurney et al., 1996). More recently, a large prospective study that involved 508,334 men and 676,288 women, indicated that individuals who regularly used vitamin E supplements for 10 or more years had less than half the risk of death from ALS than nonusers (Ascherio et al., 2005). Like for Alzheimer’s and Parkinson’s disease, however, the results are controversial. Two double-blind, placebo-controlled, randomised trials have been performed, administering to sporadic ALS patients 500 and 5000 mg of vitamin E per day, respectively. Both trials demonstrated no significant differences with respect to placebo, although a trend toward improvement was shown in those patients receiving vitamin E (Desnuelle et al., 2001; Graf et al., 2005). A lack of significant associations between intakes of antioxidant vitamins and ALS risk was also reported in two case-control studies, but both were too small to estimate the specific effect of vitamin E supplementation (Longnecker et al., 2000; Nelson et al., 2000).

5. Ataxia with vitamin E deficiency (AVED) Mutations of the a-tocopherol transfer protein (a-TTP) gene, located on chromosome 8q, lead to reduced a-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

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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 those of Friedreich’s ataxia, but these two conditions can be distinguished by analysis of the frataxin gene on chromosome 9, where large GAA repeats are found in the first intron of Friedreich’s ataxia patients (Koenig and Mandel, 1997) and by measurement of the plasma a-tocopherol levels. In fact, AVED patients have normal intestinal vitamin E absorption but, because of a-TTP lack, intrahepatocytic vitamin E incorporation into very low density lipoproteins before release in blood circulation is defective, leading to important reduction of the serum vitamin E level. The largest group of AVED patients is found in North Africa; they share one of the most common mutation for the a-TTP gene (744delA). However, different mutations have been found among various ethnic groups in Europe, North America and Asia (Yokota et al., 1997). In a recent study, the first case of ataxia with isolated vitamin E deficiency has been identified in the Netherlands (Ponten et al., 2006). An Italian study conduced by Mariotti and coll. involved 16 patients from 12 families; they have the most common mutations 744delA and 513insTT, but two novel pathogenic mutations have been identified, a truncating mutation (219insAT) and a missense mutation (Gly246Arg). In spite of the development of spasticity and retinitis pigmentosa in a few patients during therapy, the vitamin E supplementation allowed a stabilization of the neurological conditions in most of the patients (Mariotti et al., 2004). This result suggests that a prompt genetic characterization of AVED may promote an early effective treatment of the disease. Different pathological conditions, e.g. hepatocellular carcinoma, which compromise a-TTP gene expression, lead to reduced plasma level of a-tocopherol. Moreover, the uptake of dietary antioxidants (tocopherols, carotenoids, flavonoids) and transport by chylomicrons from intestine to the liver is impaired in abetalipoproteinemia and lipid malabsorption syndromes such as cholestatic liver disease, shortbowel syndrome, and cystic fibrosis, which often show symptoms similar to AVED (Kayden and Traber, 1993). It is unknown whether the degenerative neurological symptoms in patients with vitamin E deficiency syndromes are the result of insufficient protection by antioxidants or are due to a lack of specific and non-antioxidant effects mediated by atocopherol. In these diseases, the transport of a-tocopherol is impaired in either the liver or intestine by the complete absence of a transport pathway, leading to extreme low plasma a-tocopherol levels (Traber et al., 1992). It can be assumed that conditions may exist with partially impaired vitamin E uptake and transport, such as heterozygotic mutation of vitamin E binding proteins (Gotoda et al., 1995) or less penetrant mutations, with consequent less severe symptoms or delayed outcome. In fact, the age of symptom onset in AVED patients depends on the type of mutation in the a-TTP gene (Cavalier et al., 1998). Individuals with an inherent lower efficiency of tocopherol uptake may benefit most from supplemental intake of a-tocopherol. Moreover, if polymorphisms in transport and/or action of vitamin E exist, they could significantly affect the outcome

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of epidemiological studies, in which the initial plasma level and the individual efficiency of uptake and transport of a-tocopherol often are not known.

6. 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 a-tocopherol may help protect against neurodegenerative diseases, or should we improve the trial conditions? Although biochemical, cellular, and molecular biology data about a-tocopherol have increased dramatically, many molecular phenomena are still far from being fully elucidated. The clinical intervention studies discussed above have not considered important factors such as Apo E polymorphisms, possibly influencing the effect of a-tocopherol treatment. They also neglected to measure the basal level of a-tocopherol in plasma before and after the supplementation or to consider the possibility that pro-oxidant effects of a-tocopherol may be protected by ascorbic acid. Finally, the existence of a-tocopherol binding proteins should be taken into consideration: the complexities of a-tocopherol absorption and metabolism are another variable in the puzzle of in vivo a-tocopherol function. Clinical aspects are also worth some comments. It is possible that the wrong stage of disease (irreversible) was chosen in some studies; age is not the sole element in determining the phase of the disease. It appears that vitamin E treatments should be started much earlier, continue for a longer period, and be consumed with vitamin C for its effect to become measurable. The population of choice should be selected according to age, Apo E genotype, gender, and vitamin E status. a-Tocopherol is beginning to reveal important, non-antioxidant functions (see review in Ricciarelli et al., 2001). It is possible that novel reactions and novel genes, found to be under a-tocopherol control, may help and clarify the relationships between molecular and clinical events.

Acknowledgements Research in the authors’ laboratory is supported by grants from PRIN no. 2006065711_002.

References Abou-Sleiman, P.M., Muqit, M.M., Wood, N.W., 2006. Expanding insights of mitochondrial dysfunction in Parkinson’s disease. Nat. Rev. Neurosci. 7, 207–219. Adams Jr., J.D., Wang, B., 1994. Vitamin E uptake into the brain and 1-methyl-4-phenyl-1,2,3,6tetrahydropyridine toxicity. J. Cereb. Blood Flow Metab. 14, 362–363.

602

R. Ricciarelli et al. / Molecular Aspects of Medicine 28 (2007) 591–606

Alam, Z.I. et al., 1997. A generalised increase in protein carbonyls in the brain in Parkinson’s but not incidental Lewy body disease. J. Neurochem. 69, 1326–1329. Alonso, A.C., Grundke-Iqbal, I., Iqbal, K., 1996. Alzheimer’s disease hyperphosphorylated tau sequesters normal tau into tangles of filaments and disassembles microtubules. Nat. Med. 2, 783–787. Ascherio, A. et al., 2005. Vitamin E intake and risk of amyotrophic lateral sclerosis. Ann. Neurol. 57, 104–110. Beal, M.F., 1995. Aging, energy, and oxidative stress in neurodegenerative diseases. Ann. Neurol. 38, 357– 366. Behl, C., Davis, J.B., Lesley, R., Schubert, D., 1994. Hydrogen peroxide mediates amyloid beta protein toxicity. Cell 77, 817–827. Ben Hamida, C. et al., 1993. Localization of Friedreich ataxia phenotype with selective vitamin E deficiency to chromosome 8q by homozygosity mapping. Nat. Genet. 5, 195–200. Blake, C.I., Spitz, E., Leehey, M., Hoffer, B.J., Boyson, S.J., 1997. Platelet mitochondrial respiratory chain function in Parkinson’s disease. Mov. Disord. 12, 3–8. Bossy-Wetzel, E., Schwarzenbacher, R., Lipton, S.A., 2004. Molecular pathways to neurodegeneration. Nat. Med. 10 (Suppl.), S2–S9. Bruijn, L.I. et al., 1998. Aggregation and motor neuron toxicity of an ALS-linked SOD1 mutant independent from wild-type SOD1. Science 281, 1851–1854. Burton, G.W., Joyce, A., Ingold, K.U., 1983. Is vitamin E the only lipid-soluble, chain-breaking antioxidant in human blood plasma and erythrocyte membranes? Arch. Biochem. Biophys. 221, 281–290. Butterfield, D.A., Castegna, A., Drake, J., Scapagnini, G., Calabrese, V., 2002. Vitamin E and neurodegenerative disorders associated with oxidative stress. Nutr. Neurosci. 5, 229–239. Canevari, L., Abramov, A.Y., Duchen, M.R., 2004. Toxicity of amyloid beta peptide: tales of calcium, mitochondria, and oxidative stress. Neurochem. Res. 29, 637–650. Castellani, R., Smith, M.A., Richey, P.L., Perry, G., 1996. Glycoxidation and oxidative stress in Parkinson disease and diffuse Lewy body disease. Brain Res. 737, 195–200. Cavalier, L. et al., 1998. Ataxia with isolated vitamin E deficiency: heterogeneity of mutations and phenotypic variability in a large number of families. Am. J. Hum. Genet. 62, 301–310. Chi, D.S., Gong, L., Daigneault, E.A., Kostrzewa, R.M., 1992. Effects of MPTP and vitamin E treatments on immune function in mice. Int. J. Immunopharmacol. 14, 739–746. Clement, A.M. et al., 2003. Wild-type nonneuronal cells extend survival of SOD1 mutant motor neurons in ALS mice. Science 302, 113–117. Coyle, J.T., Puttfarcken, P., 1993. Oxidative stress, glutamate, and neurodegenerative disorders. Science 262, 689–695. Curtain, C.C. et al., 2001. Alzheimer’s disease amyloid-beta binds copper and zinc to generate an allosterically ordered membrane-penetrating structure containing superoxide dismutase-like subunits. J. Biol. Chem. 276, 20466–20473. Desnuelle, C., Dib, M., Garrel, C., Favier, A., 2001. A double-blind, placebo-controlled randomized clinical trial of alpha-tocopherol (vitamin E) in the treatment of amyotrophic lateral sclerosis. ALS riluzole-tocopherol Study Group. Amyotroph. Lateral Scler. Other Motor Neuron Disord. 2, 9–18. Dexter, D.T. et al., 1989. Basal lipid peroxidation in substantia nigra is increased in Parkinson’s disease. J. Neurochem. 52, 381–389. Dexter, D.T. et al., 1994. Increased levels of lipid hydroperoxides in the parkinsonian substantia nigra: an HPLC and ESR study. Mov. Disord. 9, 92–97. Dupuis, L. et al., 2004. Mitochondria in amyotrophic lateral sclerosis: a trigger and a target. Neurodegeneration Dis. 1, 245–254. Dyrks, T., Dyrks, E., Masters, C.L., Beyreuther, K., 1993. Amyloidogenicity of rodent and human beta A4 sequences. FEBS Lett. 324, 231–236. Engelhart, M.J. et al., 2002. Dietary intake of antioxidants and risk of Alzheimer disease. Jama 287, 3223– 3229. Etminan, M., Gill, S.S., Samii, A., 2005. Intake of vitamin E, vitamin C, and carotenoids and the risk of Parkinson’s disease: a meta-analysis. Lancet Neurol. 4, 362–365. Evans, P.H., 1993. Free radicals in brain metabolism and pathology. Br. Med. Bull. 49, 577–587.

R. Ricciarelli et al. / Molecular Aspects of Medicine 28 (2007) 591–606

603

Fahn, S., 1992. A pilot trial of high-dose alpha-tocopherol and ascorbate in early Parkinson’s disease. Ann. Neurol. 32 (Suppl.), S128–S132. Fahn, S., Cohen, G., 1992. The oxidant stress hypothesis in Parkinson’s disease: evidence supporting it. Ann. Neurol. 32, 804–812. Floyd, R.A., Hensley, K., 2002. Oxidative stress in brain aging. Implications for therapeutics of neurodegenerative diseases. Neurobiol. Aging 23, 795–807. Garcia-Alloza, M., Dodwell, S.A., Meyer-Luehmann, M., Hyman, B.T., Bacskai, B.J., 2006. Plaquederived oxidative stress mediates distorted neurite trajectories in the Alzheimer mouse model. J. Neuropathol. Exp. Neurol. 65, 1082–1089. Gong, L., Daigneault, E.A., Acuff, R.V., Kostrzewa, R.M., 1991. Vitamin E supplements fail to protect mice from acute MPTP neurotoxicity. Neuroreport 2, 544–546. Gotoda, T. et al., 1995. Adult-onset spinocerebellar dysfunction caused by a mutation in the gene for the alpha-tocopherol-transfer protein. N. Engl. J. Med. 333, 1313–1318. Graf, M. et al., 2005. High dose vitamin E therapy in amyotrophic lateral sclerosis as add-on therapy to riluzole: results of a placebo-controlled double-blind study. J. Neural Transm. 112, 649–660. Grundke-Iqbal, I. et al., 1986. Microtubule-associated protein tau. A component of Alzheimer paired helical filaments. J. Biol. Chem. 261, 6084–6089. Gurney, M.E. et al., 1996. Benefit of vitamin E, riluzole, and gabapentin in a transgenic model of familial amyotrophic lateral sclerosis. Ann. Neurol. 39, 147–157. Halliwell, B., 1992. Oxygen radicals as key mediators in neurological disease: fact or fiction? Ann. Neurol. 32 (Suppl.), S10–S15. Halliwell, B., 1999. Antioxidant defence mechanisms: from the beginning to the end (of the beginning). Free Radic. Res. 31, 261–272. Hensley, K. et al., 1995. Brain regional correspondence between Alzheimer’s disease histopathology and biomarkers of protein oxidation. J. Neurochem. 65, 2146–2156. Ingold, K.U. et al., 1987. Vitamin E remains the major lipid-soluble, chain-breaking antioxidant in human plasma even in individuals suffering severe vitamin E deficiency. Arch. Biochem. Biophys. 259, 224–225. Jenner, P., 1991. Oxidative stress as a cause of Parkinson’s disease. Acta Neurol. Scand. Suppl. 136, 6–15. Jenner, P., 1994. Oxidative damage in neurodegenerative disease. Lancet 344, 796–798. Jenner, P., 2003. Oxidative stress in Parkinson’s disease. Ann. Neurol. 53 (Suppl. 3), S26–S36, discussion S36–S38. Kayden, H.J., Traber, M.G., 1993. Absorption, lipoprotein transport, and regulation of plasma concentrations of vitamin E in humans. J. Lipid Res. 34, 343–358. Kikuchi, A. et al., 2002. Systemic increase of oxidative nucleic acid damage in Parkinson’s disease and multiple system atrophy. Neurobiol. Dis. 9, 244–248. Knight, J.A., 1997. Reactive oxygen species and the neurodegenerative disorders. Ann. Clin. Lab. Sci. 27, 11–25. Koenig, M., Mandel, J.L., 1997. Deciphering the cause of Friedreich ataxia. Curr. Opin. Neurobiol. 7, 689–694. Law, A., Gauthier, S., Quirion, R., 2001. Say NO to Alzheimer’s disease: the putative links between nitric oxide and dementia of the Alzheimer’s type. Brain Res. Brain Res. Rev. 35, 73–96. Lee, H.S., Park, C.W., Kim, Y.S., 2000. MPP(+) increases the vulnerability to oxidative stress rather than directly mediating oxidative damage in human neuroblastoma cells. Exp. Neurol. 165, 164– 171. Lei, S.Z. et al., 1992. Effect of nitric oxide production on the redox modulatory site of the NMDA receptor-channel complex. Neuron 8, 1087–1099. Lenaz, G. et al., 2002. Role of mitochondria in oxidative stress and aging. Ann. N.Y. Acad. Sci. 959, 199– 213. Li, J., Billiar, T.R., Talanian, R.V., Kim, Y.M., 1997. Nitric oxide reversibly inhibits seven members of the caspase family via S-nitrosylation. Biochem. Biophys. Res. Commun. 240, 419–424. Longnecker, M.P. et al., 2000. Dietary intake of calcium, magnesium and antioxidants in relation to risk of amyotrophic lateral sclerosis. Neuroepidemiology 19, 210–216.

604

R. Ricciarelli et al. / Molecular Aspects of Medicine 28 (2007) 591–606

Longo, F.M., Massa, S.M., 2004. Neurotrophin-based strategies for neuroprotection. J. Alzheimers Dis. 6, S13–S17. Lovell, M.A., Ehmann, W.D., Butler, S.M., Markesbery, W.R., 1995. Elevated thiobarbituric acidreactive substances and antioxidant enzyme activity in the brain in Alzheimer’s disease. Neurology 45, 1594–1601. Mariotti, C. et al., 2004. Ataxia with isolated vitamin E deficiency: neurological phenotype, clinical follow-up and novel mutations in TTPA gene in Italian families. Neurol. Sci. 25, 130–137. Mark, M.H., 2001. Lumping and splitting the Parkinson Plus syndromes: dementia with Lewy bodies, multiple system atrophy, progressive supranuclear palsy, and cortical-basal ganglionic degeneration. Neurol. Clin. 19, 607–627. Markesbery, W.R., 1997. Oxidative stress hypothesis in Alzheimer’s disease. Free Radic. Biol. Med. 23, 134–147. Markesbery, W.R., Carney, J.M., 1999. Oxidative alterations in Alzheimer’s disease. Brain Pathol. 9, 133– 146. Markesbery, W.R., Lovell, M.A., 1998. Four-hydroxynonenal, a product of lipid peroxidation, is increased in the brain in Alzheimer’s disease. Neurobiol. Aging 19, 33–36. Martin, A., Janigian, D., Shukitt-Hale, B., Prior, R.L., Joseph, J.A., 1999. Effect of vitamin E intake on levels of vitamins E and C in the central nervous system and peripheral tissues: implications for health recommendations. Brain Res. 845, 50–59. Mattson, M.P., 2004. Pathways towards and away from Alzheimer’s disease. Nature 430, 631–639. McGeer, P.L., McGeer, E.G., Yasojima, K., 2000. Alzheimer disease and neuroinflammation. J. Neural Transm. Suppl. 59, 53–57. Mecocci, P. et al., 1998. Oxidative damage to DNA in lymphocytes from AD patients. Neurology 51, 1014–1017. Mecocci, P., MacGarvey, U., Beal, M.F., 1994. Oxidative damage to mitochondrial DNA is increased in Alzheimer’s disease. Ann. Neurol. 36, 747–751. Migliore, L. et al., 2002. Oxidative damage and cytogenetic analysis in leukocytes of Parkinson’s disease patients. Neurology 58, 1809–1815. Montiel, T., Quiroz-Baez, R., Massieu, L., Arias, C., 2006. Role of oxidative stress on beta-amyloid neurotoxicity elicited during impairment of energy metabolism in the hippocampus: protection by antioxidants. Exp. Neurol. 200, 496–508. Morris, M.C., Evans, D.A., Bienias, J.L., Tangney, C.C., Wilson, R.S., 2002. Vitamin E and cognitive decline in older persons. Arch. Neurol. 59, 1125–1132. Nelson, L.M., Matkin, C., Longstreth Jr., W.T., McGuire, V., 2000. Population-based case-control study of amyotrophic lateral sclerosis in western Washington State. II. Diet. Am. J. Epidemiol. 151, 164–173. Nishida, Y. et al., 2006. Deletion of vitamin E enhances phenotype of Alzheimer disease model mouse. Biochem. Biophys. Res. Commun. 350, 530–536. Nunomura, A. et al., 2001. Oxidative damage is the earliest event in Alzheimer disease. J. Neuropathol. Exp. Neurol. 60, 759–767. Odunze, I.N., Klaidman, L.K., Adams Jr., J.D., 1990. MPTP toxicity in the mouse brain and vitamin E. Neurosci. Lett. 108, 346–349. Parkinson Study Group, 1989. DATATOP: a multicenter controlled clinical trial in early Parkinson’s disease. Arch. Neurol. 46, 1052–1060. Parkinson Study Group, 1993. Effects of tocopherol and deprenyl on the progression of disability in early Parkinson’s disease. N. Engl. J. Med. 328, 176–183. Penn, A.M. et al., 1995. Generalized mitochondrial dysfunction in Parkinson’s disease detected by magnetic resonance spectroscopy of muscle. Neurology 45, 2097–2099. Perkins, A.J. et al., 1999. Association of antioxidants with memory in a multiethnic elderly sample using the Third National Health and Nutrition Examination Survey. Am. J. Epidemiol. 150, 37–44. Perry, T.L. et al., 1985. Partial protection from the dopaminergic neurotoxin N-methyl-4-phenyl-1,2,3,6tetrahydropyridine by four different antioxidants in the mouse. Neurosci. Lett. 60, 109–114. Petersen, R.C. et al., 2005. Vitamin E and donepezil for the treatment of mild cognitive impairment. N. Engl. J. Med. 352, 2379–2388.

R. Ricciarelli et al. / Molecular Aspects of Medicine 28 (2007) 591–606

605

Pham, D.Q., Plakogiannis, R., 2005. Vitamin E supplementation in cardiovascular disease and cancer prevention: Part 1. Ann. Pharmacother. 39, 1870–1878. Ponten, S.C., Kwee, M.L., Wolters, E.C., Zijlmans, J.C., 2006. First case of ataxia with isolated vitamin E deficiency in the Netherlands. Parkinsonism Relat. Disord., in press. Puglielli, L., Tanzi, R.E., Kovacs, D.M., 2003. Alzheimer’s disease: the cholesterol connection. Nat. Neurosci. 6, 345–351. Ren, Y.R. et al., 2006. Genetic vitamin E deficiency does not affect MPTP susceptibility in the mouse brain. J. Neurochem. 98, 1810–1816. Ricciarelli, R., Zingg, J.M., Azzi, A., 2001. Vitamin E: protective role of a Janus molecule. Faseb J. 15, 2314–2325. Rinaldi, P. et al., 2003. Plasma antioxidants are similarly depleted in mild cognitive impairment and in Alzheimer’s disease. Neurobiol. Aging 24, 915–919. Ripps, M.E., Huntley, G.W., Hof, P.R., Morrison, J.H., Gordon, J.W., 1995. Transgenic mice expressing an altered murine superoxide dismutase gene provide an animal model of amyotrophic lateral sclerosis. Proc. Natl. Acad. Sci. USA 92, 689–693. Rosen, D.R. et al., 1993. Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature 362, 59–62. Rota, C., rimbach, G., Minihane, A.M., Stoecklin, E., Barella, L., 2005. Dietary vitamin E modulates differential gene expression in the rat hippocampus: potential implication for its neuroprotective properties. Nutr. Neurosci. 8, 21–29. Samii, A., Nutt, J.G., Ransom, B.R., 2004. Parkinson’s disease. Lancet 363, 1783–1793. Sano, M. et al., 1997. A controlled trial of selegiline, alpha-tocopherol, or both as treatment for Alzheimer’s disease. The Alzheimer’s Disease Cooperative Study. N. Engl. J. Med. 336, 1216–1222. Savitt, J.M., Dawson, V.L., Dawson, T.M., 2006. Diagnosis and treatment of Parkinson disease: molecules to medicine. J. Clin. Invest. 116, 1744–1754. Selkoe, D.J., 2005. Defining molecular targets to prevent Alzheimer disease. Arch. Neurol. 62, 192–195. Smith, C.D. et al., 1991. Excess brain protein oxidation and enzyme dysfunction in normal aging and in Alzheimer disease. Proc. Natl. Acad. Sci. USA 88, 10540–10543. Smith, M.A., Harris, P.L., Sayre, L.M., Perry, G., 1997. Iron accumulation in Alzheimer disease is a source of redox-generated free radicals. Proc. Natl. Acad. Sci. USA 94, 9866–9868. Smith, M.A., Rottkamp, C.A., Nunomura, A., Raina, A.K., Perry, G., 2000. Oxidative stress in Alzheimer’s disease. Biochim. Biophys. Acta 1502, 139–144. Stolzing, A., Widmer, R., Jung, T., Voss, P., Grune, T., 2006. Tocopherol-mediated modulation of agerelated changes in microglial cells: Turnover of extracellular oxidated protein material. Free Radic. Biol. Med. 40, 2126–2135. Subbarao, K.V., Richardson, J.S., Ang, L.C., 1990. Autopsy samples of Alzheimer’s cortex show increased peroxidation in vitro. J. Neurochem. 55, 342–345. Sung, S. et al., 2004. Early vitamin E supplementation in young but not aged mice reduces Abeta levels and amyloid deposition in a transgenic model of Alzheimer’s disease. Faseb J. 18, 323–325. Tanzi, R.E., Bertram, L., 2001. New frontiers in Alzheimer’s disease genetics. Neuron 32, 181–184. Traber, M.G. et al., 1992. Discrimination between forms of vitamin E by humans with and without genetic abnormalities of lipoprotein metabolism. J. Lipid Res. 33, 1171–1182. Troncoso, J.C., Costello, A., Watson Jr., A.L., Johnson, G.V., 1993. In vitro polymerization of oxidized tau into filaments. Brain Res. 613, 313–316. Weber, C.A., Ernst, M.E., 2006. Antioxidants, supplements, and Parkinson’s disease. Ann. Pharmacother. 40, 935–938. Wong, P.C. et al., 1995. An adverse property of a familial ALS-linked SOD1 mutation causes motor neuron disease characterized by vacuolar degeneration of mitochondria. Neuron 14, 1105–1116. Yatin, S.M., Aksenov, M., Butterfield, D.A., 1999. The antioxidant vitamin E modulates amyloid betapeptide-induced creatine kinase activity inhibition and increased protein oxidation: implications for the free radical hypothesis of Alzheimer’s disease. Neurochem. Res. 24, 427–435. Yokota, T. et al., 1997. Friedreich-like ataxia with retinitis pigmentosa caused by the His101Gln mutation of the alpha-tocopherol transfer protein gene. Ann. Neurol. 41, 826–832.

606

R. Ricciarelli et al. / Molecular Aspects of Medicine 28 (2007) 591–606

Yokota, T. et al., 2000. Postmortem study of ataxia with retinitis pigmentosa by mutation of the alphatocopherol transfer protein gene. J. Neurol. Neurosurg. Psychiatr. 68, 521–525. Yokota, T. et al., 2001. Delayed-onset ataxia in mice lacking alpha -tocopherol transfer protein: model for neuronal degeneration caused by chronic oxidative stress. Proc. Natl. Acad. Sci. USA 98, 15185– 15190. Zarkovic, N. et al., 2003. Anticancer and antioxidative effects of micronized zeolite clinoptilolite. Anticancer Res. 23, 1589–1595. Zeevalk, G.D., Manzino, L., Sonsalla, P.K., Bernard, L.P., 2006. Characterization of intracellular elevation of glutathione (GSH) with glutathione monoethyl ester and GSH in brain and neuronal cultures: relevance to Parkinson’s disease. Exp. Neurol., in press. Zhang, S.M. et al., 2002. Intakes of vitamins E and C, carotenoids, vitamin supplements, and PD risk. Neurology 59, 1161–1169. Zhu, X., Raina, A.K., Perry, G., Smith, M.A., 2004. Alzheimer’s disease: the two-hit hypothesis. Lancet Neurol. 3, 219–226.