Pyridoxine and Levodopa in The Treatment of Parkinsonism

Yahr, Melvin D.

doi:10.1001/jama.1972.03200060085023

Cited by 12 publications

(4 citation statements)

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“…Treatment strategies of PD with pyridoxine were published as early as 1954, but abandoned because of metabolic interaction with the therapeutically more potent L-DOPA in the periphery. 26 Today, this effect can be negated in the presence of a peripheral DDC inhibitor and a recent study showed that high doses of pyridoxine therapy (at 400mg/day) might be beneficial for the treatment of PD. 24 Independent of L-DOPA therapy, a prospective, population-based cohort study showed that dietary vitamin B6 might decrease the risk of PD, although this effect was restricted to smokers.…”

Section: Discussionmentioning

confidence: 99%

Single‐cell expression profiling of dopaminergic neurons combined with association analysis identifies pyridoxal kinase as Parkinson's disease gene

Elstner

Morris

Heim

et al. 2009

Annals of Neurology

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Objective-The etiology of Parkinson disease (PD) is complex and multifactorial, with hereditary and environmental factors contributing. Monogenic forms have provided molecular clues to disease mechanisms but genetic modifiers of idiopathic PD are still to be determined.Methods-We carried out whole-genome expression profiling of isolated human substantia nigra (SN) neurons from patients with PD vs. controls followed by association analysis of tagging single-nucleotide polymorphisms (SNPs) in differentially regulated genes. Association was investigated in a German PD sample and confirmed in Italian and British cohorts.Results-We identified four differentially expressed genes located in PD candidate pathways, ie, MTND2 (mitochondrial, p = 7.14 × 10 −7 ), PDXK (vitamin B6/dopamine metabolism, p = 3.27 × 10 −6 ), SRGAP3 (axon guidance, p = 5.65 × 10 −6 ), and TRAPPC4 (vesicle transport, p = 5.81 × 10 −6 ). We identified a DNA variant (rs2010795) in PDXK associated with an increased risk of PD in the German cohort (p = 0.00032). This association was confirmed in the British (p = 0.028) and Italian (p = 0.0025) cohorts individually and reached a combined value of p = 1.2 × 10 −7 (odds ratio [OR], 1.3; 95% confidence interval [CI], 1.18-1.44).Interpretation-We provide an example of how microgenomic genome-wide expression studies in combination with association analysis can aid to identify genetic modifiers in neurodegenerative disorders. The detection of a genetic variant in PDXK, together with evidence accumulating from clinical studies, emphasize the impact of vitamin B6 status and metabolism on disease risk and therapy in PD.Parkinson's disease (PD) is a neurodegenerative disorder, characterized by age-related dysfunction and loss of dopaminergic neurons in the substantia nigra (SN) pars compacta (SNc). Hereditary forms of PD have provided evidence for linkage to 13 loci and nine causative genes, and their functional study has greatly helped to elucidate molecular disease mechanisms. 1 For idiopathic PD, both genetic and environmental factors are believed to modulate disease risk, but the impact of genetic variants remains unclear. 2 Genome-wide association (GWA) studies offer an unbiased approach for detecting effects in common variants, but large studies with sufficient power are still lacking. Restriction to candidate genes increases the a priori odds for phenotypic involvement and thus the chance of detecting significant associations. Here, we applied a functional genomic approach for the discovery of candidate genes and key regulatory pathways. We focused directly on the In order to isolate high-quality RNA from frozen human brain tissues, tissue pH and RNA integrity numbers (RIN) were measured in homogenates of frontal cortex and mid-brain sections from 41 suitable cases and 39 controls. This provided eight cases and nine agematched controls of good RNA quality for laser microdissection (LMD). Postmortem data for matched cases/controls were as follows: age at death 78.6 ± 6.5/76.8 ± 9.8 years; postmorte...

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Section: Discussionmentioning

confidence: 99%

Single‐cell expression profiling of dopaminergic neurons combined with association analysis identifies pyridoxal kinase as Parkinson's disease gene

Elstner

Morris

Heim

et al. 2009

Annals of Neurology

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“…It should be noted, however, that pyridoxine doses in these studies were much higher than doses taken during the standard supplementation. Moreover, after introducing aromatic-L-amino-acid decarboxylase inhibitors (such as carbidopa) to therapy with levodopa, the negative effect of pyridoxine disappeared [ 72 , 77 - 79 ]. Nowadays, the vast majority of patients administer fixed-dose formulations of levodopa with carbidopa or benserazide; hence concomitant vitamin B6 supplementation should not affect the efficacy of treatment [ 80 ].…”

Section: Resultsmentioning

confidence: 99%

How to Optimize the Effectiveness and Safety of Parkinson’s Disease Therapy? – A Systematic Review of Drugs Interactions with Food and Dietary Supplements

Wiesner

Paśko

Kujawska

2022

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Background: Despite increasing worldwide incidence of Parkinson’s disease, the therapy is still suboptimal due to the diversified clinical manifestations, lack of sufficient treatment, the poor patient’s adherence in advanced patients, and varied response. Proper intake of medications regarding food and managing drug-food interactions may optimize Parkinson’s disease treatment. Objectives: We investigated potential effects that food, beverages, and dietary supplements may have on the pharmacokinetics and pharmacodynamics of drugs used by parkinsonian patients; identified the most probable interactions; and shaped recommendations for the optimal intake of drugs regarding food. Methods: We performed a systematic review in adherence to PRISMA guidelines, and included a total of 81 studies in the qualitative synthesis. Results and Conclusions: We found evidence for levodopa positive interaction with coffee, fiber and vitamin C, as well as for the potential beneficial impact of low-fat and protein redistribution diet. Contrastingly, high-protein diet and ferrous sulfate supplements can negatively affect levodopa pharmacokinetics and effectiveness. For other drugs, the data of food impact are scarce. Based on available limited evidence, all dopamine agonists (bromocriptine, cabergoline, ropinirole), tolcapone, rasagiline, selegiline in tablets, safinamide, amantadine and pimavanserin can be taken with or without meal. Opicapone and orally disintegrating selegiline tablets should be administered on an empty stomach. Of monoamine oxidase B inhibitors, safinamide is the least susceptible for interaction with the tyramine-rich food, whereas selegiline and rasagiline may lose selectivity to monoamine oxidase B when administered in supratherapeutic doses. The level of presented evidence is low due to the poor studies design, their insufficient actuality, and missing data.

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“…This gene encodes the pyridoxal kinase protein involved in the conversion of vitamin B6 to pyridoxal-5-phosphate, an important cofactor in intermediary metabolism [ 57 ]. Low levels of vitamin B6 have been linked with an increased PD incidence in several studies [ 22 , 59 , 88 ]. Moreover, mutations in PDXK cause autosomal recessive axonal peripheral polyneuropathy [ 19 ], PDXK was among the genes differentially expressed in the substantia nigra of PD patients and a DNA variant (rs2010795) in this gene has been associated with an increased risk of PD [ 32 ].…”

Section: Discussionmentioning

confidence: 99%

Transcriptomic profiling of Parkinson's disease brains reveals disease stage specific gene expression changes

et al. 2023

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Parkinson´s disease (PD) is a progressive neurodegenerative disorder characterized by both motor and non-motor symptoms. Aggravation of symptoms is mirrored by accumulation of protein aggregates mainly composed by alpha-synuclein in different brain regions, called Lewy bodies (LB). Previous studies have identified several molecular mechanisms as autophagy and inflammation playing a role in PD pathogenesis. Increased insights into mechanisms involved in early disease stages and driving the progression of the LB pathology are required for the development of disease-modifying strategies. Here, we aimed to elucidate disease stage-specific transcriptomic changes in brain tissue of well-characterized PD and control donors. We collected frontal cortex samples from 84 donors and sequenced both the coding and non-coding RNAs. We categorized our samples into groups based on their degree of LB pathology aiming to recapitulate a central aspect of disease progression. Using an analytical pipeline that corrected for sex, age at death, RNA quality, cell composition and unknown sources of variation, we found major disease stage-specific transcriptomic changes. Gene expression changes were most pronounced in donors at the disease stage when microscopic LB changes first occur in the sampled brain region. Additionally, we identified disease stage-specific enrichment of brain specific pathways and immune mechanisms. On the contrary, we showed that mitochondrial mechanisms are enriched throughout the disease course. Our data-driven approach also suggests a role for several poorly characterized lncRNAs in disease development and progression of PD. Finally, by combining genetic and epigenetic information, we highlighted two genes (MAP4K4 and PHYHIP) as candidate genes for future functional studies. Together our results indicate that transcriptomic dysregulation and associated functional changes are highly disease stage-specific, which has major implications for the study of neurodegenerative disorders.

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Pyridoxine and Levodopa in The Treatment of Parkinsonism

Cited by 12 publications

References 4 publications

Single‐cell expression profiling of dopaminergic neurons combined with association analysis identifies pyridoxal kinase as Parkinson's disease gene

Single‐cell expression profiling of dopaminergic neurons combined with association analysis identifies pyridoxal kinase as Parkinson's disease gene

How to Optimize the Effectiveness and Safety of Parkinson’s Disease Therapy? – A Systematic Review of Drugs Interactions with Food and Dietary Supplements

Transcriptomic profiling of Parkinson's disease brains reveals disease stage specific gene expression changes

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