"Functional foods," "nutraceuticals," "designer foods" and "medicinal foods" are terms that describe foods, and key ingredients isolated from foods, that have non-nutritive or tertiary functional properties. Researchers, healthcare practitioners, laypersons, and the popular media use these words interchangeably. The purpose of this column is to detail valid scientific information available on the physiologic actions of known constituents and combinations of constituents, as they naturally occur in "functional foods," highlighting their medicinal and nutritive mechanisms of action in the body.

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The study of free radicals, antioxidants and the phytochemical-rich whole foods in human medicine is producing revolutionary data that promises a new age of health and neurodegenerative disease management. Of particular interest to me is the role of reactive oxygen species (ROS) in chronic neurodegenerative diseases (e.g. Alzheimer's disease, Parkinson's disease, multiple sclerosis) and how antioxidant-rich foods protect the integrity of neuronal cells in the central nervous system, particularly when challenged by neurotoxins.

For years, medical interest in the relationship between nutrition and neurodegenerative disorders has focused largely on etiology and the influence of dietary macronutrients (fat, carbohydrates and protein) on the rate and severity of disease. While the cause of these disorders remains unknown and the influence of macronutrients is unclear, recent studies on antioxidant intake from foods and oxidative stress in neurodegenerative disorders are strengthening the rationale in support of a nutritionally sound, antioxidant and phytochemical-rich, whole food-based eating regime.

The Central Nervous System and Oxidative Stress
The central nervous system is most vulnerable to oxidative stress simply because it utilizes very high amounts of oxygen, while exhibiting reduced free radical scavenging capabilities under stress. (1-4) As such, free radicals and the oxidative stress they generate represent one molecular biological basis that explains the correlation between exposures to environmental stressors (e.g. diet, environmental toxins, heavy metals) and neuronal changes that mediate behavioral deficits in neurodegenerative disorders.

The free radical hypothesis has been most utilized in the research community to explain the onset, progression and increased incidence of heart disease and cancer,(5-8) though this hypothesis is likely to be most applicable to neurodegenerative disorders. Interestingly, diseases such as diabetes mellitus, hypertension, ischemic heart disease and hyperlipidemia are known to increase the level of oxidative stress in the body and have been associated with an increased risk for vascular dementia and other neurodegenerative diseases such as Parkinson's disease.(9-12) The precise mechanism whereby oxidative stress causes its deleterious effects is not fully understood. However, factors such as increases in DNA oxidation products,(1) deficits in calcium regulatory mechanisms that lead to cell death,(13,14) and lipid and protein peroxidation,(15,16) are known to play a role.

The increased recognition of the role that oxidative stress plays on the onset and progression of neurodegenerative diseases has markedly influenced the number of researchers studying the effects of antioxidant vitamins in altering or forestalling the neurodegenerative changes that accompany these health challenges.(17-20)

Experiments that examined the effects of diets rich in select herbs, fruits and vegetables on neurodegeneration suggest that the combined effects of known (antioxidant) and unknown compounds within whole foods improve neuronal and behavioral parameters in susceptible individuals.(13,21-26)

Free Radical Attack on Neurons
It has been estimated that free radicals may modify approximately 10,000 DNA base pairs every day.(27) Neurons are particularly vulnerable to free radical attack because:

• They have a low glutathione content
• Their membranes are rich in vulnerable polyunsturated fatty acids, and
• Brain metabolism consumes a great deal of oxygen

The free radical hypothesis for the neurodegeneration evident in conditions such as Alzheimer's disease (AD), Parkinson's disease and multiple sclerosis is supported by the fact that these conditions are age-related and/or immunerelated and damage from reactive oxygen species is known to accumulate with age and with the autoimmune process. Brain trauma can also result in free radical release and is a known cause for AD and dementia. The free radical hypothesis also accounts for the fact that numerous genetic and non-genetic pathways may be involved in these diseases, which is why it is so difficult to determine the cause and find cures.

Whole Foods that Maintain Membrane Function and Integrity of the Brain: Searching Beyond the Oxidative Stress Theory
It is a well-known fact that a decline in endogenous antioxidants leads to increased lipid peroxidation and neuronal vulnerability. Joseph et al.(28) attempted to counter decreases in antioxidant protection in rats by supplementing their diets with antioxidant-rich foods and an antioxidant isolate. The researchers looked at decreases in neurotransmitter receptor sensitivity, loss of calcium homeostasis, and loss of cognitive performance after 8 months on a control diet or diets containing either vitamin E or extracts of strawberry or spinach. Strawberries and spinach have both been identified as being high in antioxidant activity.(29)

The antioxidant activity of strawberry and spinach diets were matched to vitamin E based on Trolox equivalents (1.36 mmol Trolox equivalent per kilogram of diet). Interestingly enough, the spinach diet was more effective in reducing neuronal vulnerability to oxidative stress than vitamin E even though both diets were of equal antioxidant capacity in terms of Trolox equivalents. This reflects the importance of the whole food matrix in the bioavailability of dietary micronutrients. Further, these researchers speculate that there are other effects of the phytochemicals contained in spinach and strawberries in addition to antioxidant protection. Flavonoids in these foods, for example, increase membrane fluidity hence reducing susceptibility to neuronal membrane rigidity.(24-26)

Oxotremorine enhancement of dopamine release from brain striatal slices was significantly greater in susceptible rats consuming antioxidant supplementation relative to controls, with a particularly strong response for spinach (Figure 1). Because dopaminergic neurons are affected by several neurodegenerative disorders, this result suggests that diets high in antioxidants, especially spinach, may protect neuronal function in these cells.

The cognitive function of the rats was tested using a Morris water maze. Rats fed the spinach diet had a significantly shorter latency time to find a submerged platform in the memory trial of the swimming test than did controls (Figure 2). Rats in both the spinach and vitamin E groups scored the shortest distances in reaching the platform compared to the control group (Figure 2). These differences were not a result of swim speed because this was not significantly different between the groups.

Martin et al.(23) also looked at the effects of antioxidant rich foods on neurological function only to conclude that factors in these foods, other than antioxidants, play a significant role in neurological protection. Rats were fed diets enriched in fruits and vegetables, but containing either high or low levels of vitamin E, for eight months. Striatal dopamine release and the distributions of vitamins C and E in the brains of the rats were measured after the trial period. Rats supplemented with strawberry, spinach, or vitamin E had significantly greater striatal dopamine release compared with controls. In addition, animals fed high vitamin E levels had much higher [alpha]-tocopherol levels in brain and peripheral tissues than those fed low vitamin E. Thus, a diet rich in antioxidants, particularly vitamin E, appears to be important for aspects of brain function.

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This study was based on the premise that oxidative stress is an important etiological factor in the development of neurodegenerative diseases and that prevention of oxidative damage may therefore prevent or delay onset of said diseases.

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Fruits and vegetables contain large amounts of antioxidant molecules, including vitamin E. In addition to protecting brain cells from free radical attack, vitamin E may even have structure-specific roles in the signal transduction pathways and neurotransmitter distribution in neurons. It is interesting to note that while vitamin E levels in the brain were lower for spinach versus vitamin E supplementation, both groups showed reversal of neurological decline in previous studies by this group. Similarly, dopamine release was enhanced by all the diets even though vitamin E in the brain was low in vegetable diets compared to the vitamin E supplemented diet. This suggests that factors in spinach and strawberries other than vitamin E play a role in neurological protection.

The brain does not seem to accumulate vitamin E above a maximum level even when the diet is enriched in vitamin E, although it does in some peripheral tissues. This suggests that as far as brain function is concerned, vitamin E may have an optimal intake for achieving the necessary levels of vitamin E for brain function.

Youdim et al.(31) reviewed the known effects of phytochemicals, classically identified as antioxidants, on neurodegenerative disorders. They emphasized the fact that phytochemicals possess many properties including antioxidant, antiallergic, anti-inflammatory, antiviral, antiproliferative, and anticarcinogenic.(32-36) They agreed with the conclusions made by Joseph et al.(30) and Martin et al.(23) that while the antioxidative properties in select whole foods do play a role in protecting against neurodegenerative disorders, it is over-simplistic to assume that that is the primary role that these foods play in protecting brain function. Further research must be done to look at tertiary properties inherent in whole foods that undoubtedly play a role in maintaining and protecting neuronal cell function over time.

Final Thoughts
The research summarized above, and expanded upon in the references cited below, in addition to research cited in my previous articles published in TLfDP on caloric restriction and detoxification, suggest to me that the following measures might reduce one's risk for further neuronal damage that occurs with neurodegenerative disorders:

• Caloric Restriction--Limit calorie intake throughout adult life to 1800-2200 calories per day depending upon weight
• Whole Foods--Include whole, unprocessed foods in at least 80% of one's diet and supplement regimen.
• Fruits and Vegetables--Increase intake of vegetables and fruits that are particularly rich in antioxidants, flavonoids and phenolic compounds (including spinach, strawberries, grapes, kale, carrots and wheat germ).
• Mental Activity--Take part in a mental activity (reading, problem solving, mathematical equation, research, trivia, etc.) daily to increase activity in neuronal circuits thereby enhancing resistance of neurons to oxidative stress and damage.
• Exercise--Maintain cerebral vascular integrity by partaking in moderate aerobic activity daily.

© COPYRIGHT 2006 Dr. Gina L. Nick

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