’ s Disease? Can Catechol-O-methyltransferase Inhibitor Prevent Polyneuropathy in Parkinson

Received: May 12, 2013 Revised: May 31, 2013 Accepted: June 13, 2013.

Corresponding author: In-Uk Song

Department of Neurology, Incheon St. Mary's Hospital, The Catholic University of Korea, 665, Bupyeong-6-dong, Bupyeong-gu, Incheon 403-720, Korea Tel: +82-32-280-5010, Fax: +82-32-280-5244, E-mail: catholicnu@gmail.com

Copyright Ⓒ 2013 The Korean Academy of Clinical Geriatrics

This is an open access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Can Catechol-O-methyltransferase Inhibitor Prevent Polyneuropathy in Parkinson’s Disease?

Hye-Young Jeong, In-Uk Song, Sung-Woo Chung

Department of Neurology, College of Medicine, The Catholic University of Korea, Seoul, Korea

Background: Polyneuropathy has recently been described in higher proportions for Parkinson’s disease. The homocysteine (hcy) levels in PD treated with levodopa are thought to be elevated by increased synthesis from the metabolism of levodopa by COMT. It was thought that COMT-inhibitor (COMT-I) may reduce elevated hcy levels. We conducted this study to clarify that COMT-I on patients with PD is able to prevent occurrence of polyneuropathy in PD.

Methods: 37-PD without neuropathy (PDWo) and 41-PD with polyneuropathy (PDP) were compared with 48 healthy controls.

All PD patients performed electrophysiological tests. Plasma hcy levels were measured in all subjects and compared with each groups. And we evaluated to relate with hcy level and polyneuropathy in two groups of PD (levodopa-alone treated group and levodopa plus COMT-inhibitor treated group).

Results: The hcy levels of PDP showed higher than those of PDWo as well as healthy controls. In regarding to effect of COMT-I, no correlation was found hcy levels in two subgroups in PD. There was no significant effect of COMT-I on occurrence of polyneuropathy in PD.

Conclusion: Our findings agree with previous studies indicating that levodopa treatment in PD patients results in elevated hcy concentrations, whereas COMT-I show no preventive effect on involvement of peripheral nerve system in PD patients.

Key Words: Parkinson’s disease, Polyneuropathy, COMT-inhibitor, Homocysteine

INTRODUCTION

Non-motor symptoms of Parkinson’s disease (PD), in- cluding sensory disorders, cognitive impairment, sleep dis- order and autonomic disturbance, are gaining increasing attention.

Of these non-motor symptoms, sensory dis- orders are a well- recognized non-motor manifestation of PD that affects between 40% and 75% of patients during their illness.

Polyneuropathy has recently been described in significantly higher proportions in patients with PD than in the control subjects, despite the poorly understood

sensory disorders in PD and the difficulties of treatment.

This finding was hypothesized to be related to the ele-

vation of plasma homocysteine (hcy) following the man-

agement of PD with levodopa.

The mechanism under-

lying elevated hcy level in PD is the O-methylation of

levodopa. This reaction is catalyzed by the enzyme cat-

echol-O-methyltransferase (COMT) and requires S-adeno-

sylmethionine (SAM) as the methyl donor for the pro-

duction of S-adenosylhomocysteine (SAH), which is hydro-

lyzed rapidly to hcy. The chronically increased hcy syn-

thesis exceeds the capacity of cells to metabolize hcy, thus

leading to elevated hcy level.

Previous animal study has demonstrated that pretreatment with a COMT-inhibitor (COMT-I) can block the elevation of hcy levels when lev- odopa is given.

These findings suggest that a COMT-I, such as entacapone, may reduce levodopa-induced elevated hcy levels in patients with PD. Despite these findings, it is unclear whether hyperhomocysteinemia in PD is related to involvement of peripheral nerve system. Furthermore, to my knowledge, no study has assessed the effects of COMT-I on polyneuropathy in PD patients.

Therefore, we conducted this study in order to clarify that COMT-I on patients with PD is able to block the elevation of hcy level and consequently to prevent occur- rence of polyneuropathy in PD.

MATERIALS AND METHODS

A total of 78 PD patients (37 PD patients without neuropathy (PDWo) and 41 PD patients with poly- neuropathy (PDP)) were compared with 48 healthy con- trols to confirm the value of hcy as a potential cause of polyneuropathy associated with PD patients.

All PD patients were diagnosed, according to the UK Parkinson’s Disease Society Brain Bank Clinical Diagnosis criteria and performed nerve conduction study to diagnose polyneuropathy. The lifetime dose and the duration of in- take of L-dopa were determined for each patient by a ret- rospective chart review. Motor severity of PD was eval- uated, according to the staging system by Hoehn and Yahr (H & Y stage). We also categorized PD patients in- to two groups depending on whether the administration of COMT-I; levodopa alone-treated PD patients group (group 1) and levodopa plus COMT-I-treated PD patients group (group 2). All patients in group 2 took entacapone dosage of 600 mg/day since PD was diagnosed. The nerve conduction study measured motor conduction of the both median, ulnar, peroneal, and tibial nerve and sensory con- duction of the both median, ulnar, superficial peroneal and sural nerves. Patients were asked to provide history of other systemic illnesses, recreational alcohol use, toxic ex- posures, and any family history of neuropathy in order to

exclude other possible causes of polyneuropathy. Prior to neuro-electrophysiological examination, a complete neuro- logical examination by an experienced neurologist and the magnetic resonance image of the brain was performed in all subjects to exclude neurological diseases other than PD. All patients identified within this study had routine blood work to rule out the possible causes for polyneuro- pathy. This included a complete blood count, electrolytes, creatinine, liver enzymes, thyroid function tests, fasting glucose, hemoglobin A1C, erythrocyte sedimentation rate, antinuclear antibody and rheumatoid factor.

Plasma hcy level was measured, routinely, in all pa- tients and healthy controls. Venous blood samples from patients and healthy controls, who had fasted for 8 to 10 h, were collected in tubes that contained ethylenediami- netetraacetic acid. Laboratory data were evaluated by an examiner who was blind to the clinical details and patient evolution.

Statistical analysis was performed using the SPSS soft- ware package, version 17.0. The results were expressed as the mean±standard deviation. Analysis of variance (ANOVA) with post-hoc test was used to compare continuous varia- bles in the two disease groups and the healthy controls group. The correlations between Hcy and age, daily levo- dopa dosage or duration of PD were analyzed with Spearman’s rank order correlation. Independent t-tests were used to compare continuous variable and Pearson chi-square analysis was used to compare categorical varia- ble in each group. Statistical significance was assumed at the 5% level.

RESULTS

The demographic characteristics of all subjects are sum- marized in Table 1. There was significant difference be- tween the hcy levels of PDP and those of PDWo, as well as the healthy controls, but there was no significant dif- ference between those of PDWo and healthy controls.

There were no significant differences between PDWo and

PDP for the duration of PD symptoms and treatment,

daily levodopa dose and motor severity of PD evaluated

Table 1. Baseline characteristics of all the subjects with PD and healthy controls

　 PDWo PDP HC P value

Total number of subjects Gender, male

Age (year)*

Vit. B12 (pg/ml)*

Folate (ng/ml)*

Homocysteine level (μml/L)

Duration of PD symptoms (month) Duration of PD treatment (month) Levodopa equivalent dosage/day (mg) Hoehn & Yahr stage

37 5 67.38±7.55 677.25±383.71 16.27±11.34

12.47±4.19 30.89±14.89 28.51±16.89 651.26±456.96

2.04±1.01

41 13 69.76±8.55 661.22±412.56 12.98±11.81

22.79±24.85 39.28±41.78 36.22±40.40 706.13±396.85

2.32±0.84

48 11 66.23±11.83 654.14±257.24

17.01±14.82 12.52±4.19

0.163 0.228 0.867 0.284 0.002 0.263 0.269 0.582 0.177 PD: idiopathic Parkinson's disease. PDWo: PD without neuropathy, PDP: PD with polyneuropathy, HC: healthy control, Independent t-tests were used to compare continuous variable between PDWo and PDP. *One-way Post-hoc comparison.

Post-hoc comparison of homocysteine level: HC=PDWo<PDP.

Table 2. Comparison of characteristics among 2 subgroup in patients with PD and healthy control gruop

　 Group 1 Group 2 HC P value

Total number of subjects Age (year)*

Vit. B12 (pg/ml)*

Folate (ng/ml)*

Homocysteine level (μml/L)*

Number of PD with polyneuropathy

Duration of PD treatment (month) Duration of PD symptoms (month) Levodopa equivalent dosage/day (mg) Hoehn & Yahr stage

45 70.02±6.46 687.15±401.85

15.21±12.87 17.00±12.34

21 25.58±12.15 30.38±11.64 591.39±319.08

1.99±0.93

33 66.73±9.74 677.54±431.13

13.02±10.27 18.59±25.14

20 42.09±45.08 41.29±45.65 790.48±512.93

2.47±0.87

48 66.23±11.83 654.14±257.24

17.01±14.82 12.52±4.19

0 ND ND ND ND

0.136 0.213 0.195 0.162 0.257 0.21 0.15 0.054 0.022 Value are expressed as mean±standard deviation. PD: idiopathic Parkinson's disease, HC: healthy control, ND: not done, Group 1:

levdopa alone-treated PD patients, Group 2: levodopa plus COMT-inhibitor PD patients. Independent t-tests were used to compare continuous variable between each groups. *One-way Post-hoc comparison: Group 1=Group 2=Healthy control.

Pearson chi-square analysis was used.

by using H & Y stage.

In regarding to effect of COMT-I, no correlation was found between plasma hcy levels in group 1 and those in group 2. In addition, there was no significant difference of number of polyneuropathy between group 1 and group 2. However, group 2 showed longer duration of treatment and more severity of motor symptoms than group 1.

These findings are presented in Table 2.

DISCUSSION

In this study, we ascertained a significant correlation between plasma hcy levels and polyneuropathy in PD patients. Recently, it has been discovered that pharmaco-

therapeutic management of PD with levodopa is asso-

ciated with elevated hcy.

The hcy may increase the sus-

ceptibility to mitochondria toxins, contribute to free radi-

cal formation, exert glutaminergic-associated neurotoxicity,

induce inflammation, and impair DNA repair mechanism.

The hcy accumulation may also occur with deficiency or

alteration in the metabolism of cobalamin, which can lead

to polyneuropathy.

Another reports suggested vascular

hypothesis due to increased serum hcy level. Vascular and

neural diseases are closely related. Blood vessels depend on

normal nerve function, and nerves depend on adequate

blood flow. The first pathological change in the micro-

vasculature is vasoconstriction. As the disease progresses,

neuronal dysfunction correlates closely with the develop-

ment of vascular abnormalities, such as capillary basement membrane thickening and endothelial hyperplasia, which contribute to diminished oxygen tension and hypoxia.

Neuronal ischemia is a well-established characteristic of neuropathy.

Increased hcy level has related to decreased production of nitric oxide resulting in state of vasocon- striction.

Previous studies suggested that elevated hcy levels in levodopa-treated PD might be caused by levodopa treat- ment, rather than by the disease itself.

The present study also showed that hcy levels in PDP were elevated more than those in the controls. However, the present study showed no difference between hcy levels in PDWo and those in the controls. Unlike previous clinical studies, these findings could suggest that only PD patients with polyneuropathy may be susceptible to daily levodopa ex- posure and consequent elevated hcy levels.

On the other hand, COMT-I is used currently in the treatment of PD. recent studies have also discussed poten- tial use of COMT-I to decrease hcy concentrations.

These findings support the hypothesis that inhibition of peripheral COMT by mean of COMT-I not only improves the bioavailability of levodopa due to a decrease in pe- ripheral degradation, but it can also lower the hcy levels.

Consequently, it was assumed that lower hcy level in- duced by COMT-I could prevent occurrence of neuro- pathy in PD patients. However, unlike above-mentioned previous studies, the present study showed that there are no relationship between hcy level and COMT-I. Further- more, we did not find any correlation between admin- istration of COMT-I and occurrence of polyneuropathy in PD. Therefore we could assume that pretreatment with COMT-I in PD patients did not prevent the effects of levodopa on hcy levels as well as the occurrence of poly- neuropathy in PD patients.

In conclusion, our findings agree with previous studies indicating that elevated hcy concentration in PD patients maybe results in occurrence of polyneuropathy, whereas

COMT-I show no preventive effect on involvement of pe- ripheral nerve system in PD patients. Therefore, we sug- gest that future longitudinal studies with a large number of patients are needed to clarify preventive effect of COMT-I on occurrence of polyneuropathy in PD patients and relationship between COMT-I and hcy concentration in PD patients.

REFERENCES

1. Park A, Stacy M. Non-motor symptoms in Parkinson's disease. J Neurol 2009;256(Suppl 3):293-8.

2. Schestatsky P, Kumru H, Valls-Sole J, Valldeoriola F, Marti MJ, Tolosa E, et al. Neurophysiologic study of central pain in patients with Parkinson disease. Neurology 2007;69:

2162-9.

3. Toth C, Breithaupt K, Ge S, Duan Y, Terris JM, Thiessen A, et al. Levodopa, methylmalonic acid, and neuropathy in idiopathic Parkinson disease. Ann Neurol 2010;68:28-36.

4. Rajabally YA, Martey J. Neuropathy in Parkinson disease:

prevalence and determinants. Neurology 2011;77:1947-50.

5. Lamberti P, Zoccolella S, Iliceto G, Armenise E, Fraddosio A, de Mari M, et al. Effects of levodopa and COMT inhibitors on plasma homocysteine in Parkinson's disease patients. Mov Disord 2005;20:69-72.

6. Nissinen E, Nissinen H, Larjonmaa H, Vaananen A, Helkamaa T, Reenila I, et al. The COMT inhibitor, en- tacapone, reduces levodopa-induced elevations in plasma ho- mocysteine in healthy adult rats. J Neural Transm 2005;112:

1213-21.

7. Toth C, Brown MS, Furtado S, Suchowersky O, Zochodne D.

Neuropathy as a potential complication of levodopa use in Parkinson's disease. Mov Disord 2008;23:1850-9.

8. Miranda-Massari JR, Gonzalez MJ, Jimenez FJ, Allende-Vigo MZ, Duconge J. Metabolic correction in the management of diabetic peripheral neuropathy: improving clinical results be- yond symptom control. Curr Clin Pharmacol 2011;6:260-73.

9. Tooke JE. Peripheral microvascular disease in diabetes.

Diabetes Res Clin Pract 1996;30(Suppl):61-5.

10. Urban PP, Wellach I, Faiss S, Layer P, Rosenkranz T, Knop K, et al. Subacute axonal neuropathy in Parkinson's disease with cobalamin and vitamin B6 deficiency under duodopa therapy. Mov Disord 2010;25:1748-52.

11. Zoccolella S, Lamberti P, Armenise E, de Mari M, Lamberti SV, Mastronardi R, et al. Plasma homocysteine levels in Parkinson's disease: role of antiparkinsonian medications.

Parkinsonism Relat Disord 2005;11:131-3.

▪ 국문요약 ▪

연구배경: 다발성말초신경병증은 최근에 파킨슨병에서 높은 유병율을 보이고 있다. 파킨슨병에서 호모시스테인의 혈 중농도는 레보도파의 치료로 인하여 증가될 수 있는데 이러한 레보도파의 대사는 COMT를 통해서 이루어 진다. 따 라서 COMT 억제제를 통해 레보도파의 대사를 억제하면 호모시스테인의 혈중농도를 억제할 수 있어 이를 통해 파 킨슨병에서의 다발성말초신경병증의 발생을 억제시킬 수 있으리라 생각되어 이 연구를 진행한다.

방법: 37명의 말초신경병증이 없는 파킨슨병환자와 41명의 다발성 말초신경병증을 가진 파킨슨병환자를 48명의 정상 군과 비교분석 하였다. 모든 파킨슨병 환자군은 신경생리검사를 시행하였고, 모든 연구 참여군에게는 혈중 호모시 스테인의 수치를 측정하여 각각의 군끼리 비교하였다. 그리고 COMT 억제제로 치료한 군과 사용하지 않은 군으로 파킨슨환자군을 나누어 혈중 호모시스테인농도와 말초신경병증여부를 비교 분석 하였다.

결과: 정상군과 말초신경병증이 동반되지 않은 파킨슨병군에 비해 호모시스테인 혈중농도는 다발성말초신경병증이 동반된 파킨슨병군에서 더 높게 나타났다. 하지만 COMT 억제제를 사용여부에 따른 두군의 의미 있는 차이는 보이 지 않았다.

결론: 본 연구에서 레보도파치료를 받은 파킨슨병 환자에서 혈중 호모시스테인의 수치가 정상군보다 증가된 소견을 보였으나 COMT 억제제는 파킨슨병에서 말초신경병증에 대한 의미 있는 영향력을 보여주지 못하였다.

중심단어: 파킨슨병, 다발성신경병증, COMT 억제제, 호모시스테인