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Dr. JGD Birkmayer's excerpted work on an open study of the effects of NADH administered to Parkinson's patients is presented here for research purposes. For the student, Dr. Birkmayer outlines a hypothesis which would use a novel approach in attempting to stimulate the natural dopamine production capabilities of the brain. The Introduction outlines the problem and the postulated solution. The Excerpts of the Results shows the greatest functional improvement in those patients who are younger in age and had the shortest duration of L-DOPA treatment. They were the ones with the least TH deficit. The Excerpts of the Discussion show that NADH was used as an adjunct to the normal medication the patients were on. There was no "washout". While it was hoped that NADH would stimulate natural L-DOPA production, it was noticed that the addition of carbidopa in combination with NADH yielded a better and longer lasting clinical improvement than NADH alone. This could lead to the conclusion that the action observed may be in fact a peripheral action rather than a stimulation action. --------------------------------------------------------------------------- Nicotinamide adenine dinucleotide (NADH)--a new therapeutic approach to Parkinson's disease Comparison of oral and parenteral application Birkmayer JGD, Vrecko C, Volc D, Birkmayer W. Acta Neurol Scand 1993; 87; Suppl 146: 32-35 Introduction It is generally accepted that Parkinson's disease is caused biochemically by a deficit of dopamine in the basal ganglia of the brain stem (1). The immediate precursor of dopamine, L-DOPA, is able to substitute the shortage in dopamine (2), whereas tyrosine, a precursor of L-DOPA, is unable to do so. This indicates that the biosynthesis of dopamine is blocked at the metabolic conversion from tyrosine to L-DOPA. The enzyme catalyzing this reaction is tyrosine hydroxylase (TH) the activity of which is considerably diminished in substantia nigra of parkinsonian patients (3,4). Indirect evidence for the central role of TH in the biosynthesis of dopamine has been gained long ago by applying alpha-methylparatyrosine, an inhibitor of TH, to parkinsonian patients. Under this medication the disability of the patients deteriorated indicating a further reduced L-DOPA biosynthesis (5). In 1981 Nagatsu and coworkers (6) showed that H4biopterin, the coenzyme of TH, is reduced to about 50% in the brain of parkinsonian patients in comparison to that of age matched healthy control. This may be one of the reasons for the reduced TH activity. For the time being the first choice of therapy is still substitution by L-DOPA which is the end product of TH and readily converted into dopamine. L-DOPA is known to act as feedback inhibitor of TH (7). Thus the exogenous supplied L-DOPA will inhibit TH activity already reduced in parkinsonian patients even further. Taking this into account we considered a new concept to overcome the dopamine deficit namely to stimulate TH activity in order to increase L-DOPA biosynthesis. This may be accomplished by adding the reduced or missing co-factors. Since we know that the coenzyme of TH H4biopterin is also reduced in the brain of parkinsonian patients, therapeutic application of this substance was considered. However, clinical trial of H4biopterin did not show any beneficial clinical effect with Parkinsonian patients (8,9). The failure of this approach was the impermeability of the blood brain barrier for H4biopterin. Therefore, this substance cannot reach its target, the substantia nigra in the brain. The question was whether it is possible to stimulate the H4biopterin biosynthesis in the brain. The H4biopterin deficiency could be due either to a decreased biosynthesis or to a lack in the biological active form. If a diminished biosynthesis of H4biopterin is the cause of TH defect, stimulation of H4biopterin biosynthesis should elevate the enzyme activity.; The key enzyme in H4biopterin biosynthesis is the quinoidH2pteridin reductase (10). This enzyme needs the reduced nicotinamide adenine dinucleotide (NADH) as coenzyme. Our idea was to stimulate H4biopterin biosynthesis by applying NADH which increases the quinonoidH2pteridine reductase activity and due to this the amount of H4biopterin increases. Owing to this NADH may endogenous L-DOPA biosynthesis by the postulated mechanism. An increase in L-DOPA production should be reflected by an improvement of the clinical symptoms of parkinsonian patients. In order to investigate our concept in more detail more than 800 parkinsonian patients have been treated with NADH and the possible mechanism of action of NADH has been studied in a dopamine producing neuroblastoma cell-line. Excerpts from Results ... A positive correlation between age and disability before treatment as well as between duration of the disease and disability before treatment appears to be most plausible. According to this one might expect that both high age and long duration of the disease coincide with a marked improvement. However, a refined statistical analysis ends up with the contrary, meaning that a negative correlation between age and improvement of the treatment as well between duration of the disease and improvement after treatment is obtained. For an accurate assessment of the real relationship between these variables (disability before treatment, age, duration of disease and improvement) it is necessary to subtract the effects of the variable disability before treatment. The results of this calculation show that in general younger patients and patients with a shorter duration of disease respectively have a better chance to gain a marked improvement than older patients and patients with a longer duration of the disease. Excerpts from the Discussion .... It should be pointed out that most of the patients included in this study received in addition to NADH the classical medication such as Madopar(rt) or Sinemet(rt) with or without addition, such as deprenyl, bromocryptine or amantadine. In many of these patients the daily dose of L-DOPA could be reduced considerably. In some patients it could be omitted totally. The question is whether or not the well established L-DOPA therapy should be replaced by NADH treatment. Arguments in favour of the new NADH treatment become apparent when the biochemical and pharmacological differences behind these 2 therapeutic concepts are considered. The L-DOPA therapy follows the principle of substitution meaning that dopamine deficit is filled up by substituting with its immediate precursor L-DOPA. However, as we know substitution of certain biological substances by exogenous supply will lead to a depression of the organism's own biosynthesis. This holds for cortisone, thyroxine, aldosterone, many other hormones and metabolic substances. It is certainly valid also for L-DOPA biosynthesis. In other words exogenous supply of L-DOPA will inhibit its endogenous biosynthesis. As already mentioned the L-DOPA producing enzyme, TH, is considerably reduced in parkinsonian patients (3,4). It is also known that TH is inhibited by its end product L-DOPA (7,15). This implies that TH working already insufficiently is further inhibited by the exogenous supplied L-DOPA. A further reduction in enzymatic activity will be the consequence. Whether or not this is the cause of the frequent observed "off"-effect, in particular after long-term treatment with L-DOPA, remains to be elucidated.... It may be argued that the beneficial effect observed under NADH medication is not a central nervous system related but a peripheral one. If this is actually the case an increase in L-DOPA in the blood will be the consequence. From this amount a certain percentage will reach the brain by potentially the same mechanism by which exogenously supplied L-DOPA reaches the brain. Indirect evidence for this assumption is derived from the observation that a DOPA decarboxylase inhibitor such as carbidopa, given to a number of patients in combination with NADH yielded a better and longer lasting clinical improvement than NADH alone....... References 1. Carlsson A, Lindquist M, Magnusson T et al. On the presence of 3-hydroxytyramine in brain. Science 1958; 127: 471-473 2. Birkmayer W, Hornykiewicz O, Der L-Dioxphenylalanin L-DOPA Effekt bei der Parkinson Akinese. Wr klin Wschr 1961; 73: 787-793 3. Lloyd KG, Davidson L, Hornykiewicz O. The neurochemistry of Parkinson's disease: effect of L-DOPA therapy. J Pharmacol Exp Ther 1975; 195: 453-464. 4. Riederer P, Rausch WD, Birkmayer W et al. CNS modulation and adrenall tyrosine hydroxylase in Parkinson's disease and metabolic encephalopathies. Neural J Transm (suppl.) 14: 121-131. 5. Birkmayer W. Der Alpha-methyl-p-Tyrosin Effekt bei extrapyramidalen Erkrankungen. Wr klin Wschr 1969; 81: 10-13. 6. Nagatsu T, Namaguchi T, Kato T. et al. Biopterine in human blood and urine from controls and Parkinsonian patients: Application of a new radioimmunoassay. Clin Chim Acta 1982; 109: 305-311. 7. Ames M., Lerner P., Lovenberg W. Tyrosine hydroxylase activation by protein phosphorylation and end product inhibition. J Biol Chem 1978; 253: 27-31. 8. Birkmayer W, Riederer P. Die Parkinson Krankheit, Wien Springer Verlag. 1985. 9. Nagatsu T, Tamaguchi T, Rahman K. et al. Catecholamine related Enzymes and Biopterin Cofactor in Parkinson's Disease Abstr. VII Int. Symp. of Parkinson's Disease, Frankfurt 1982: 82. 10. Nichol CA, Smith GK, Duch DS Biosynthesis and metabolism of tetrahydrobiopterin and molybdopterin. Ann Rev Biochem 1985; 54: 729-764. 11. Birkmayer W, Neumayer E. Die moderne medikamentose Behandlung Des Parkinsonismus. Z Neurol 1972; 202: 257-280. 12. Birkmayer W, Birkmayer JGD. Nicotinamidadenindinucleotide (NADH): The New Approach in the Therapy of Parkinson's Disease. Ann Clin Sci 1989; 19: 38-43. 13. Birk