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A New Therapeutic Approach for Treating PARKINSON'S DISEASE

• Document cataloged:
  Birkmayer JGD, Vrecko C, Volc D, Birkmayer W.
  Nicotinamide adenine dinucleotide (NADH) -
  a new therapeutic approach to Parkinson’s disease
  Comparison of oral and parental application.
  Acta Neurol Scand 1993: 87: Suppl 146; 32-35.
• Clinical research address:
  Birkmayer-Institut fur Parkinsontherapie, Schwarzpanierstrasse 15, A-1090
  Vienna, Austria

Authors:

• Dr. G.D.Birkmayer with Birkmayer-Institut for Parkinsontherapie in Vienna, Austria
• Dr. D.Volc with Birkmayer-Institut for Parkinsontherapie in Vienna, Austria
• Dr. W. Birkmayer with Birkmayer-Institut for Parkinsontherapie in Vienna, Austria
• Dr. C.Vrecko with Department of Medical Chemistry, University of Graz, Graz, Austria

Summary:
The reduced coenzyme nicotinamide adenine dinucleotide (NADH) has been used as medication in 885 parkinsonian patients in an open label trial. About half of the patients received NADH by intravenous infusion, the other part orally by capsules. In about 80 % of the patients a beneficial clinical effect was observed: 19.3% of the patients showed a very good (30 - 50 %) improvement of disability, 58.8% a moderate (10 - 30 %) improvement. 21.8 % did not respond to NADH. Statistical analysis of the improvement in correlation with the disability prior to treatment, the duration of the disease and the age of the patients revealed the following results: All these 3 parameters have a significant although weak influence on the improvement. The disability before the treatment has a positive regression coefficient (t < 0.01). the duration of the disease has a negative regression coefficient (< 0.01) and so has the age a negative regression coefficient (t< 0.05). In other words younger patients and patients with a shorter duration of disease have a better change to gain a marked improvement than older patients and patients with longer duration of the disease. The orally applied form of NADH yielded an overall improvement in the disability was comparable to that of the parenterally applied form.

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 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 H4 biopterin, 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 till 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 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 cofactors. 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 with 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 H4 biopterin biosynthesis in the brain. The H4 biopterin deficiency could be due either to a decreased biosynthesis or to a lack in the biological active form. If a diminished biosynthesis of H4 biopterin is the cause of TH defect, stimulation of H4 biopterin biosynthesis should elevate the enzyme activity. The key enzyme in H4 biopterin biosynthesis is the quinoidH2pteridin reductase ( ¹⁰ ). This enzyme needs the reduced nicotinamide adenine dinucleotide (NADH) as coenzyme. Our idea was to stimulate H4 biopterin biosynthesis by applying NADH which increases the quinonoid H2 pteridine reductase activity and due to this amount of H4 biopterin increases. Owing to this NADH may stimulate endogenous L-DOPA biosynthesis by the postulate 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.

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