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A New Therapeutic Approach for Treating PARKINSON'S DISEASE

DISCUSSION:
This study confirms and extends our previous reports on the clinical benefit of NADH for parkinsonian patients ( ^{12, 13, 14}). The new finding of this report is that the oral form of NADH shows a beneficial clinical effect comparable to that of the intravenously applied NADH. The galenic formulation of the oral form of NADH is a critical factor with regard to its clinical efficacy. When we first used NADH filled in gelatin capsules the effect was not convincing. This was most likely due to the rapid dissolution ( approximately 10 - 15 minutes) of the capsules leading to a release of NADH into the acid condition of the stomach. Since NADH is rapidly oxidized below pH 7.6 the conditions in the stomach will inactivate NADH by converting it to NAD+. The investigations of this report were therefore performed with NADH capsules coated with an acid-stable film and a release time of 2 - 3 hours. With this galenic formulation of NADH an improvement in disability could be achieved which was comparable to that of intravenously applied NADH. 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 or Sinemet 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 favor 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. The NADH therapy on the other hand follows an opposite strategy, namely the stimulation of the endogenous L-DOPA biosynthesis by activation of the key enzyme TH. There are a number of arguments in favor with NADH treatment one of which is that patients which do not respond to the classical L-DOPA therapy even if higher dosages are applied, show an improvement after NADH treatment. The stimulation of L-DOPA biosynthesis may occur via enhanced production of the TH coenzyme H4 biopterin. As shown by Nagatsu and coworkers the levels of H4 biopterin in the brain and cerebrospinal fluid of Parkinsonian patients are reduced about 50 % in comparison to that of age matched healthy individuals. The cause of this H4 biopterin deficiency is still obscure. If the deficit in H4 biopterin is due to a decreased biosynthesis, the biochemical mechanism of the NADH action may be explainable. H4 biopterin is formed from H2pterin by an enzyme called quinoiddihydropteridinreductase (DHPR), an enzyme which needs NADH as essential cofactor ( ¹⁰ ). There is indirect evidence that DHPR influences TH activity via H4 biopterin because substances which competitively inhibit DHPR such as 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP) induce parkinsonian symptoms ( ¹⁶ ). A valid argument for clinical efficacy of NADH as stimulation of L-DOPA biosynthesis would be the measurement of an increase of L-DOPA concentration in the brain, in particular in substantia nigra. For obvious reasons it is impossible to gain these data because nobody, for the time being, is able to measure the L-DOPA concentration in the substantia nigra directly before and after NADH treatment. Therefore we have to rely on indirect evidence one of which is the metabolic product of dopamine and homovanillinic acid (HVA) respectively. The level of this substance increases after NADH treatment parallel to the improvement in disability. Furthermore by tissue culture experiments using dopamine producing neuroblastoma cells we were able to show that NADH is able to increase the production of dopamine. Furthermore NADH does stimulate the enzymatic activity of TH directly when added to the culture medium. These findings indicate that NADH acts directly on TH due to this stimulates dopamine biosynthesis which is a considerable support for our clinical concept of stimulation the endogenous dopamine production. It may be argued that the beneficial clinical 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.

The new therapeutic principle for treating Parkinson’s disease, namely the stimulation of the endogenous L-DOPA biosynthesis, could overcome the drawback of the L-DOPA treatment in the sense that it could avoid further destruction of the residual nigra cells caused by the action of radicals which are formed in considerable quantities by auto-oxidation of L-DOPA. A double-blind study is in progress in our Institute which will provide a definite conclusion about the clinical efficacy of this essential autosomal substance as new therapeutic concepts for Parkinson’s disease.

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