A good one too. Full text as well=

A Water Extract of Mucuna pruriens Provides Long-Term Amelioration of Parkinsonism with Reduced Risk for Dyskinesias

Parkinsonism Relat Disord. Author manuscript; available in PMC 2011 August 1.
Published in final edited form as:
Parkinsonism Relat Disord. 2010 August; 16(7): 458–465.
Published online 2010 May 31. doi: 10.1016/j.parkreldis.2010.04.015

PMCID: PMC2909380

Abstract
Dopaminergic anti-parkinsonian medications, such as levodopa (LD) cause drug-induced dyskinesias (DID) in majority of patients with Parkinson's disease (PD). Mucuna pruriens, a legume extensively used in Ayurveda to treat PD, is reputed to provide anti-parkinsonian benefits without inducing DID. We compared the behavioral effects of chronic parenteral administration of a water extract of Mucuna pruriens seed powder (MPE) alone without any additives, MPE combined with the peripheral dopa-decarboxylase inhibitor (DDCI) benserazide (MPE+BZ), LD+BZ and LD alone without BZ in the hemiparkinsonian rat model of PD. A battery of behavioral tests assessed by blinded investigators served as outcome measures in these randomized trials. In experiment 1, animals that received LD+BZ or MPE+BZ at high (6mg/Kg) and medium (4mg/Kg) equivalent doses demonstrated significant alleviation of parkinsonism, but, developed severe dose-dependent DID. LD+BZ at low doses (2mg/Kg) did not provide significant alleviation of parkinsonism. In contrast, MPE+BZ at an equivalent low dose significantly ameliorated parkinsonism. In experiment 2, MPE without any additives (12mg/Kg and 20mg/Kg LD equivalent dose) alleviated parkinsonism with significantly less DID compared to LD+BZ or MPE+BZ. In experiment 3, MPE without additives administered chronically provided long-term anti-parkinsonian benefits without causing DID. In experiment 4, MPE alone provided significantly more behavioral benefit when compared to the equivalent dose of synthetic LD alone without BZ. In experiment 5, MPE alone reduced the severity of DID in animals initially primed with LD+BZ. These findings suggest that Mucuna pruriens contains water soluble ingredients that either have an intrinsic DDCI-like activity or mitigate the need for an add-on DDCI to ameliorate parkinsonism. These unique long-term antiparkinsonian effects of a parenterally administered water extract of Mucuna pruriens seed powder may provide a platform for future drug discoveries and novel treatment strategies in PD.
Keywords: basal ganglia, 6-hydroxydopamine (6-OHDA), nigrostriatal degeneration, movement disorders, complementary and alternative medicine

Other Sections▼

INTRODUCTION
Chronic use of current anti-parkinsonian medications causes disabling abnormal involuntary movements known as drug-induced dyskinesias (DID) in majority of patients with advanced Parkinson's disease (PD) that are expensive and difficult to treat [1]. Hence, newer anti-PD treatments that reduce or eliminate the risk of DID are much sought after [2]. The dried endocarp powder of the Mucuna pruriens bean is used to treat parkinsonism (Kampavata) in the Ayurvedic Indian medical system [3, 4]. Review of the Ayurvedic literature and current Ayurvedic practioners indicate that PD patients treated with Mucuna pruriens do not develop DID. Mucuna pruriens has been shown to contain natural levodopa (LD, [5–11]), which has been presumed to be the mechanism of its action in PD. Under this presumption, many experimental studies have concomitantly administered Mucuna pruriens with a dopa-decarboxylase inhibitor (DDCI) like benserazide (BZ, [12]) or carbidopa (CD, [13]); or used subjects that concurrently took a DDCI as part of their treatment regimen without adequate washout [14]. However, no DDCI is utilized in Ayurveda with Mucuna pruriens treatment. Therefore, in the present study, we assessed the antiparkinsonian effects of a water extract of Mucuna pruriens seed powder (MPE) for the amelioration of parkinsonism in the 6-hydroxydopamine (6-OHDA)-lesioned hemiparkinsonian (HP) rat model of PD. We show that this water extract has a unique anti-PD effect that does not require the addition of a DDCI and that MPE is more effective and has reduced severity of DID than conventional LD+DDCI therapy.



DISCUSSION
Our study is the first to demonstrate that a simple water extract of Mucuna pruriens endocarp powder with no additives has a superior effect to the combination of MPE+BZ on parkinsonism and that MPE alone is superior to LD alone or LD+BZ combinational therapy in terms of efficacy of ameliorating parkinsonism with dramatically reduced risk for DID. This result is consistent with the observations by Ayurvedic practitioners that PD patients treated with Mucuna pruriens alone do not exhibit any significant DID. Interestingly, we found that addition of BZ to MPE induced severe DID. The most probable explanation for our findings is that the inhibitory effect of BZ on peripheral DDC allowed the abrupt and rapid increased transport of natural LD contained in MPE across the blood brain barrier without being inactivated in the peripheral blood. This increased availability of LD to the brain is the most likely cause of the severity of DID in MPE+BZ treated animals. An alternative explanation is that the natural form of LD contained in MPE is in combination with one or more natural agents that protect it from rapid decarboxylation by DDC and allow gradual protected transport across the blood brain barrier. A third possibility is that MPE may have natural anti-dyskinetic agents that prevents or mitigates DID and that the addition of BZ to MPE negates these beneficial anti-DID compounds. These hypotheses are the topic of ongoing fractionation studies using MPE. Previous reports in the rat have suggested that chronic Mucuna pruriens treatment has no significant effect on LD content or dopamine and its metabolites in the nigra or striatum [25]. However, these experiments were performed in a manner that did not directly test whether LD levels in the brain were acutely altered after administration of Mucuna pruriens. In these studies, animals were fed orally Mucuna pruriens powder mixed with rat chow nightly for 52 weeks then sacrificed in the morning several hours after the last drug exposure. Therefore, it is possible that nigrostriatal catecholamine content was higher immediately after exposure than it was at the time of brain examination. Future studies that measure nigrostriatal LD and dopamine content in a strict time course post-drug administration will be necessary to further delineate whether addition of BZ or other DDCI to MPE will cause a rapid increase of LD and dopamine in the striatum. Moreover, unlike other preparations derived from Mucuna pruriens that required significant proprietary processing, we utilized a simple water extract of Mucuna pruriens dried endocarp that can be stored up to 1 week in a refrigerator and show that such an extract can provide significant behavioral amelioration of parkinsonism with minimal risk for DID in a sustained fashion.
We observed an apparent bimodal time course of behavioral benefit in the stepping and vibrissae-evoked forelimb placement tests when HP rats were treated with LD+BZ (Fig. 4A and B) and LD alone (Fig. 4B) with an initial benefit noted at 30 mins post-treatment, followed by a reduction in benefit at 60 mins post-treatment and resumption of benefit at 90 mins post-treatment. The behavioral rater and independent blinded evaluations of the tapes did not reveal any DID that significantly interfered with the ability of the animals to perform these behavioral tasks. A previous study evaluating adjusting steps (modified step test) in 6-OHDA lesioned rats at a time course of 15 and 45 mins post-LD (6mg/Kg) treatments reported more behavioral benefit at the 45 mins time point than the 15 mins time point [12]. The differences in results between this study and the present study may be due to the use of different evaluation time points (45 mins vs. 60 mins), shorter stepping test procedure (70cm/4s vs. 90cm/5s) and/or a lower dose of BZ (6mg/Kg vs. 15mg/Kg). Thus, the reasons for this apparent bimodal time course are unclear. One possibility is that neurocognitive toxic effects of LD and LD+BZ that we did not specifically test interfered with the ability of these animals to perform the stepping and vibrissae-evoked forelimb placement tests at 60 minutes. Future studies that include neurocognitive testing may help with comparison of MPE to LD and LD+BZ in the non-motor aspects of PD.
Previous studies using a variety of formulations of Mucuna pruriens have suggested that there are anti-PD compounds besides LD in this naturally occurring seed [4, 12–14, 25–28]. However, these previous studies did not recognize the water soluble nature of these compounds and the notion that MPE is best when used by itself with no additives of DDCI. Early clinical trials of Mucuna pruriens for PD [26, 28] suggested the presence of other compounds besides LD in Mucuna pruriens endocarp powder provide anti-PD effects. In the HP-200 (a proprietary Mucuna pruriens formulation) study, two separate and distinctive populations of PD patients were recruited; the first group of patients that had PD for several years and had used anti-PD medications for several years and a second group of patients who were drug naïve newly diagnosed PD patients. The first group of patients did not have any drug washout prior to enrollment. Therefore, the effects of HP-200 by itself could only be assessed in the second group of drug naïve early PD patients, who do not develop DID. Hence the effects of Mucuna pruriens on DID could not be properly assessed in this study [26]. However, they noted that the drug naïve cohort got substantial benefits despite being on very low doses of HP-200 that contained very small quantities of natural LD, leading them to conclude that additional anti-PD agents were contained in HP-200. Vaidya et. al. also made a similar observation in their PD patients treated with Mucuna pruriens [28]. However, these investigators bought Mucuna pruriens from multiple local Ayurvedic drug providers that are known to vary in quality and used a clinical rating method that has subsequently been shown to be deficient. Moreover, these investigators allowed the use of concomitant medications without any restrictions. Therefore, critics had attributed the anti-PD effects of Mucuna pruriens in these studies mainly to the naturally present LD in the seed and not to other compounds found in Mucuna pruriens.
A subsequent preclinical behavioral study evaluated the rotational effects of Mucuna pruriens in the 6-OHDA lesioned HP rat by exposing animals orally to equivalent doses of Mucuna pruriens and LD with and without CD [13]. In this study, Mucuna pruriens + CD treated HP rats displayed significantly more contralateral rotations than equivalent doses of synthetic LD+CD. When animals were exposed to Mucuna pruriens alone, minor contralateral rotations were noted. However, these investigators did not evaluate any other behavioral effects of Mucuna pruriens. A recent study of a proprietary formulation of Mucuna pruriens that reportedly contains a higher (12.5%) concentration of natural LD was tested in combination with BZ in HP rats using behavioral tests. These investigators did not test spontaneous behaviors (e.g. cylinder test) and did not use standardized DID scales. These investigators noted that their Mucuna pruriens formulation (in combination with BZ) was more efficacious and produced a lower incidence of involuntary movements than the equivalent LD+BZ [12]. However, they did not test their formulation without added BZ.
Nagashayana et. al. evaluated Mucuna pruriens mixed with other Ayurvedic treatments in PD patients [27] who were taken off all medications 15 days prior to enrollment. The first group of patients underwent cleansing and palliative therapy while the second group underwent only palliative treatment. Only the first group exhibited significant symptomatic improvement. These findings support our results that Mucuna pruriens treatment may be more effective when the patients do not have other competing DDCI in the system and a complete washout of any DDCI may enhance the effectiveness of Mucuna pruriens. Katzenschlager and colleagues also report effectiveness of a proprietary formulation of Mucuna pruriens in 8 advanced PD patients [14]. They showed that Mucuna pruriens treated patients had a more rapid onset of action and longer “on” time when compared to LD+CD treatment of comparative doses. This single dose study was a 4-hour evaluation of this formulation of Mucuna pruriens that contained several additives. These patients were not completely washed off their existing anti-PD medications that included DDCI. Thus, this 4-hour study could not truly evaluate the effects of Mucuna pruriens (without any DDCI) on PD symptoms including the risk of causing DID. This could be an explanation for why they did not find any differences in DID between Mucuna pruriens treatment and the LD+CD treatment in their patients. Moreover, withdrawal of anti-PD medications in patients with advanced disease has morbidity and can lead to potential fatality. Therefore, a clinical research trial of Mucuna pruriens or MPE in advanced PD patients without any confounding DDCI would be extremely difficult to execute.
The present study addresses several drawbacks of previous studies by using a well-characterized animal model of PD, treatment dosing similar to what is used in PD patient population, single drug treatment with no confounding concomitant medications or additives, a full battery of validated behavioral tests including DID assessments, and histological confirmation of uniform nigrostriatal deficits in all animals. Furthermore, we demonstrate that MPE is effective with duration of action that exceed oral Mucuna pruriens and is advantageous over conventional oral anti-parkinsonian medications. Gastrointestinal dysfunction is a common problem in PD and may cause issues with absorption of oral treatments [29]. To avoid problems with oral consumption and potential issues with gastrointestinal absorption, we used a water extract of the Mucuna pruriens seed powder parenterally administered. Future studies are necessary to identify the water-soluble anti-dyskinetic and anti-parkinsonian compounds that are present in MPE.