A water extract of Mucuna pruriens provides long-term amelioration of parkinsonism with reduced risk for dyskinesias

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 M. 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 M. 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 anti-parkinsonian effects of a parenterally administered water extract of M. pruriens seed powder may provide a platform for future drug discoveries and novel treatment strategies in PD.

Figures

Fig. 1

Comparison of LD+BZ and MPE+BZ. (A) Group 1 (equivalent to 6mg/Kg LD) and Group 2 (equivalent to 4mg/Kg LD) showed significant amelioration of parkinsonism as shown by the stepping test when exposed to both LD+BZ and MPE+BZ (*p < 0.05 vs. post-lesion, **p < 0.01 vs. post-lesion). However, doses given to Group 3 (equivalent to 2mg/Kg LD) indicate that only MPE+BZ had significant relief of parkinsonism. (B) There was a dose-dependent severity of DID among the 3 groups. There was no significant difference within groups (***p < 0.001 Group 1 vs. Group 3; **p < 0.01 Group 2 MPE+BZ vs. Group 3; *p < 0.05 Group 2 LD+BZ vs. Group 3 LD+BZ).

Fig. 2

High doses of MPE alone. (A) Animals treated with MPE alone at 240mg/Kg MPE and 400mg/Kg MPE (equivalent to 12 mg/Kg and 20 mg/Kg LD) showed significant amelioration of parkinsonism in the stepping test (**p < 0.01 vs. post-lesion). (B) MPE caused significantly less DID than doses of LD+BZ and MPE+BZ (***p < 0.001 vs. LD+BZ and MPE+BZ).

Fig. 3

Long term effects of MPE alone at 400mg/Kg (equivalent to 20mg/Kg LD). (A) Significant amelioration of parkinsonism up to 90 mins post treatment in the stepping test (***p < 0.001 vs. post-lesion). (B) Almost complete restoration of forelimb usage with the vibrissae-evoked forelimb placement test after treatment (***p < 0.001 vs. post-lesion). (C) Posturing behavior as measured by the body axis bias test show less bias after drug exposure (*p < 0.05 vs. post-lesion). (D) Spontaneous forelimb usage bias was significantly decreased as shown by the cylinder test at 30 mins but not at 60 and 90 mins (**p < 0.01 vs. post-lesion). (E) Dyskinesia profiles were significantly less with MPE alone at 5 mins, 15 mins, and 30 mins after drug exposure compared to LD+BZ and MPE+BZ (**p < 0.01 vs. LD+BZ, ***p < 0.001 vs. MPE+BZ and LD+BZ at 15 and 30 mins).

Fig. 4

Comparison of LD alone (24mg/Kg), MPE alone at 480mg/Kg (equivalent to 24mg/Kg LD) and LD+BZ (6mg/Kg LD + 15mg/Kg BZ). (A) Significant amelioration of parkinsonism in the stepping test for MPE alone and LD+BZ (*p < 0.05 vs. post-lesion, ***p < 0.001 vs. post-lesion) but not with LD alone. (B) Significant restoration of forelimb usage with the vibrissae-evoked forelimb placement test after MPE alone and LD+BZ but not with LD alone (*p < 0.05, **p < 0.01, ***p < 0.001 vs. post-lesion).

Fig. 5

Dyskinesia priming effects of LD+BZ and MPE alone. (A) Group A first received LD+BZ (6mg/Kg LD + 15mg/Kg BZ) then MPE alone (480mg/Kg - equivalent to 24mg/Kg LD). (B) Group B was first treated with MPE alone at 480mg/Kg (equivalent to 24mg/Kg LD) then immediately treated with LD+BZ (6mg/kg LD + 15mg/Kg BZ)(*p < 0.05, **p < 0.01, ***p < 0.001 between treatment time points).