Natural Ingredients to Support Neuronal and Mitochondrial Health
Conventional treatment of Parkinson's disease relies heavily on targeting amelioration of symptoms, without providing neuroprotection against continual cell death in the substantia nigra. On the other hand, a variety of natural ingredients have been shown to support neuronal health and promote mitochondrial function in a variety of ways, including suppressing oxidative stress and limiting inflammation. Many natural ingredients may have a complementary effect in combination with conventional therapies.
Coenzyme Q10 (CoQ10)
The strong connection between defects in mitochondrial energy management and oxidative stress has led neuroscientists to explore a number of supplemental compounds with energy enhancing, antioxidant capabilities. Excellent laboratory and clinical evidence suggests that coenzyme Q10 (CoQ10), also known as ubiquinone or ubiquinol because of its omnipresence in living cells, is an outstanding contender in this field.134,135 CoQ10 is used in a myriad of enzymatic reactions involving the transport of electrons from energy supplying nutrients and their safe disposal within cells. CoQ10 deficiencies disrupt these reactions, contributing to many age-related neurodegenerative conditions. Plasma and platelet levels of CoQ10 are known to be low in patients with Parkinson's disease, suggesting a systemic deficiency state. A late 2008 study from England demonstrated for the first time that reduced CoQ10 levels are found in cortical regions of the brain of Parkinson's disease patients.136
In a multicenter clinical trial, 80 treatment naïve patients with early Parkinson's disease were randomly assigned to receive either placebo or CoQ10 at daily doses of 300, 600, or 1,200 mg for 16 months or until disability required drug treatment. All subjects were scored using the standard Unified Parkinson Disease Rating Scale (UPDRS), for which higher scores indicate a progressively worsening disease state. The results were compelling with a mean change of 11.99 with placebo, 8.81 with the 300 mg dose, 10.82 with the 600 mg dose, and 6.69 with the 1,200 mg dose—a significant difference. All doses were well tolerated. The authors concluded that "coenzyme Q10 appears to slow the progressive deterioration of function in Parkinson's disease."137 Two years later the same researchers showed that dosages up to 3,000 mg/day of ubiquinone were safe and well tolerated, though plasma levels reached a plateau at 2,400 mg/day.138
German researchers were intrigued by the aforementioned laboratory observations which suggested that CoQ10 might not only prevent the loss of dopaminergic neurons, but could also improve functioning of the remaining cells. Their own randomized trial results were somewhat discouraging, showing no change in UPDRS scores. However, their subjects received a lower dose of CoQ10 (100 mg three times daily) over just three months. Unlike the previous trial, they also studied patients with "mid-range" Parkinson's disease, already requiring L-DOPA. Therefore, they would have been by definition unable to detect significant neuroprotective effects. They did conclude however that the CoQ10 was safe and well tolerated.139
While exploring the relationship between mitochondrial dysfunction and Parkinson's disease, a group of pharmacologists in Egypt came across strong laboratory evidence supporting the need for high doses of CoQ10 either alone or in combination with L-DOPA therapy. They induced Parkinson's disease in rats by injecting them with a toxin known to create an accurate model of the disease. They found that the animals developed slower movements and rigidity within 20 days. Their brains also showed marked decreases in levels of dopamine and energy transfer molecules such as ATP, with increased levels of a cell death signaling protein called Bcl-2—identical to the brain of a human Parkinson's disease patient. Remarkably, after so much damage had already been done, treatment with CoQ10 prevented cell death, restored ATP levels, and decreased movement disorder scores. Another group of rats treated with L-DOPA alone showed symptomatic improvement, but it had no effect on cell survival or energy function. The researchers concluded that "addition of coenzyme Q10 in a high dose in early Parkinson's disease could be recommended based on its proved disease-modifying role on several levels of the proposed mechanisms, including improvement of respiratory chain activity."140
An animal study conducted at Cornell University demonstrated CoQ10's protective qualities as it prevented dopaminergic neurons from destruction, prevented loss of enzymes that make dopamine, and prevented the development of toxic alpha-synuclein complexes that predict severe Parkinson's disease. The researchers noted that their results "provide further evidence that administration of CoQ10 is a promising therapeutic strategy for the treatment of Parkinson's disease."141
Creatine, an important amino acid-like compound, is vital to cellular energy management. Creatine deficiency is associated with neurological damage.142 Several animal studies have shown creatine, because of its "pro-mitochondrial" effect, to be effective in preventing or slowing the progression of Parkinson's disease.54,143,144 Influential Harvard neurologists noted that "creatine is a critical component in maintaining cellular energy homeostasis, and its administration has been reported to be neuroprotective in a wide number of both acute and chronic experimental models of neurological disease."145 Studies have shown that creatine is safe and well tolerated by patients with Parkinson's disease.146
In 2006, the Neuroprotective Exploratory Trials in Parkinson’s Disease (NET-PD) group at the National Institute of Neurological Disorders and Stroke (NINDS) studied 200 treatment-naïve subjects who had been diagnosed with Parkinson’s disease within the past five years. Subjects were randomly assigned to receive creatine 10 grams/day, the antibiotic drug minocycline (a proposed neuroprotectant) 200 mg/day, or placebo for 12 months while their scores on a standard Parkinson's disease rating scale were monitored. Both creatine and minocycline performed well, yet creatine showed a substantial edge in performance over minocycline. Tolerability of the treatment was 91% in the creatine group and 77% in the minocycline group.147 However, a follow-up study published by this same research group in 2015 failed to show a benefit associated with creatine supplementation (10 grams daily) for a minimum of five years.148
While it is unclear why the latter study did not identify a benefit with creatine supplementation, small differences in inclusion criteria and patient characteristics between the two studies may have contributed. Also, some evidence suggests that perhaps creatine in combination with other neuroprotective nutrients (as opposed to alone, as in the NET-PD studies) might be of benefit: a recent animal study found that creatine, in combination with CoQ10, conferred significant neuroprotection by reducing the accumulation of alpha-synuclein and suppressing lipid oxidation. In addition, animals being treated with the nutrient combination survived longer than those not being treated.149 Clinical trials are needed to assess the effects of creatine in combination with other neuroprotective nutrients in Parkinson’s patients.
Omega-3 Fatty Acids
These natural components of omega-3 fats, obtained chiefly from fish and some plant sources, exert significant anti-inflammatory action. Their concentration in nerve cell membranes decrease with age, oxidant stress, and in neurodegenerative disorders such as Parkinson's disease.150,151 In fact, researchers in Norway have presented convincing evidence of a systematic omega-3 deficit in Parkinson's disease, Alzheimer's disease, and autism, suggesting a fundamental neurological role for these vital fat molecules.152,153 Supplementation with the omega-3 DHA can favorably modify brain functions and has been proposed as a nutraceutical tool in Parkinson's and Alzheimer's disease.154
A study from Japan found that treatment of nerve cells with omega-3 prevents apoptosis, the programmed cell death that occurs in part as the result of inflammatory stimuli in the brain. Interestingly, results were a lot better when treatment was introduced before the chemical stresses that induced apoptosis were imposed, leading them to conclude that "dietary supplementation with [omega-3s] may be beneficial as a potential means to delay the onset of the diseases and/or their rate of progression."155
Canadian researchers took this study to the next level when they supplemented mice with omega-3 before injecting them with a Parkinson's inducing chemical.156 The mice were fed either a control or a high omega-3 diet for 10 months prior to injection. Control mice demonstrated a rapid loss of the dopamine producing cells in their substantia nigra accompanied by profound drops of dopamine levels in brain tissue. These effects were prevented in the mice receiving the high omega-3 diet.
A study of primates at the same institution demonstrated actual changes in Parkinson's symptoms, providing further compelling evidence for omega-3's protective and therapeutic effects. In this study, one group of animals was first treated for several months with L-DOPA before being given omega-3 DHA, while a second group was pre-treated with omega-3 DHA before starting on L-DOPA. The study was designed this way because L-DOPA, though effective in treating Parkinson's symptoms, as stated earlier in the protocol is also known to damage dopamine producing cells and induce dyskinesias. Omega-3 DHA reduced the occurrence of dyskinesias in both groups of monkeys, without altering the beneficial effects of L-DOPA. The researchers concluded that "DHA may represent a new approach to improve the quality of life of Parkinson's disease patients."157
B vitamin deficiencies have long been implicated in many neurological disorders, including Parkinson's disease. Studies as early as the 1970's directed at demonstrating the effects of supplementation yielded discouraging results158-160 However, as our understanding of the close link between the toxic amino acid homocysteine and B vitamins grew, more targeted and mechanism-based studies became possible. Homocysteine levels are closely linked to folate, vitamins B6 and B12 status. Elevated homocysteine levels are found in cardiovascular disease as well as a variety of neurological and psychiatric disturbances.161-163 Also, L-DOPA treatment can itself lead to elevated homocysteine levels. As a result, more recent studies have led researchers to recommend B complex supplementation in those utilizing L-DOPA therapy.164
Definitive evidence supporting the benefit of this approach came from Singapore where Parkinson's disease patients, already on a stable dose of L-DOPA, were supplemented with pyridoxine (a common form of vitamin B6).165 Mean motor and activities of daily living scores improved significantly following supplementation, and worsened again when the supplements were stopped. Low serum folate is also found in Parkinson's disease patients, especially those taking L-DOPA.163 Canadian researchers demonstrated that a supplement containing folate and B12 could decrease plasma homocysteine levels in patients taking L-DOPA.166
A systematic review paper concluded that B vitamin supplementation may be of value for neurocognitive function.167 A similar review points to recent work with the active form of vitamin B6, pyridoxal-5' phosphate (P5P), noting that a number of neurological disorders including Parkinson's disease offer attractive therapeutic targets for this substance.168 The consensus among experts is that due to the deleterious effect that elevated homocysteine levels has on both Parkinson's itself and L-DOPA therapy, supplementation with folate, B6, and B12 is warranted.169-172
Thiamine, also known as vitamin B1, may benefit Parkinson’s patients. In 1999, low levels of free thiamine were detected in the cerebrospinal fluid of Parkinson’s disease patients.173 In 2013, researchers treated three newly diagnosed Parkinson’s patients with high-dose thiamine injections. Remarkably, the injections considerably improved the patients’ motor symptom deficits.174 Although only three subjects participated in this uncontrolled, informal clinical trial, the results corroborated very similar findings from another small trial in 2012.175
More recently, in 2015, an open-label clinical trial on 50 Parkinson’s disease patients showed that intramuscular injections of 100 mg of thiamine twice weekly led to significant and lasting improvements on a standardized Parkinson’s disease rating scale. Some participants—those with mild symptoms—had a complete clinical recovery. The benefits persisted throughout the follow-up period of up to about 2.2 years.176 In another open-label study, published in 2016, researchers treated 10 consecutive Parkinson’s patients with intramuscular 100 mg thiamine injections twice weekly without changing their medication regimens. Several measures of Parkinson’s disease symptoms improved significantly, and when the investigators increased the dosage of thiamine into the second month of treatment, the benefits became even more pronounced. Researchers speculated that the benefits of thiamine may arise from improvements in energy metabolism in surviving dopaminergic neurons in the substantia nigra.177 Additional clinical trials are needed to test whether oral thiamine, or thiamine derivatives such as benfotiamine, may have similarly beneficial effects.
Vitamin D functions more like a hormone than a vitamin. Vitamin D receptors are expressed ubiquitously throughout the body, including on microglial cells.178 Upon activation by vitamin D, vitamin D receptors signal for increased or decreased expression of numerous genes, many of which are immunomodulatory.179
Several studies have shown that higher levels of vitamin D protect against the onset of Parkinson's disease symptoms. Also, that patients diagnosed with Parkinson's have lower serum vitamin D levels than those without the disease.180,181
Since many of the actions of vitamin D are anti-inflammatory, Life Extension believes that maintaining optimal vitamin D blood levels (50–80 ng/mL) may quell some of the inflammatory aspects of Parkinson's disease neurodegeneration. It is likely that having optimal vitamin D levels might decrease the activation of microglial cells and reduce the release of inflammatory cytokines.
Carnitine is a vital nutrient that serves as a co-factor in fatty acid metabolism. It helps to "ferry" large fat molecules into the mitochondrial "furnaces" where they are burned for energy, making it an important component of brain energy management and mitochondrial function.182 There is a growing body of literature suggesting that carnitine supplementation, through its support of brain energy management, protects against Parkinson's disease.
Mount Sinai researchers were able to prevent chemically induced Parkinson's disease in monkeys by pre-treating them with acetyl-l-carnitine, a readily absorbed form of the nutrient.183 Moreover, Italian researchers have studied carnitine as a neuroprotectant in the brains of methamphetamine users. Methamphetamines cause the same basic mitochondrial destruction and free radical brain damage as that seen in Parkinson's patients.182,184 This work has been extended in similar studies at the U.S. National Center for Toxicological Research.185
In an intriguing study, Chinese nutritional scientists in Shanghai explored in culture both acetyl-L-carnitine and lipoic acid (each alone and in combination with the other) in preventing Parkinson's disease-like changes in human neural cells. They found that both nutrients either alone or in combination, applied for four weeks prior to a Parkinson's disease-inducing chemical, protected the cells from mitochondrial dysfunction, oxidative damage, and an accumulation of the dangerous alpha-synuclein proteins. Notably, the combination of supplements was effective at 100- to 1000-fold lower concentrations than were required for either acting alone—powerful evidence that led the researchers to state that "this study provides important evidence that combining mitochondrial antioxidant/nutrients at optimal doses might be an effective and safe prevention strategy for Parkinson's disease."186
Increased tea consumption is correlated with reduced incidence of dementia, Alzheimer's and Parkinson's disease.187 Green tea contains valuable antioxidant polyphenols known to be protective against a host of chronic age-related conditions. There is tremendous scientific interest in green tea and its active compound epigallocatechin gallate (EGCG) as a neuroprotectant in Parkinson's disease; especially since when compared to many drugs, EGCG is extremely effective at penetrating brain tissue.188,189
Israeli researchers showed that they could prevent the cellular changes associated with Parkinson's by pre-treating mice with either green tea extracts or EGCG ahead of inducing the disease by chemical injection.188,190 This research has subsequently been repeated and extended in laboratories around the world.191-195 Utilizing the brain cell cultures pretreated to develop Parkinson's-like changes, the Israeli group also showed that green tea extracts prevented activation of the inflammation producing NF-kappaB system.190 EGCG's specific anti-inflammatory properties have been demonstrated to protect cultured brain tissue from the loss of dopaminergic cells as well.196 L-theanine, a component of green and black tea, was shown by Korean scientists to prevent dopaminergic cell death such as that seen in Parkinson's disease.197
Another potential benefit of green tea extract is its ability to inhibit the dopamine degrading enzyme COMT.74 This may help to sustain dopamine levels in ailing brain tissue thereby reducing the severity of symptoms.
Just as we use multiple combinations of prescription drugs to capitalize on their synergistic effects, we can capitalize on green tea's neuroprotective effects in Parkinson's and other neurodegenerative diseases.198 While more human studies are yet to be completed, green tea polyphenols have proven to exert powerful protection for dopaminergic neurons making them a key component in the prevention and treatment of Parkinson's disease.195,199-202
Resveratrol is a polyphenolic antioxidant compound that has shown stunning potential in preventing cardiovascular disease and prolonging life.203-205 Not surprisingly, scientists interested in protecting brain tissue and enhancing the quality of life in aging individuals have directed their attention towards this remarkable compound.
Since dopamine itself is an oxidant compound which can contribute to the early destruction of neurons, Korean scientists studied the impact of resveratrol at preventing this paradoxical effect.206 They found that through the loss of mitochondrial function, human neural tissue treated with dopamine underwent rapid cell death. However, exposing the cells to resveratrol for one hour prior to dopamine treatment prevented cell loss and preserved mitochondrial function. In addition, Canadian scientists used resveratrol to prevent neuronal cell death caused by inflammation.207
Resveratrol's anti-inflammatory action was further explored by Chinese researchers who at first administered a Parkinson's disease-inducing chemical to rats, then gave them oral daily doses of resveratrol for 10 weeks. They found that after only two weeks of supplementation, the rats demonstrated significant improvement in their movement. Also, examination of their brains showed marked reduction in mitochondrial damage and loss of dopaminergic cells. Remarkably, they also found a reduction in the levels of COX-2 and TNF-alpha (inflammatory markers). They concluded with justifiable excitement that "resveratrol exerts a neuroprotective effect on [a chemically-] induced Parkinson's disease rat model, and this protection is related to the reduced inflammatory reaction."208
As with green tea extracts, it appears that resveratrol's potential for preventing Parkinson's disease may reside in its multi-modal mechanism of action targeting oxidant stress, inflammation, and systems such as sirtuins that are fundamental in regulating mitochondrial function and ultimately affecting longevity.204
Mucuna pruriensis a vine whose seeds contain a high concentration of naturally occurring L-DOPA and a variety of other psychoactive compounds.209 Compounds in Mucuna seeds act as AADC inhibitors, mimicking the action of carbidopa, and complementing the action L-DOPA in the central nervous system. In an animal experiment, Mucuna seed extract was shown to alleviate symptoms of chemically-induced Parkinson's with similar efficacy to traditional L-DOPA treatment, but without inducing dyskinesia.210 These results were repeated in another, similar trial.209
In a double-blind, randomized, placebo-controlled trial, Mucuna extract proved superior over standard L-DOPA/carbidopa therapy. Compared to traditional therapy, Mucuna led to a faster onset of symptom relief, longer duration of relief, and significantly fewer dyskinesias. The scientists conducting this study concluded that "The rapid onset of action and longer on time without concomitant increase in dyskinesias on mucuna seed powder formulation suggest that this natural source of L-dopa might possess advantages over conventional L-dopa preparations in the long term management of [Parkinson's disease]."211
Wild Green Oat Extract
Oats (Avena sativa L.) have been a foodstuff for many centuries and are an important cereal crop in North America, Europe, and Russia.212,213 Oats are the only known natural source of avenanthramides, which are bioavailable compounds with anti-inflammatory, anti-atherogenic, and antioxidant properties.214-216
Monoamine oxidase B (MAO-B) is responsible for the breakdown of dopamine in neurons217; however, excess MAO-B activity increases with age and depletes dopamine levels through excessive dopamine metabolism.218,219 Indeed, the loss of dopaminergic neurons is considered the hallmark of Parkinson’s disease, and restoration of dopaminergic signaling is the focus of most treatments.220-222 Drugs that inhibit MAO-B, such as deprenyl (Selegeline) and rasagiline (Azilect), are used in the treatment of early Parkinson’s disease.223-225 Blocking MAO-B with medications such as deprenyl not only raises dopamine levels in brain tissue, but also appears to be neuroprotective. MAO-B inhibitors block free radical formation that occurs during dopamine metabolism and blocks apoptosis (programmed cell death) of neurons.226
Wild green oat extract has shown the ability to inhibit MAO-B activity227,228 and demonstrated in numerous clinical trials to be a neuroprotective agent capable of improving cognitive function with as little as a single dose, while also increasing blood flow both systemically and to the brain by as much as 40%.229-232 Research demonstrates wild green oat extract is a neuroactive compound that shares a critical mechanism of action, MAO-B inhibition, with important Parkinson’s disease medications. This body of evidence suggests wild green oat extract is a promising natural therapy for those concerned with Parkinson’s disease.
Pyrroloquinoline Quinone (PQQ)
Pyrroloquinoline quinone, or PQQ, is a highly bioactive compound present in a vast range of cell types, and research suggests boosting PQQ levels may improve mitochondrial function, inhibit oxidative stress, and support neurological health.233-238 Since oxidative stress and mitochondrial dysfunction are believed to be key factors in Parkinson’s disease,239 PQQ is being actively studied as an agent to prevent and treat this condition.240
One mechanism by which PQQ may benefit those with Parkinson’s disease is by stimulating cerebral blood flow and oxygen use. Two studies using near-infrared spectrometry in healthy older adults have found supplementing with 20 mg PQQ daily for 12 weeks resulted in increased brain blood flow as well as increased oxygen utilization.237,241 In one of the studies, cognitive testing revealed PQQ was also associated with better preservation of cognitive function than placebo.237 These studies confirm earlier studies where PQQ prevented neurodegeneration and maintained memory function in a rodent experiment.242
A number of laboratory and animal studies have indicated PQQ can protect nerve cells from toxic and inflammatory damage by reducing oxidative stress and protecting mitochondria.240,243-245 Several preclinical studies have shown PQQ may prevent the accumulation of damaging amyloid proteins such as beta-amyloid,246-249 and might in this way protect against conditions such as Parkinson’s disease and Alzheimer’s disease.
Other Promising Nutrients
Curcumin. Curcumin, a derivative of the spice turmeric, through its potent modulation of the NF-kappa B system is a natural inhibitor of inflammation. It prevents chemically-induced changes in lab models of Parkinson's disease and exerts significant neuroprotection.250-257
Melatonin. The antioxidant hormone melatonin (synthesized and secreted by the pineal gland) may help to reduce the accumulation of alpha-synuclein proteins while preserving the cell's ability to make dopamine. It is also an invaluable sleep aid for Parkinson's patients, who often suffer from distressing problems with sleep.258-267
N-acetyl cysteine (NAC). NAC is a precursor to the potent cellular antioxidant glutathione. In animal models, NAC prevented dopamine induced neurotoxicity and protected against some of the damaging effects of alpha-synuclein proteins.268,269
Lipoic acid. Lipoic acid, a potent reducing agent, is considered a universal antioxidant due to its amphipathic nature (both fat- and water-soluble). Lipoic acid is produced naturally within the body and contributes to xenobiotic detoxification and antioxidant protection. It also contributes to cellular energy production.270 In addition to its ability to directly neutralize toxins and free radicals, lipoic acid bolsters levels of other cellular protectants such as glutathione and vitamin E.271
The low molecular weight of lipoic acid allows it to easily cross the blood-brain barrier, delivering neuroprotection within the central nervous system. Lipoic acid also combats inflammatory reactions.271 Large scale clinical trials have yet to be conducted in Parkinson's patients. However, given its potential for efficacy and excellent safety profile, lipoic acid should be considered as a therapeutic agent for Parkinson's disease.
Probiotics. Because dopaminergic signaling exerts considerable influence over intestinal function, constipation is a common problem in Parkinson's disease.
In a recent clinical trial, 40 Parkinson's patients complaining of constipation were treated with probiotics for five weeks. Probiotic therapy significantly increased the number of normal stools as well as reduced the incidence of bloating and abdominal pain.272
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