Ayurvedic constitution (prakruti) identifies risk factor of developing Parkinson's disease.

OBJECTIVE: The ancient Indian medical system, Ayurveda, is the oldest scientifically based system of medicine in the world. According to Ayurvedic concepts, there are 3 humors or Doshas: Vata, Pitta, and Kapha. The combination of these Doshas in varying degrees leads to one's constitution, referred to as Prakruti. Prakruti determines one's physical, physiologic, and mental character and disease vulnerability. This clinical study was undertaken to determine the constitutional typing of individuals with known idiopathic Parkinson's disease (PD) compared with that of nonparkinsonian controls. This study sought to validate the ancient observation that persons of Vata Prakruti are at risk for nervous system diseases. PD was used as a test case because the exact cause is not known. METHODS: Patients with established PD (n=75) and closely related controls with no known neurologic disease (n=73) were assessed for their Ayurvedic constitution (Prakruti). An Ayurvedic constitutional assessment form and an independent Ayurvedic clinical assessment were used in the patients and controls. RESULTS: The total mean score (±standard deviation) for Vata was 11.0±3.9 in patients with PD and 6.9±3.0 in controls. This finding was significant (p<0.0001), indicating that the incidence of PD is highest in those with Vata Prakruti. The incidence of PD was higher in men than in women. CONCLUSIONS: Knowledge gained from this study may be helpful in identifying the vulnerable population, delaying the onset of symptoms, or slowing disease progression or development of treatment-related complications by keeping Vata in balance through anti-Vata diet and lifestyle changes as prescribed in Ayurveda.

Mutations in SLC20A2 are a major cause of familial idiopathic basal ganglia calcification.

Familial idiopathic basal ganglia calcification (IBGC) or Fahr's disease is a rare neurodegenerative disorder characterized by calcium deposits in the basal ganglia and other brain regions, which is associated with neuropsychiatric and motor symptoms. Familial IBGC is genetically heterogeneous and typically transmitted in an autosomal dominant fashion. We performed a mutational analysis of SLC20A2, the first gene found to cause IBGC, to assess its genetic contribution to familial IBGC. We recruited 218 subjects from 29 IBGC-affected families of varied ancestry and collected medical history, neurological exam, and head CT scans to characterize each patient's disease status. We screened our patient cohort for mutations in SLC20A2. Twelve novel (nonsense, deletions, missense, and splice site) potentially pathogenic variants, one synonymous variant, and one previously reported mutation were identified in 13 families. Variants predicted to be deleterious cosegregated with disease in five families. Three families showed nonsegregation with clinical disease of such variants, but retrospective review of clinical and neuroimaging data strongly suggested previous misclassification. Overall, mutations in SLC20A2 account for as many as 41% of our familial IBGC cases. Our screen in a large series expands the catalog of SLC20A2 mutations identified to date and demonstrates that mutations in SLC20A2 are a major cause of familial IBGC. Non-perfect segregation patterns of predicted deleterious variants highlight the challenges of phenotypic assessment in this condition with highly variable clinical presentation.

The Antiparkinsonian and Antidyskinetic Mechanisms of Mucuna pruriens in the MPTP-Treated Nonhuman Primate.

Chronic treatment with levodopa (LD) in Parkinson's disease (PD) can cause drug induced dyskinesias. Mucuna pruriens endocarp powder (MPEP) contains several compounds including natural LD and has been reported to not cause drug-induced dyskinesias. We evaluated the effects of Mucuna pruriens to determine if its underlying mechanistic actions are exclusively due to LD. We first compared MPEP with and without carbidopa (CD), and LD+CD in hemiparkinsonian (HP) monkeys. Each treatment ameliorated parkinsonism. We then compared the neuronal firing properties of the substantia nigra reticulata (SNR) and subthalamic nucleus (STN) in HP monkeys with MPEP+CD and LD+CD to evaluate basal ganglia circuitry alterations. Both treatments decreased SNR firing rate compared to HP state. However, LD+CD treatments significantly increased SNR bursting firing patterns that were not seen with MPEP+CD treatments. No significant changes were seen in STN firing properties. We then evaluated the effects of a water extract of MPEP. Oral MPWE ameliorated parkinsonism without causing drug-induced dyskinesias. The distinctive neurophysiological findings in the basal ganglia and the ability to ameliorate parkinsonism without causing dyskinesias strongly suggest that Mucuna pruriens acts through a novel mechanism that is different from that of LD.

Differential effects of dopaminergic neurotoxins on DNA cleavage.

AIMS: Environmental and endogenous toxins are considered to increase the risk of dopaminergic neurodegeneration. Parkinson's disease is a neurological disorder occurring due to the death of dopaminergic neurons in substantia nigra. The present study investigated the effect of parkinsonian neurotoxins salsolinol and rotenone on plasmid and genomic DNA. MAIN METHODS: Salsolinol or rotenone (0-1000 µM) alone or in presence of divalent metals (copper or iron) was incubated with plasmid DNA pBR322 (1 µg) or calf thymus DNA (1 µg). In order to study their effects on restriction endonuclease sites, the plasmid DNA was incubated with the neurotoxins (salsolinol or rotenone), extracted and subjected to restriction enzyme digestion (BamHI, EcoRV, HindIII, SalI). KEY FINDINGS: Exposure of rotenone or salsolinol alone to the plasmid or calf thymus DNA did not induce any strand scission or damage. However, salsolinol in the presence of divalent copper induced strand scission and damage in both plasmid and genomic DNA. All of the tested restriction endonucleases linearized the plasmid DNA pre-treated with salsolinol or rotenone suggesting that these neurotoxins did not selectively damage the restriction enzyme sites in the DNA. SIGNIFICANCE: The above observations suggest that salsolinol and rotenone differentially interact with DNA in inducing damage in the presence of copper, and behave similarly in their binding to DNA by not damaging the selected restriction endonuclease cleavage sites. CONCLUSION: Risk for neuronal degeneration can be significantly augmented by the environmental and endogenous toxins in the presence of various metals due to their deleterious effects on DNA.

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

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.

Centella asiatica extract selectively decreases amyloid beta levels in hippocampus of Alzheimer's disease animal model.

PSAPP mice expressing the 'Swedish' amyloid precursor protein and the M146L presenilin 1 mutations are a well-characterized model for spontaneous amyloid beta plaque formation. Centella asiatica has a long history of use in India as a memory enhancing drug in Ayurvedic literature. The study investigated whether Centella asiatica extract (CaE) can alter the amyloid pathology in PSAPP mice by administering CaE (2.5 or 5.0 g/kg/day) starting at 2 months of age prior to the onset of detectable amyloid deposition and continued for either 2 months or 8 months. A significant decrease in amyloid beta 1-40 and 1-42 was detectable by ELISA following an 8 month treatment with 2.5 mg/kg of CaE. A reduction in Congo Red stained fibrillar amyloid plaques was detected with the 5.0 mg/kg CaE dose and long-term treatment regimen. It was also confirmed that CaE functions as an antioxidant in vitro, scavenging free radicals, reducing lipid peroxidation and protecting against DNA damage. The data indicate that CaE can impact the amyloid cascade altering amyloid beta pathology in the brains of PSAPP mice and modulating components of the oxidative stress response that has been implicated in the neurodegenerative changes that occur with Alzheimer's disease.

Antiparkinson drug--Mucuna pruriens shows antioxidant and metal chelating activity.

Parkinson's disease is a neurodegenerative disorder for which no neurorestorative therapeutic treatment is currently available. Oxidative stress plays an important role in the pathophysiology of Parkinson's disease. The ancient Indian medical system, Ayurveda, traditionally uses Mucuna pruriens to treat Parkinson's disease. In our earlier studies, Mucuna pruriens has been shown to possess antiparkinson and neuroprotective effects in animal models of Parkinson's disease. The antioxidant activity of Mucuna pruriens was demonstrated by its ability to scavenge DPPH radicals, ABTS radicals and reactive oxygen species. Mucuna pruriens significantly inhibited the oxidation of lipids and deoxyribose sugar. Mucuna pruriens exhibited divalent iron chelating activity and did not show any genotoxic/mutagenic effect on the plasmid DNA. These results suggest that the neuroprotective and neurorestorative effect of Mucuna pruriens may be related to its antioxidant activity independent of the symptomatic effect. In addition, the drug appears to be therapeutically safe in the treatment of patients with Parkinson's disease.

Anti-Parkinson botanical Mucuna pruriens prevents levodopa induced plasmid and genomic DNA damage.

Levodopa is considered the 'gold standard' for the treatment of Parkinson's disease. However, a serious concern is dyskinesia and motor fluctuation that occurs after several years of use. In vitro experiments have shown that in the presence of divalent copper ions, levodopa may induce intense DNA damage. Mucuna pruriens cotyledon powder (MPCP) has shown anti-parkinson and neuroprotective effects in animal models of Parkinson's disease that is superior to synthetic levodopa. In the present study two different doses of MPCP protected both plasmid DNA and genomic DNA against levodopa and divalent copper-induced DNA strand scission and damage. It exhibited chelation of divalent copper ions in a dose-dependent manner. The copper chelating property may be one of the mechanisms by which MPCP exerts its protective effects on DNA.

Neuroprotective mechanisms of ayurvedic antidementia botanical Bacopa monniera.

Alzheimer's disease is a neurodegenerative disorder characterized by progressive dementia. Bacopa monniera is described in the Ayurvedic Materia Medica, as a therapeutically useful herb for the treatment of cognitive impairment, thus supporting its possible anti-Alzheimer's properties. Our studies have shown that Bacopa monniera reduces beta-amyloid deposits in the brain of an Alzheimer's disease animal model. The objective of this study was to establish the presence of endogenous substances in Bacopa monniera extract (BmE) that will impact components of the oxidative stress cascade such as the reduction of divalent metals, scavenging of reactive oxygen species, alterations of lipoxygenase activity and hydrogen peroxide-induced lipid peroxidation. The extract contained polyphenols and sulfhydryl contents suggestive of endogenous antioxidant activity. The results demonstrated that BmE reduced divalent metals, dose-dependently scavenged reactive oxygen species, decreased the formation of lipid peroxides and inhibited lipoxygenase activity. These data combined with our previous studies that have shown that BmE treatment reduces beta-amyloid levels in the brain of an Alzheimer's disease doubly transgenic mouse model of rapid amyloid deposition (PSAPP mice) suggesting mechanisms of action relevant to the treatment of Alzheimer's disease.

Bacopa monniera extract reduces amyloid levels in PSAPP mice.

PSAPP mice expressing the "Swedish" amyloid precursor protein and M146L presenilin-1 mutations are a well-characterized model for spontaneous amyloid plaque formation. Bacopa monniera has a long history of use in India as an anti-aging and memory-enhancing ethnobotanical therapy. To evaluate the effect of Bacopa monniera extract (BME) on amyloid (Abeta) pathology in PSAPP mice, two doses of BME (40 or 160 mg/kg/day) were administered starting at 2 months of age for either 2 or 8 months. Our present data suggests that BME lowers Abeta 1-40 and 1-42 levels in cortex by as much as 60%, and reverses Y-maze performance and open field hyperlocomotion behavioral changes present in PSAPP mice. The areas encompassed by Congo Red-positive fibrillar amyloid deposits, however, were not altered by BME treatment. The data suggest that BME has potential application in Alzheimer's disease therapeutics.

Trichopus zeylanicus combats fatigue without amphetamine-mimetic activity.

Chronic fatigue is a complex and little understood symptom for which there is no safe and effective pharmacotherapy. The present study was conducted to investigate the effectiveness of Trichopus zeylanicus whole plant powder on fatigue in young Sprague Dawley rats, and aged normal and long-living mutant Ames dwarf mice. Fatigue was evaluated by subjecting the animals to a forced swim test. Trichopus zeylanicus (250 and 500 mg/kg) treated young Sprague-Dawley rats resisted fatigue at a significant level (p < 0.005) compared with controls by an extended swim time in the forced swim test. Oral Trichopus zeylanicus (500 mg/kg) treatment for 2 weeks significantly increased the mobility time in the aged mutant (p < 0.05) and normal mice (p < 0.01) and significantly increased the swim time in the forced swim test in the aged normal mice (p < 0.05). Amphetamine-mimetic activity in Trichopus zeylanicus was excluded by suitable tests. These results show that Trichopus zeylanicus whole plant powder has anti-fatigue effects in young Sprague-Dawley rats and aged normal and mutant Ames dwarf mice providing scientific evidence for the Kani tribal practice in India.

Botanical therapies in chronic fatigue.

Chronic fatigue often occurs in aging and in various neurological, psychiatric and systemic diseases. The available therapies in modern medicine are limited. The exploration of potential alternative therapies from traditional medicine is reviewed, as there are several botanicals with experimental evidence of efficacy based on animal models and clinical studies.

Antioxidant and DNA protecting properties of anti-fatigue herb Trichopus zeylanicus.

Chronic fatigue is considered a complex symptom for which currently there is no curative treatment available. Oxidative stress plays an important role in the etiology of fatigue and antioxidant treatment might be a valuable therapeutic approach. The Kani, a tribal high altitude living population in southern India, traditionally use the seeds of Trichopus zeylanicus to combat fatigue. In this study, the antioxidant properties of Trichopus zeylanicus were established on free radicals (DPPH and ABTS), its ability to reduce iron, lipoxygenase activity and hydrogen peroxide-induced lipid peroxidation. The effects of Trichopus zeylanicus on reactive oxygen species induced plasmid DNA (pBR322) cleavage were also investigated. Trichopus zeylanicus significantly scavenged free radicals, reduced lipid peroxidation and inhibited lipoxygenase activity. Trichopus zeylanicus also exhibited iron-chelating activity and inhibited reactive oxygen species induced DNA damage. Trichopus zeylanicus contains NADH, polyphenols and sulfhydryl compounds, which have the ability to scavenge reactive oxygen species suggesting that the antioxidant activity may be an important mechanism of action of Trichopus zeylanicus to combat fatigue.

Botanical therapies in sexual dysfunction.

Sexual dysfunction is a serious medical and social symptom that occurs in 10%-52% in men and 25%-63% in women. Numerous central and peripheral neural circuits control sexual activity. Impairment of one or more of these functional circuits may have a significant impact on personal, social and biological relationships. Although several aspects of sexual motivation and performance are known, a complete picture of the various factors that control human sexual activity is still unknown. The available drugs and treatments have limited efficacy, unpleasant side effects and contraindications in certain disease conditions. A variety of botanicals are known to have a potential effect on the sexual functions, supporting older claims and offering newer hopes. This review, while evaluating various factors that control sexual function, identifies a variety of botanicals that may be potentially useful in treating sexual dysfunction.

What is and what is not 'Fahr's disease'.

Bilateral almost symmetric calcification involving striatum, pallidum with or without deposits in dentate nucleus, thalamus and white matter is reported from asymptomatic individuals to a variety of neurological conditions including autosomal dominant inheritance to pseudo-pseudohypoparathyroidism. While bilateral striopallidodentate calcinosis is commonly referred to as 'Fahr's disease' (a misnomer), there are 35 additional names used in the literature for the same condition. Secondary bilateral calcification is also reported in a variety of genetic, developmental, metabolic, infectious and other conditions. In autosomal dominant or sporadic bilateral striopallidodentate calcinosis no known calcium metabolism abnormalities are known to date. Clinically, parkinsonism or other movement disorders appear to be the most common presentation, followed by cognitive impairment and ataxia. When presence of movement disorder, cognitive impairment and ataxia are present, a computed tomography scan of the head should be considered to rule-in or rule-out calcium deposits. Calcium and other mineral deposits cannot be linked to a single chromosomal locus. Further genetic studies to identify the chromosomal locus for the disease are in progress.

Neuroprotective effects of the antiparkinson drug Mucuna pruriens.

Mucuna pruriens possesses significantly higher antiparkinson activity compared with levodopa in the 6-hydroxydopamine (6-OHDA) lesioned rat model of Parkinson's disease. The present study evaluated the neurorestorative effect of Mucuna pruriens cotyledon powder on the nigrostriatal tract of 6-OHDA lesioned rats. Mucuna pruriens cotyledon powder significantly increased the brain mitochondrial complex-I activity but did not affect the total monoamine oxidase activity (in vitro). Unlike synthetic levodopa treatment, Mucuna pruriens cotyledon powder treatment significantly restored the endogenous levodopa, dopamine, norepinephrine and serotonin content in the substantia nigra. Nicotine adenine dinucleotide (NADH) and coenzyme Q-10, that are shown to have a therapeutic benefit in Parkinson's disease, were present in the Mucuna pruriens cotyledon powder. Earlier studies showed that Mucuna pruriens treatment controls the symptoms of Parkinson's disease. This additional finding of a neurorestorative benefit by Mucuna pruriens cotyledon powder on the degenerating dopaminergic neurons in the substantia nigra may be due to increased complex-I activity and the presence of NADH and coenzyme Q-10.

Effect of antiparkinson drug HP-200 (Mucuna pruriens) on the central monoaminergic neurotransmitters.

HP-200, which contains Mucuna pruriens endocarp, has been shown to be effective in the treatment of Parkinson's disease. Mucuna pruriens endocarp has also been shown to be more effective compared to synthetic levodopa in an animal model of Parkinson's disease. The present study was designed to elucidate the long-term effect of Mucuna pruriens endocarp in HP-200 on monoaminergic neurotransmitters and its metabolite in various regions of the rat brain. HP-200 at a dose of 2.5, 5.0 or 10.0 g/kg/day was mixed with rat chow and fed daily ad lib to Sprague-Dawley rats (n = 6 for each group) for 52 weeks. Controls (n = 6) received no drug. Random assignment was made for doses and control. The rats were sacrificed at the end of 52 weeks and the neurotransmitters were analyzed in the cortex, hippocampus, substantia nigra and striatum. Oral administration of Mucuna pruriens endocarp in the form of HP-200 had a significant effect on dopamine content in the cortex with no significant effect on levodopa, norepinephrine or dopamine, serotonin, and their metabolites- HVA, DOPAC and 5-HIAA in the nigrostriatal tract. The failure of Mucuna pruriens endocarp to significantly affect dopamine metabolism in the striatonigral tract along with its ability to improve Parkinsonian symptoms in the 6-hydorxydopamine animal model and humans may suggest that its antiparkinson effect may be due to components other than levodopa or that it has an levodopa enhancing effect.

Malignant melanoma and levodopa in Parkinson's disease: causality or coincidence?

Levodopa is the major drug used in the treatment of patients with Parkinson's disease. However, levodopa continues to be 'contra-indicated' for patients with Parkinson's disease associated with malignant melanoma. Case reports have suggested that levodopa has a causal relationship with malignant melanoma due to their shared dopamine biochemical pathway. Clinical characteristics of 54 patients with both Parkinson's disease and melanoma were analyzed (43 cases from the literature and 11 from our institution). The results suggest that the occurrence of both Parkinson's disease and melanoma in these patients is coincidental rather than causal. It did not appear that the Parkinson's disease patients on levodopa therapy were predisposed to melanoma, nor did levodopa therapy appear to exaggerate melanoma if it were previously present.

Analyses of nursing home residents with Parkinson's disease using the minimum data set.

This study profiles over 79,000 nursing home residents with Parkinson's disease (PD) at admission using the 'minimum data set'. Results show that residents with PD averaged 79.7 years of age at admission and 48.4% were male. They tended to be physically dependent, as well as cognitively impaired. More than one in three had fallen in the prior 30 days. There was a high prevalence of dementia and depression. Ninety percent of these residents did not receive active or passive range of motion care and less than 10% had been recently evaluated by a licensed mental health specialist. To enhance the quality of life for nursing home residents with PD, appropriate and adequate rehabilitative, mental health, and cognitive care need to be implemented.