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.
 
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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