The following technical article on NADH may be of value to your health care practitioner:

The Clinical Benefit Of NADH as Stimulator of Endogenous L-Dopa Biosynthesis in Parkinsonian Patients

*W. Birkmayer, **J.G.D. Birkmayer, **K. Vrecko, and **B. Paletta *Birkmayer Institute for Parkinsontherapy, Vienna; **Department of Medical Chemistry, University of Graz, Graz, Austria

Advances in Neurology, Vol. 53: Parkinson's Disease: Anatomy, Pathology, and Therapy, edited by M.B. Streifler, A.D. Korczyn, E. Melamed, and M.B.H. Youdim, Raven Press, New York ©1990.

Treatment of Parkinson's disease with L-dopa (LD) in combination with decarboxylase and monoamine oxidase inhibitors is a pure substitutional therapy designed to correct the lack of dopamine in the brain.1 The dopamine deficit is caused by the diminished tyrosine hydroxylase (TH) in the substantia nigra.2 However, catecholamines such as dopamine and its precursor LD inhibit TH via a feedback mechanism.3,4 This suggests that application of LD to PD patients may further decrease the already reduced TH activity. Therefore, therapeutic strategies other than substitution have to be considered, e.g., stimulation of endogenous dopamine production in the brain. This may be achieved by activating the LD producing enzyme.

As shown by Nagatsu et al.,5 this enzyme is an iron-containing protein with tetrahydrobiopterin (H4biopterin) as coenzyme. H4biopterin is reduced in the brain of PD patients6 and has therefore been used in clinical trials, but with only partial success. On the other hand, it has been shown that the special iron compound oxyferriscorbone(R) is able to improve the symptoms of parkinsonian patients7,8, suggesting production of endogenous LD in the brain of parkinsonians. The stimulation of LD biosynthesis is reflected by an increase in the urine level of homovanillic acid (HVA).8 We believe that this occurs by TH activation by the iron compound oxyferriscorbone, because there is no other enzyme except TH which catalyzes LD formation, and it also has been shown that this enzyme can be markedly activated in vitro by iron.9 Our findings have already been confirmed.10,11 After long-term iron medication, however, its effectiveness subsides in some patients. This prompted us to look for other therapeutic modalities. Our choice was nicotinamidadenindinucleotide (NADH), which promotes the formation of H4biopterin, the active coenzyme of tyrosine hydroxylase.

Materials and Methods

Dagnosis and disability scores of the parkinsonian patients were established according to the method of Birkmayer and Neumayr.12 Nicotinamideadeninedinucleotide, reduced form disodium salt (synonyms: beta-NADH, reduced DPN, beta-DPNH), was purchased from Sigma Diagnostics (St. Louis, Missouri). Twenty-five mg of NADH were dissolved in 100 ml of 0.9% sterile sodium chloride, pH 7.4, and infused intravenously in 30 min. NADH solutions were always prepared fresh immediately prior to use. Disability scores were determined before, 1 hr after, and 4 hrs. after the NADH infusion.

Forty patients have been treated so far. All of them exhibited a pronounced drop of their disability score. The patients' ages ranged from 48 to 85, duration of the disease ranged from 2 to 20 years. The overall improvement of the disability of all patients was 46.25%. A very good response was exhibited in 65% of the patients: more than 30% improvement of disability, 35% of the patients a moderate benefit of up to 30%.
Walking and pushing ability improved considerably as did posture, speech, and mimics. The action of NADH lasted between 1 and 4 days, depending on the severity of the symptoms. Withdrawal of NADH led to a relapse with worsening of disability. About one-fifth of the patients did well on NADH alone, and LD-therapy could be omitted. In the other patients the LD dosage could be reduced materially.

Fifteen patients have been examined with regard to the duration of the daily pattern of phases. The daily "on" phases could be increased by 6 to 10 hr. In a number of patients so examined, the urine level of the dopamine metabolite HVA was markedly increased. Such HVA increase is also observed after treatment with LD. As NADH is not a precursor of LD, it seems most likely that it stimulates endogenous LD biosynthesis.

The beneficial clinical effect of NADH on the disability of parkinsonian patients has been demonstrated. A possible mechanism by which this may occur is shown in the simplified pathway of LD biosynthesis. L-Dopa is formed from tyrosine by the enzyme TH. This is an iron-containing enzyme with H4Biopterin as coenzyme. H4Biopterin provides electrons to reduce molecular oxygen and is in turn oxidized to the quinonoid-H2-pterin. The dihydropteridine reductase (DHPR) regenerates H4biopterin. The cofactor of this enzyme is NADH.13 H4Biopterin in brain and in cerebrospinal fluid of PD patients is reduced.6 This H4biopterin deficiency could be due either to a decreased biosynthesis or to a lack in the biologically active form of H4biopterin. It could well be that H4biopterin is exhausted in parkinsonian patients because of an enormous consumption, perhaps caused by a toxic agent. The idea is derived from the observation that MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), a neurotoxin that can induce parkinsonism in men and animals, inhibits DHPR, the enzyme which regenerates tetrahydrobiopterin, the coenzyme required for endogenous dopamine formation.14 MPTP seems to be a competitive inhibitor of DHPR with respect to NADH. If this is so, NADH should be able to neutralize the toxic effect of MPTP or other free radical-inducing agents. There are two arguments in favor of our hypothesis. First, the clinical effect of NADH closely resembles that of LD, indicating that this coenzyme stimulates the endogenous LD biosynthesis. Second, the improvement in the clinical symptoms parallels an increase in the urine level of HVA, which also
has been found with the standard LD therapy.

1. Birkmayer W. Riederer P. Parkinson's disease, New York: Springer Verlag Wien, 1983.
2. McGeer PL, McGeer EG, Wada JA. Distribution of tyrosine hydroxylase in human and animal brain. J Neurochem 1971;18:1647.
3. Ames M., Lerner P., Lovenberg W. Tyrosine hydroxylase: Activation by protein phosphorylation and end product inhibition. J Biol Chem 1978;253:27-31.
4. Nagatsu T., Levitt M, Udenfriend S. Tyrosine hydroxylase: The initial step in norepinephrine synthesis. J biol Chem 1964; 239:2910-2917.
5. Nagatsu T., Namaguchi T, Kato T, et al. Biopterine in human brain and urine from controls and parkinsonian patients: Application of a new radioimmunoassay. Clin Chim Acta 1981; 109:305.
6. Nagatsu T, Kato T, Numata Y, et al. Phenylethanolamine-N-methyl-transferase and other enzymes of catecholamine metabolism in human brain. Clin Chim Acta 1977:75:221-232.
7. Birkmayer W. Birkmayer JGD. Iron, a new aid in the treatment of Parkinson patients. J Neural Transm 1986; 67:287-292.
8. Birkmayer JGD, Birkmayer W. Improvement of disability and akinesia of patients with Parkinson's disease by intravenous iron substitution. Ann Clin Sci 1987; 17:32-35.
9. Rausch WD, Hirata Y, Nagatsu T, et al. Tyrosine hydroxylase activity in caudate nucleus from Parkinson's disease. Effects of iron and phosphorylating agents. J Neurochem 1988; 50:202-208.
10. Ott E, Birkmayer W, Birkmayer JGD. J Movment Dis 1988 (in press).
11. LLiceto G, De Mari M, Federico F, et al. Iron in Parkinson's disease: Preliminary reports. J Neurol Sci Suppl 1987; 7:62.
12. Birkmayer W, Neumayr E. Die moderne medikamentose Behandlung des Parkinsonismus. Z Neurol 1972; 202:257.
13. Nichol CA, Smith GK, Duch DS. Biosynthesis and metabolism of tetrahydrobiopterin and molybdopterin. Ann Rev Biochem 1985; 54-729-764.
14. Blair JA, Parveen H, Barford PA, et al. Aetiology of Parkinson's disease. Lancet 1984; 1:167.

Jorg G.D. Birkmayer, M.D., Ph.D.
Professor of Medicine and Clinical Chemistry

Jorg G.D. Birkmayer, M.D., Ph.D., is a world leader in the field of medical research concentrating on Cancer Biology and Neurochemistry. His research in Neurochemistry has focused on possible treatments for Alzheimer's and Parkinson's Disease. Dr. Birkmayer is the Associate Professor of Medicine, Clinical Chemistry and Director of Laboratories in Neurochemistry at the University of Graz.

In addition to his academic work, Dr. Birkmayer is the Medical Director of Labor Birkmayer, a laboratory for medical diagnostics in Vienna, and Director of Laboratories for five private hospitals in Vienna since 1983. He previously taught Cell Biology and Physiological Chemistry at the University of Munich. In 1988 he was appointed to the post of Secretary General of the newly founded Birkmayer Institute for Parkinson Therapy. He was Secretary General for 10 consecutive years of the International Conference on Human Tumor Markers.

Peer review journal articles that Dr. Birkmayer has had published includes:

"Nicotineamide Adenine Dinucleotide (NADH) - a New Therapeutic Approach to Parkinson's Disease Comparison of Oral and Parenteral Application," published in The Journal of Neural Transmission in 1993;

"Stimulation of Dopamine Biosynthesis in Cultured PC12 Phaeochromocytoma Cells by the Coenzyme Nicotineamide Adenine Dinucleotide (NADH)," in The Journal of Transmission in 1993;

"The Coenzyme NADH as a Biological Antidepressive Agent," New Trends in Clinical Neuropharmacology 1991.

Dr. Birkmayer is a member of the following scientific organizations: New York Academy of Sciences, the International Academy of Tumor Marker Oncology, The United States Association for Clinical Scientists, The International Society for Preventative Oncology, and the Austrian Society for Clinical Chemistry and Laboratory Medicine.

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