Alzheimer's Disease: Functional Therapeutics in Neurodegenerative Disease
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Alzheimer's Disease: Functional Therapeutics in Neurodegenerative Disease
One of the most promising agents for up-regulation of mitochondrial function is Coenzyme Q-10. Coenzyme Q-10, in addition to having free-radical scavenging properties, is known to play a pivotal role in transporting electrons in the mitochondria for ATP production. The usefulness of Coenzyme Q-10 in specific mitochondrial myopathies has been well described. Bresolin and co-workers in Milano, Italy have described enhanced mitochondrial activity as evidenced by reduction of serum lactate and pyruvate following standard muscle exercise with generally improved neurologic functions in Kearns Sayre syndrome and chronic progressive external ophthalmoplegia. Idebenone, a Coenzyme Q-10 derivative with increased blood-brain barrier penetration, produced enhanced cerebral metabolism in a 36-year-old man with MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes) during a five-month treatment protocol providing Idebenone up to 270 mg per day. Cerebral metabolism in this study was followed with PET (positron emission tomography) studies.
Finally, preliminary studies by Jenkins have demonstrated lowering of cerebral lactate levels in vivo in Huntington’s disease in a patient receiving Coenzyme Q-10 310 mg per day. There was an average of 29% decrease in lactate levels following treatment as demonstrated by magnetic resonance spectroscopy.
Phosphatidylserine enhances both neuronal and mitochondrial stability and activity and reduces mitochondrial free-radical production. Researchers at Stanford University School of Medicine evaluated a group of 149 patients meeting criteria for “age-associated memory impairment” over a period of twelve weeks with either phosphatidylserine (100 mg t.i.d.) or placebo. Actual improvement in the treated group on psychometric testing related to learning and memory was seen in a majority of patients, specifically those who had scored above the range of cognitive performance associated with dementing disorders such as Alzheimer’s disease, but who were performing in the low normal range for persons of the same age. As the authors reported, “Results of this study suggest that phosphatidylserine may be a promising compound for the treatment of memory deficits that frequently develop in the later decades of adulthood. Effects were present on a number of outcome variables related to such important tasks of daily life as learning and recalling names, faces, and numbers. Drug effects may also generalize to other difficult tasks involving learning, memory, and concentration since improvement was also present on a standard neuro-psychological test that measures the ability to remember details of a story after it is read. This finding may be related to the common complaint in later adulthood of difficulty in remembering what one just read in a newspaper, book, or magazine article.” Similar results have been noted in other studies.[36,37]
Monoamine oxidase type B (MAO-B) catalyzes the oxidation of dopamine to dihydroxyphenylacetaldehyde with formation of hydrogen peroxide. In the absence of adequate glutathione peroxidase (well described in Parkinson’s disease), excessive hydrogen peroxide is available to participate in the Fenton reaction whereby hydrogen peroxide combines with ferrous iron forming ferric iron and the highly reactive hydroxyl radical. Thus, inhibition of MAO-B may offer therapeutic benefit in Parkinson’s disease and in other neurodegenerative conditions characterized by free-radical production as a consequence of oxidation of cerebral catecholamines. Selegeline, a potent inhibitor of MAO-B, having long been demonstrated to delay the need for dopamine-replacement therapy in Parkinson’s disease, is now being evaluated for its ability to improve cognitive defects associated with Alzheimer’s disease. Interestingly, it has been demonstrated that extracts of Ginkgo biloba leaf also have a profound inhibitory influence on MAO-B. In addition, Ginkgo biloba is known to be involved in such diverse processes as homeostasis of inflammation, reduction of oxidative stress, membrane protection, and neuro-transmission modulation. Le Bars and co-workers, in research recently published in the Journal of the American Medical Association, evaluated 202 patients suffering from Alzheimer’s disease or multi-infarct dementia over a 52-week period of time. These subjects received either an extract of Ginkgo biloba or placebo. In the treatment group a substantial number of patients either stabilized or actually demonstrated improvement in cognitive performance as measured by psychometric testing, and this was of sufficient magnitude that it was frequently recognized by the care-giver.
Increased intra-cellular calcium is known to enhance the conversion of the enzyme xanthine dehydrogenase (which metabolizes xanthine to uric acid plus NADH) to xanthine oxidase (converts xanthine to uric acid plus superoxide radical). This provides another mechanism whereby increased cytosolic calcium enhances the free-radical load. Unpublished research by Dr. Stanley Appel is evaluating the efficacy of allopurinol (a potent inhibitor of xanthine dehydrogenase and xanthine oxidase) in amyotrophic lateral sclerosis. Clearly, the enzymatic shift favoring xanthine oxidase with its resultant increase in superoxide formation has implications in many other neurodegenerative entities. Since allopurinol inhibits both xanthine dehydrogenase and xanthine oxidase, overall production of uric acid is decreased. Uric acid may have antioxidant properties, thus selective inhibition of xanthine oxidase would be more ideal. Sheu and co-workers at Tai Pei Medical College have demonstrated the specific inhibitory effect of silymarin on xanthine oxidase.
As described above, the role of nitric oxide in acute and chronic neurological illnesses is multi-factorial. Dietary inhibition of nitric oxide formation by citrulline was described above. Kong, and co-workers at the National Institute of Environmental Health Sciences have demonstrated that glial cell cultures stimulated to produce nitric oxide by a combination of lipopolysaccharide and interferon-gamma are significantly inhibited with respect to nitric oxide production when treated with genistein.
Acetyl-L-carnitine has been demonstrated to specifically increase cellular ATP production. It was shown to prevent MPTP-induced neuronal injury in rats. Further, Acetyl-L-carnitine reduces production of mitochondrial free-radicals, helps maintain transmembrane mitochondrial potential, and enhances NAD/NADH electron transfer. Thal and colleagues at the University of California San Diego evaluated the efficacy of Acetyl-L-carnitine, 1 gram t.i.d. for twelve months in a multi-center, placebo-controlled study of 431 patients with Alzheimer’s disease, 83% of whom completed the one year study. Their results demonstrated “…a trend for early-onset patients on Acetyl-L-carnitine to decline more slowly than early-onset Alzheimer’s disease patients on placebo.”
Alpha lipoic acid is emerging as one of the most promising agents for neuro-protection in neurodegenerative diseases. This potent antioxidant demonstrates excellent blood-brain barrier penetration. It acts as a metal chelator for ferrous iron, copper, and cadmium, and also participates in the regeneration of endogenous antioxidants including vitamins E, C, and glutathione. Although no large clinical evaluation of the usefulness of alpha lipoic acid in neurodegenerative diseases has as yet been published, an excellent review in a paper entitled “Neuro-protection by the metabolic antioxidant alpha lipoic acid” by Packer and co-workers in Frankfort, Germany provides enough justification for strong consideration of alpha lipoic acid as a neuro-protectant for neurodegenerative conditions.
The lipophilic antioxidant vitamin E is thought to play a major role in defending mitochondria against oxidative stress. Since mitochondrial ATP production is a membrane-bound event, reducing oxidative membrane damage would likely slow the decline of oxidative phosphorylation potential. In a report published in the New England Journal of Medicine, researchers at Columbia University College of Physicians and Surgeons studied 341 patients with Alzheimer’s disease of moderate severity receiving selegeline 10 mg per day, alpha-tocopherol (vitamin E) 2000 i.u. a day, both, or placebo, over a two-year period of time. The results revealed that the primary outcomes of death, institutionalization, loss of the ability to perform basic activities of daily living, or severe dementia were prolonged in the groups receiving selegeline or vitamin E compared to the groups receiving placebo or selegeline and vitamin E.
Melatonin, in addition to having free-radical scavenging properties, has also been demonstrated to increase gene expression for antioxidant enzymes. Kotler has demonstrated increased levels of mRNA for glutathione peroxidase, copper-zinc superoxide dismutase, and manganese superoxide dismutase in melatonin-treated rat brain cortex. These properties in addition to the ability of melatonin to readily traverse the blood-brain barrier as well as its lipid and aqueous solubility provide substantiation for consideration of melatonin in neurodegenerative conditions.
Glutathione is an important cerebral mitochondrial antioxidant maintaining both vitamin E and vitamin C in their reduced state and removing potentially damaging peroxides. A profound decrease in brain glutathione has been demonstrated in Parkinson’s disease. Intravenous reduced glutathione has been used as a treatment of early Parkinson’s disease. Sechi administered reduced glutathione 600 mg twice daily for thirty days in an open label study on patients with early Parkinson’s disease. All patients improved “significantly” after glutathione therapy, with a 42% decline in disability. The therapeutic effect lasted for 2-4 months after therapy. They concluded, “Our data indicate that in untreated Parkinson’s disease patients, glutathione has symptomatic efficacy and possibly retards the progression of the disease.”
The nutritional supplement N-acetyl-L-cysteine has been demonstrated to increase intra-cellular cysteine levels, enhancing glutathione production. In addition, glutathione may be enhanced by the use of alpha lipoic acid (see above), L-cysteine, L-methionine, L-glutamine, reducing xenobiotic challenges, reducing drug challenges which induce cytochrome P450 enzymes, complementary antioxidants including vitamins C and E, and silymarin, which acts by increasing glutathione retention. Finally, it is noted that N-acetyl-cysteine may act as a potent antioxidant in that it inhibits the production of nitric oxide. NADH plays a pivotal role in the function of complex I of the respiratory chain. Enzyme function of NADH ubiquinone reductase in the platelets of Parkinson’s disease patients is noted to be 30-60% lower than that of aged match controls. This activity increases following administration of NADH. Birkmayer has demonstrated improvements of short-term memory and other cognitive functions in Parkinson’s patients treated with NADH. He felt that NADH would prove helpful in Parkinson’s disease since NADH stimulates tyrosine hydroxylase, the rate-limiting enzyme for dopamine biosynthesis. Because deficiencies of dopamine and noradrenalin are found in patients with senile dementia of the Alzheimer’s type, he studied the usefulness of NADH in 17 patients suffering from dementia of the Alzheimer’s type in an open label trial. Using the mini-mental status examination, he found that all 17 patients treated with NADH, 5 mg twice a day, improved. Minimum improvement was 6 points with a maximum of 14 and a mean of 8.35 points with therapy ranging from 8 to 12 weeks.
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