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Biopterin in Parkinson's Disease

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Biopterin in Parkinson's Disease J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.50.1.85 on 1 January 1987. Downloaded from Journal of Neurology, Neurosurgery, and Psychiatry 1987;50:85-87 Short report Biopterin in Parkinson's disease A P MOORE,* P 0 BEHAN,* W JACOBSON,t W L F ARMAREGOt From the Institute ofNeurological Sciences, Southern General Hospital, Glasgow,* Department ofPaediatrics, University ofCambridge, Addenbrooke's Hospital, Cambridge,t Department ofBiochemistry, John Curtin School ofMedical Research, The Australian National University,: Canberra, Australia SUMMARY Tetrahydrobiopterin is an essential co-factor in the natural synthesis of dopamine. Oral tetrahydrobiopterin was given in small doses to four patients with early Parkinson's disease but had no discernible effect. The major pathology identified in Parkinson's disease treated with dopamine. Other workers have also doc- is a loss of nigrostriatal dopamine cells and a decrease umented a similar mild and short-lived effect of tetra- in striatal dopamine.' The low dopamine levels can be hydrobiopterin.6 The therapeutic trials producing corrected by giving levodopa, which is converted to benefit used a single-shot oral regime in patients who Protected by copyright. dopamine in the brain, and its administration reverses had already been treated with conventional dopami- many of the clinical features of Parkinsonism. nergic preparations. Unfortunately, although this replacement therapy is In a randomised double-blind placebo controlled now conventional, there are many problems associ- crossover trial, we investigated the effects of repeated ated with its use so that it is important to consider small doses of tetrahydrobiopterin in Parkinsonian alternative approaches. patients who had received no previous dopaminergic Tetrahydrobiopterin is an essential co-factor of therapy. tyrosine hydroxylase, the rate-limiting enzyme in the natural synthesis of dopamine. Levodopa therapy Patients and methods by-passes this step. In Parkinsonian subjects, the biopterin content of cerebrospinal fluid is reduced to Permission was obtained from the hospital ethical commit- 50% of that in control subjects,2 while in post mor- tee to carry out the study, and informed consent was tem obtained from patients. Four subjects, two men and two striatal samples it is reduced by 80%.3 It women, were selected whose Parkinson's disease had been has been postulated that tetrahydrobiopterin diagnosed by a consultant neurologist but who had not yet supplements might increase tyrosine hydroxylase received treatment. Their characteristics are outlined in the activity in Parkinsonian patients and boost endo- table. They each had clear-cut bradykinesia and rigidity but http://jnnp.bmj.com/ genous dopamine production. only two were tremulous. Some preliminary findings using this approach All examinations were performed in hospital at approxi- have been published. However, the results are mately the same time of day, which was about two hours conflicting and in each report the number of subjects after the morning dose of the trial drug. Patients were is small. Although 10 mg/kg intravenous tetra- assessed twice in the week before commencing treatment to hydrobiopterin appeared to have no benefit when establish a baseline and minimise any learning effect and given for three consecutive days,4 single oral doses of then on each day of treatment and one week later. They were assessed again after levodopa plus benserazide therapy was on September 29, 2021 by guest. 1 g of tetrahydrobiopterin temporarily abolished established. hypokinesia and rigidity and reduced tremor5 when In each assessment patients were rated using given in an open trial to two subjects previously (1) The Hoehn and Yahr scale, which allocates patients roughly into one of five grades of Parkinsonism. (2) The Webster scale, which grades the severity of certain Address for reprint requests: Dr AP Moore, Institute ofNeurological individual symptoms and signs to give an aggregate Science, Southern General Hospital, Glasgow G51 4TF, UK. score. Received 25 March 1986. (3) A rated neurological examination, which is similar to Accepted 15 May 1986 the Webster scale but scores different body parts indi- 85 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.50.1.85 on 1 January 1987. Downloaded from 86 Moore, Behan, Jacobson, Armarego Table Patient characteristics and mean disability scores Patient Hoehn and Yahr Webster RNE OT Age (yr) Duration ofdisease (months) 1 Placebo 2-5 12 3 19 5 245 60 36 Tetrahydrobiopterin 2 11 8 17 2 242 2 Placebo 2 14-8 284 169 63 30 Tetrahydrobiopterin 2 14-0 29-3 165 3 Placebo 1 71 10 285 41 36 Tetrahydrobiopterin 1 8 3 12-7 275 4 Placebo 2 94 13-2 173 58 30 Tetrahydrobiopterin 2 8-8 12 6 180 RNE- rated neurological examination. OT-objective test. vidually for each feature and does not rely on patients lative effect was noted. subjective reports. The role of tetrahydrobiopterin in dopamine (4) Objective tests (OT), a short battery of timed tests of synthesis is similar to its place in the biosynthesis of repetitive limb movements, developed in this depart- catecholamines and serotonin. In ment as a measure of bradykinesia, usually the most hyperphenyl- disabling feature of Parkinsonism. alaninaemia, the ability to synthesise tetra- Patients' comments on the drug's effectiveness and side hydrobiopterin is deficient, and treatment with tetra- effects were also noted. hydrobiopterin supplements alone has been suc- Each patient received either placebo or oral tetra- cessful.7 Although the drug does not cross the hydrobiopterin, 200 mg daily in three divided doses for four blood-brain barrier easily, it can do so when given in consecutive days on a randomised, double-blind basis. After high dosage (1 g). Endogenous tetrahydrobiopterin a 24 hour "washout" period, the other drug was then admin- is present in striatal dopaminergic terminals,8 and it Protected by copyright. istered for the next four days. Each drug was given as a has been suggested that more lipophilic analogues powder which was then dissolved in water together with I g of tetrahydrobiopterin would of effervescent ascorbic acid. One week after the trial reach this site patients were started on conventional treatment with more easily.5 In rats a two to threefold increase of levodopa plus benserazide. The results were obtained by catecholamine synthesis in the striatum was found by comparing the means of each test score whilst taking one group of investigators following injection of placebo, with the means whilst taking the active drug, using tetrahydrobiopterin into the cerebral ventricles,9 but Student's t test. others could not confirm this although high tissue levels of tetrahydrobiopterin were achieved.10 Results Tetrahydrobiopterin is effective in hyper- phenylalaninaemia because there is a severe reduction No significant difference was detected in any of the in endogenous levels of tetrahydrobiopterin, without cases, given either placebo or tetrahydrobiopterin. reduction of hydroxylase enzyme levels. The lesser No clinical impression of benefit nor trend towards diminution of tetrahydrobiopterin levels in improvement was noted during treatment with tetra- Parkinson's disease may merely reflect loss of dopa- hydrobiopterin, although two patients did report an minergic neurons, so that the ratio of co-factor increased sense of well-being. There were no side to tyrosine hydroxylase in surviving neurons is nor- http://jnnp.bmj.com/ effects. All four patients subsequently responded well mal. Thus tetrahydrobiopterin administration in to levodopa plus a decarboxylase inhibitor. Parkinson's disease would be aimed at increasing the activity of existing tyrosine hydroxylase above the Discussion level induced by endogenous tetrahydrobiopterin.5 That this may be possible is suggested by the existence Tetrahydrobiopterin given orally has twice been of multiple forms of tyrosine hydroxylase, with some reported to be effective in Parkinson's disease,5 6 forms being in a less active state and subsaturated whereas a similar dose given as an intravenous bolus with endogenous tetrahydrobiopterin.8 on September 29, 2021 by guest. apparently produced no clinical benefit.4 It is possible In Parkinson's disease, 70-80% of striatal therefore, that the time course of tetrahydrobiopterin dopamine cells may be lost before clinical features are entry into the brain is critical, or that not all patients apparent, and up to this point there are several com- are sensitive.5 Single large oral doses of tetra- pensatory mechanisms for the surviving dopaminer- hydrobiopterin (I g) produced observable beneficial gic cells." Treatment aimed at restoring or boosting effects lasting for approximately five hours after 4 or natural metabolic function is more likely to be 5 hours. We have shown, however, that a similar total effective in patients with relatively early disease. It is dose distributed over 4 days is not helpful: no cumu- possible that treatment with exogenous dopamine J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.50.1.85 on 1 January 1987. Downloaded from Biopterin in Parkinson's disease 87 reduces striatal capacity to produce endogenous hydroxylase cofactor (tetrahydrobiopterin) in Parkin- dopamine, so that patients not treated with levodopa sonism In: Hassler RG, Christ JF, eds. Advances in may be more likely to respond to tetrahydro- Neurology Vol. 40. New York: Raven Press, biopterin. Biopterin is expensive and scarce, and so 1984:459-62. has been tested
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