A common pathological hallmark of many neurodegenerative diseases is the presence of oxidative stress caused by an accumulation of reactive oxygen species (ROS).
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ROS include superoxide anion radicals (O2∙−), hydrogen peroxide (H2O2), hydroxyl radical (∙OH), singlet oxygen (1O2), alkoxyl radicals (RO∙), peroxyl radicals (ROO·), and peroxynitrites (ONOO−) and all contribute to oxidative stress.
Oxidative stress can lead to cell damage that eventually leads to cell death. Cells typically have mechanisms in place to deal with ROS by specific scavenging enzymes and compounds to maintain a normal balance, however, an excessive accumulation of ROS and free radicals can be devastating to neural health.
Lowering the levels of enhanced oxidative stress by antioxidant supplementation may be beneficial in the prevention or delay of neurodegeneration. It is important to note that a fine balance between oxidative and antioxidative stress is needed for optimal cellular health, and both extremes can be damaging to health. In this article, antioxidant supplementation in the treatment and prevention of Alzheimer’s disease and Parkinson’s disease will be discussed.
Alzheimer’s Disease (AD)
Oxidative stress can lead to protein oxidation, lipid oxidation, DNA oxidation, and glycoxidation, which are all features of AD. The products of these; which are damaging, can be found across the brain as well as in the cerebrospinal fluid (CSF), blood and urine of patients with AD.
Vitamin E (α-tocopherol) is a powerful lipid-soluble antioxidant that can ameliorate the toxicity of β-amyloid as well as lead to improvements in cognition in mouse studies. Furthermore, treatment with 2000 IU a day of α-tocopherol in patients with moderate-severe AD reduced neuronal damage and slowed down the progression of AD.
Another study found that Vitamin E can inhibit lipid peroxidation within the brain to significantly reduce the levels of β-amyloid and plaque formation in a mouse model of AD, however, only before the pathology of AD became apparent, i.e. the pre-disease state. Vitamin E supplementation had no beneficial effect later on in disease course once the pathology of AD has progressed, irrespective of whether oxidative stress was lowered. This suggests that oxidative stress is an early event in AD pathogenesis and needs to be targeted pre-symptomatically if beneficial effects are to be seen.
Despite this promising research, the evidence of an effective antioxidant based treatment for AD has had mixed results. Whilst Vitamin E can confer antioxidant effects within the brain, the same effects have not been found in the plasma for half of the patients tested. Many other studies that have found promising results in rodent pre-clinical studies have failed to replicate such protective and preventative effects in clinical trials.
The most commonly used treatments for AD are acetylcholinesterases which have some limited beneficial effects in patients, but not all. Vitamin B12 has been shown to confer similar effects as acetylcholinesterases in that they increased choline acetyltransferase activity in cholinergic neurons in cat models as well as improving cognition in some AD patients. Perhaps the inclusion of Vitamin B12 in combination with Vitamin E may have a combined effect that needs to be carefully tested in controlled trials in the future.
Other studies have looked at the role of dietary supplements and herbal remedies in the treatment or prevention of AD, including omega-3, Gingko Biloba, turmeric (curcumin) and caffeine with some promising results. Animal studies have shown that 500mg a day of caffeine (equivalent to 5-6 cups) or epigallocatechin-gallate esters green tea have been shown to inhibit β-amyloid production, as well as cholesterol-induced increases in tau-phosphorylation and ROS levels. However, caffeine as a therapy for AD in a controlled study environment has not yet been performed at a clinical level.
Parkinson’s Disease (PD)
Oxidative stress within dopaminergic neurons of the substantia nigra is well documented, especially that of lipid peroxidation (as in with AD). Vitamin E, as with AD, has produced mixed results in the oxidative based treatments for PD. One study found that dietary Vitamin E diminished the risk of developing PD in both women and men, but Vitamin E supplements failed to confer a protective or beneficial effect. However subsequent studies have contradicted the promising finding of dietary Vitamin E intake and reduced risk of PD, including 2000 IU per day supplementation. Duration of life, the time course of the disease and clinical outcome was not significantly altered with Vitamin E.
Mitochondrial dysfunction is a key pathological hallmark of neurodegenerative diseases, including AD and PD. Common genetic forms of PD have mutations to mitochondrial associated genes: PINK-1 and Parkin. CoQ10 is a part of the electron transport chain involved in ATP (energy) production in mitochondria. This enzyme is found lower in patients with PD.
Animal studies in both rodents and non-human primates have shown the neuroprotective effects of CoQ10 protecting neurons from cell death. Clinical trials using CoQ10 have also shown mild improvements to the Unified Parkinson’s Disease Rating Scale (UPDRS) at concentrations above 300mg/day, especially at 15000mg/day dosages. However, overall these studies have not shown significant improvements to motor symptoms. These failed observations may be due to the reduced ability of CoQ10 to penetrate the brain at a sufficient therapeutic dose.
Another pathological hallmark of PD is that of an abundance of iron accumulation within the substantia nigra, both total iron and iron(III) levels. The iron itself can cause oxidative stress primarily by participating in the Fenton reaction producing ∙OH hydroxyl radicals. It has been shown that Iron, with the addition of dopamine, can produce the neurotoxic compound 6-OHDA (commonly used to induce PD in animal models).
Metal depletion or iron-chelating therapies may, therefore, provide a therapeutic strategy in the treatment of PD. A compound, desferrioxamine (DFO) can inhibit nigrostriatal iron accumulation as well as ∙OH hydroxyl radicals and lipid peroxidation levels. In animal models induced by 6-OHDA, injections of DFO were able to, in part, prevent striatal dopamine levels and also restore normal behavioral phenotypes. However, this was done directly into the brain and DFO is a large hydrophilic compound unable to normally cross the blood-brain-barrier (BBB). Newer derivatives, such as VK28, can cross the BBB in 6-OHDA animal models.
Clinical studies of a newer iron chelation agent, deferiprone (DFP), which can cross the BBB in patients, significantly reduced iron levels within the brain and produced a better behavioral outcome in patients with PD with no major side-effects. Therefore iron-chelating agents could provide a novel antioxidant therapeutic strategy in PD.
Melatonin is another promising therapy for PD (and AD to some extent), especially for its radical scavenging roles. In mouse models of PD, melatonin administration was able to prevent further dopaminergic neurodegeneration in the substantia nigra by combating oxidative stress. Melatonin at physiological levels performs other functions such as inducing sleep, but under certain conditions, it can behave as a free radical scavenger. Melatonin is also able to permeate through to organelles including mitochondria to confer its protective effects, given that mitochondrial dysfunction is a key pathological hallmark of PD and AD. Controlled clinical trials are needed to validate these findings in patients.
Antioxidants, dietary or supplemental, seem to confer only mild protective effects on AD and PD pathology and disease outcome. However, many studies have failed to see significant pathological and symptomatic improvements, despite success in animal studies. Studies investigating antioxidant therapies used pre-symptomatically seem to show better effects than in those with moderate disease progression. This may be as oxidative stress is an early stage of the disease, and by the time symptoms start, core pathology has taken root and in some cases over 50% of neurons have already degenerated.
Nonetheless, some novel compounds do seem to have beneficial effects – especially that of the iron chelator DFP in the treatment of PD. In AD, the evidence is less promising, though the carefully curated combination of compounds such as Vitamin E + B12 may be able to provide additional protective effects, especially if used earlier on in disease course. Further controlled studies are needed to validate whether antioxidant therapies are useful in the treatment of neurodegenerative diseases including AD and PD.
Feng & Wang (2012). Antioxidant Therapies for Alzheimer's Disease. Oxid Med Cell Longev. 2012: 472932. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3410354/
Filograna et al, 2016. Anti-Oxidants in Parkinson’s Disease Therapy: A Critical Point of View. Curr Neuropharmacol. 14(3): 260–271. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4857623/