A Diet Low in Animal Fat and Rich in N -Hexacosanol and Fisetin Is Effective in Reducing Symptoms of Parkinson's Disease

Introduction

I diopathic Parkinson's disease (PD) is a progressive neurological disorder caused by degeneration of the dopaminergic neurons in the substantia nigra region of the brain, resulting in a movement disorder characterized by resting tremor, rigidity, bradykinesia, and postural instability. Although the causes of idiopathic PD are not known, it appears that genetic and environmental factors may be predisposing to PD. ^1,2 Oxidative stress and inflammatory processes are believed to play a role in the dopaminergic degeneration of neurons that occurs with PD. ^1,3 Components of diet play key protective or damaging roles with respect to oxidative stress and inflammation. Fruits and vegetables are rich in beneficial antioxidants and flavonoids. ^{4 –6} Animal fats may hasten free radical damage and oxidative stress. ^7,8 In cell culture studies both fisetin and hexacosanol have shown promising results as potential neuroprotectants, as they appear to enhance neural survival and growth.

n-Hexacosanol (C₂₆), a long-chain, saturated primary alcohol, was shown to regenerate sensory fibers and improve neuromuscular function following a sciatic nerve crush in mice; both the number of regenerative fibers and the diameter and thickness of myelin improved. ⁹ Hexacosanol-treated cultures had neurite outgrowth length four to six times greater and collaterals seven to ten times greater than the untreated controls for some types of neurons. ¹⁰ n-Hexacosanol has also been shown to increase phagocytosis capacity and macrophage capacity in mice. ¹¹ Hexacosanol may also have anticholinergic activity as it was previously found to reduce overexpression of muscarinic acetylcholine receptors in animal studies; ¹² this property could be relevant for PD because hypercholinergic activity is a consequence of the dopamine depletion that occurs in PD and anticholinergic medications were used to treat PD in the past.

Fisetin (3,7,3′,4′-tetrahydroxyflavone) is a flavonoid and potent antioxidant belonging to the class of polyphenol compounds present in fruits and vegetables. ¹³ In cell cultures fisetin promoted neurite differentiation and cell survival following toxic oxidative insults, as well as activating extracellular signal-regulated kinase. ¹⁴ Of 28 different flavonoids tested, only four—fisetin, lutenolin, quercetin, and isorhamnetin—promoted neurite differentiation; fisetin was the most effective. Only two—fisetin and quercetin—maintained glutathione levels when there was oxidative stress. ¹⁵ The major intracellular antioxidant is glutathione. Fisetin increased intracellular glutathione levels, produced long neurites in cortical neurons, and increased proteasome activity in the primary cortical neuron. ^15,16 Zheng et al. ¹⁷ also observed an anti-inflammatory activity of fisetin on brain microglia in vitro and suggested that this activity might help treat neuroinflammatory conditions, including PD. Fisetin was shown to exhibit monoamine oxidase (MAO)-B inhibitory activity in vitro; ¹⁸ however, more recent studies of in vivo administration of fisetin in mice showed that fisetin dose-dependently inhibited MAO-A activity and caused an increase in levels of 5-hydroxytryptamine and noradrenaline but did not inhibit MAO-B activity in the mice brain. ¹⁹ Foods particularly rich in fisetin are strawberries (with about 160 μg/g) and persimmons and apples (with about 16–32 μg/g). Small amounts of fisetin are also found in kiwis, peaches, grapes, tomatoes, onions, and cucumbers. ^15,20

Epidemiological studies regarding the protective effects of various food items toward development of PD in the population have been conducted with some indication that foods rich in vitamin E may be protective from PD risk and that coffee consumption is inversely related to PD risk; however, the evidence from these epidemiological studies about a potential protective effect of fruit and vegetable consumption with respect to protection from PD risk was not conclusive. ^{21 –24} In spite of the evidence of neuroprotective effects of antioxidants in animal studies and of epidemiological research on the effects of dietary factors over a lifetime in protecting from the risk of developing PD, very little research has been published on the potential therapeutic effects of diets or antioxidants in individuals who have already developed symptoms of PD.

Subject and Methods

This case report describes a dietitian with a history of significant exposure to neurotoxins. Her history revealed over 10,000 hours of inhaled pesticide exposure from 1985 to 1989, several hours of an herbicide exposure on an open wound in 1987, and carbon monoxide poisoning in 1994. A nonsmoker with little alcohol intake who walked a mile a day, she was diagnosed in 2000 at 53 years of age with PD by a staff neurologist at a teaching hospital. A movement disorder specialist confirmed the diagnosis of classical PD. Her attending neurologist concurred with the diagnosis.

After being diagnosed with PD in 2000, the patient started experimenting with several diets in the search for one that would ameliorate her symptoms. The “basic diet” that she followed consisted predominantly of fresh or frozen foods, whole foods that were minimally processed, such as fruits, vegetables, 100% whole grains, nonfat milk products, extra virgin olive oil, nuts, seeds, tea, coffee, spices, small amounts of dark chocolate, and less than 25 g of animal fat daily from lean meats, low-fat cheese, and eggs. Air-popped popcorn was also consumed, and it helped reduce the nausea that was caused by the levodopa medication taken. Few commercially prepared foods were used. Foods that were avoided are listed in Table 1. From 2000 to 2008 the basic diet failed to prevent decline due to PD. In early 2008 blueberry and pomegranate juices were added to the basic diet for 4 months, but symptoms of PD continued to worsen; the juices were discontinued. In January 2009 a good source of fisetin, strawberries, and a good source of hexacosanol, wheat germ, were added to the basic diet. Specifically, 1–2 cups of strawberries (about 150 g) was included daily as a source of fisetin and other polyphenols. The estimated daily intake of fisetin from strawberries was 24 mg, with an additional variable daily intake of fisetin derived from other fruits and vegetables consumed each day. Other fruits and vegetables rich in polyphenols that were consumed were kiwis, peaches, dark grapes, raisins, tomatoes, onions, lettuce, french beans, broccoli, celery, and green bell peppers. As a source of n-hexacosanol-rich foods, 1–2 tablespoons (about 8 g) of wheat germ was included daily. Whole wheat was also consumed daily. Brown rice was consumed several times weekly as a source of rice-bran oil, another source of hexacosanol.

Wheat-germ oil and rice-bran oil commercially available as dietary supplements in pills or other formulation were not used in this diet; wheat germ and whole wheat or brown rice as a foods were selected as a potentially safer and more effective sources of hexacosanol, in addition to being sources of tocopherol and folic acid. For a well-balanced diet, extra virgin olive oil, nuts, seeds, other fruits and vegetables apart from the ones listed above, 100% whole grains, decaffeinated coffee, black tea, and green tea were also consumed as desired. Beer and wine were seldom consumed because of possible food–drug interactions with the anti-parkinsonian medications taken.

The daily caloric intake was approximately 2000–2200 kcal, of which approximately 55% was from carbohydrates (1100–1210 kcal), approximately 15% from proteins (300–330 kcal), and approximately 30% from fat (600–660 Kcal). An example of a typical daily diet is shown in Table 2. This diet provides an estimated daily amount of approximately 250 μg of hexacosanol from wheat germ and whole wheat (mostly from the homemade waffles and muffins), calculated assuming a content of approximately 6.5 μg of hexacosanol/g of wheat germ and of 3.5 μg of hexacosanol/g of whole wheat. The hexacosanol content of wheat and wheat germ varies depending on wheat varieties. ^25,26

Results

No symptoms improved in the first 3 months of following the diet. Gradual improvement began after the third month. By June 2009 the improvement was significant and has been maintained until this writing, over 2 years later. The patient reported significant improvement in dressing, showering, walking, conversing, climbing stairs, gardening, cleaning, typing, and writing. A pronounced tremor of the jaw was the latest tremor to develop and the only tremor to disappear.

On June 30, 2009, the patient's attending neurologist observed an almost complete absence of the previous cogwheel rigidity, micrographia, bradykinesis, dystonia, constricted arm swing with gait, hypomimia, and retropulsion. It is interesting that although most motor symptoms were resolved by the diet, tremors and seborrhea persisted and did not appear to be changed significantly by the dietary regimen; the only tremor that subsided was the jaw tremor.

Noncompliance with the diet by consuming pastry resulted in a worsening of symptoms for several weeks. Omitting wheat germ for 3 weeks also resulted in a gradual worsening of symptoms, which improved within several weeks of reintroduction of wheat germ to the diet.

It appears that the “basic diet” low in animal fats and the enhancement with hexacosanol- and fisetin-rich foods are both needed for effective control of symptoms in this patient.

The patient's medication dosage in December 2008, before beginning the complete diet rich in fisetin and hexacosanol, included 7½ carbidopa/levodopa 25/100 and 1 mg of rasagiline daily. By June 2009, 6 months after starting the complete diet rich in fisetin and hexacosanol, the patient was able to reduce the medication dose to 4½ carbidopa/levodopa 25/100 and ½ mg of rasagiline daily, while benefiting from amelioration of motor symptoms. In October 2011 medication doses were 6 carbidopa/levodopa 25/100 CR and ¼ mg of rasagiline, while maintaining the significant improvement in all motor movements obtained in 2009.

Discussion

In this patient, adherence with a strict diet that drastically limited trans-fat and animal fat intake and rich in food sources of fisetin and hexacosanol resulted in considerable improvement in the patient's quality of life without increasing medication doses. It is interesting that although the diet alleviated most of the motor symptoms of PD, it did not affect most tremors. To our knowledge, this is one of the few studies that tested dietary factors as complementary therapeutic agents to drugs in managing PD. This case would suggest that hexacosanol and flavonoids such as fisetin in the diet may positively affect neuronal function or slow down neurodegenerative processes. The overall macronutrient and micronutrient content of the basic diet low in animal fat may also account for much of the final diet's success. It is interesting that a recent study in animal models of PD found that a high-fat diet exacerbated 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced dopaminergic degeneration in mice, ²⁷ which supports the concept of a deleterious effect of a high-fat diet toward survival of dopaminergic neurons in the context of PD. The exact mechanisms of action and optimal “doses” of all specific components in the diet described here, however, have yet to be elucidated.

The patient in this case study may have developed PD because of heavy exposure to neurotoxins during her lifetime; it is not known if this diet would be beneficial for patients whose disease resulted from causes different than exposure to neurotoxins, or if the effectiveness of this diet also depends on individual genetic factors. If further studies of this diet confirmed its effectiveness in groups of patients with PD with various symptoms and etiology, it would represent a promising complementary treatment for PD. Because this is essentially a “healthy diet,” the danger of side effects is minimal. The fact that it may help prevent an increase in the dose of standard medications used to treat PD could lessen the occurrence of side effects, such as dyskinesia, that are often observed with l-dopa medications. A limitation of this dietary regimen may be that compliance with such a strict, expensive, complex diet would be difficult in the general population.

In conclusion, this case study suggests that adherence to a diet has the potential to significantly improve the quality of life and productivity of at least some of those suffering from this devastating neurological disorder. Further studies in the form of clinical trials with groups of patients with PD will need to address if the results observed here are unique to this patient or if they can be applied to the population of patients with PD at large.