RESUMEN
Deposition of amyloid-ß (Aß) in the brain can impair neuronal function and contribute to cognitive decline in Alzheimer's disease (AD). Here, we found that dopamine and the dopamine precursor levodopa (also called l-DOPA) induced Aß degradation in the brain. Chemogenetic approaches in mice revealed that the activation of dopamine release from ventral tegmental area (VTA) neurons increased the abundance and activity of the Aß-degrading enzyme neprilysin and reduced the amount of Aß deposits in the prefrontal cortex in a neprilysin-dependent manner. Aged mice had less dopamine and neprilysin in the anterior cortex, a decrease that was accentuated in AD model mice. Treating AD model mice with levodopa reduced Aß deposition and improved cognitive function. These observations demonstrate that dopamine promotes brain region-specific, neprilysin-dependent degradation of Aß, suggesting that dopamine-associated strategies have the potential to treat this aspect of AD pathology.
Asunto(s)
Enfermedad de Alzheimer , Péptidos beta-Amiloides , Dopamina , Neprilisina , Área Tegmental Ventral , Neprilisina/metabolismo , Neprilisina/genética , Animales , Dopamina/metabolismo , Péptidos beta-Amiloides/metabolismo , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Ratones , Área Tegmental Ventral/metabolismo , Área Tegmental Ventral/efectos de los fármacos , Levodopa/farmacología , Encéfalo/metabolismo , Ratones Transgénicos , Modelos Animales de Enfermedad , Humanos , Proteolisis/efectos de los fármacos , Ratones Endogámicos C57BL , Corteza Prefrontal/metabolismo , MasculinoRESUMEN
Boiled lotus rhizome discs (BLRDs), as common processed products of lotus rhizome, have gained increasing attention from consumers and food manufacturers. However, the blue pigment formed during boiling affects its appearance and reduces the appetite of BLRDs. In this study, the effects of polyphenols and iron contents on blue pigment formation in BLRDs in different regions and months were investigated. Results revealed that blue variation was more serious in March and April of the second year in Wuhan, and polyphenols and iron contents in these two months were significantly higher than those in other months. Then, UPLC and UV-Vis analysis showed that polyphenols causing the formation of blue pigment in BLRDs were L-dopa, gallocatechin, catechin, epigallocatechin, chlorogenic acid and epicatechin, among which L-dopa (52.450 mg/100 g in fresh lotus rhizome (FLR)) and gallocatechin (36.210 mg/100 g in FLR) possessed the greatest effect. Moreover, the ESI-Q-TOF-MS analysis of L-dopa-iron chelate and gallocatechin-iron chelate suggested that the blue pigment of BLRDs was mainly in the form of bis-complexes under boiling conditions. The study on formation mechanism of blue pigment in BLRDs can provide a reference for lotus rhizome processing.
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Hierro , Polifenoles , Rizoma , Rizoma/química , Polifenoles/química , Polifenoles/análisis , Hierro/química , Quelantes del Hierro/química , Pigmentos Biológicos/química , Catequina/química , Catequina/análogos & derivados , Catequina/análisis , Levodopa/química , Lotus/química , Cromatografía Líquida de Alta Presión , Culinaria , Calor , Ácido Clorogénico/química , Espectrometría de Masa por Ionización de ElectrosprayRESUMEN
Introduction: Parkinson's disease (PD) is an incurable, progressive, neurodegenerative disorder. As PD advances and symptoms progress, patients become increasingly dependent on family and carers. Traditional cost-effectiveness analyses (CEA) only consider patient and payer-related outcomes, failing to acknowledge impacts on families, carers, and broader society. This novel Social Return on Investment (SROI) analysis aimed to evaluate the broader impact created by improving access to levodopa (LD) device-aided therapies (DATs) for people living with advanced PD (aPD) in Australia. Methods: A forecast SROI analysis over a three-year time horizon was conducted. People living with aPD and their families were recruited for qualitative interviews or a quantitative survey. Secondary research and clinical trial data was used to supplement the primary research. Outcomes were valued and assessed in a SROI value map in Microsoft Excel™. Financial proxies were assigned to each final outcome based on willingness-to-pay, economic valuation, and replacement value. Treatment cost inputs were sourced from Pharmaceutical Benefits Schedule (PBS) and Medicare Benefits Scheme (MBS) published prices. Results: Twenty-four interviews were conducted, and 55 survey responses were received. For every $1 invested in access to LD-based DATs in Australia, an estimated $1.79 of social value is created. Over 3 years, it was estimated $277.16 million will be invested and $406.77 million of social return will be created. This value is shared between people living with aPD (27%), their partners (22%), children (36%), and the Australian Government (15%). Most of the value created is social and emotional in nature, including reduced worry, increased connection to family and friends, and increased hope for the future. Discussion: Investment in LD-based DATs is expected to generate a positive social return. Over 50% of the value is created for the partners and children of people living with aPD. This value would not be captured in traditional CEA. The SROI methodology highlights the importance of investing in aPD treatment, capturing the social value created by improved access to LD-based DATs.
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Análisis Costo-Beneficio , Levodopa , Enfermedad de Parkinson , Humanos , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/economía , Enfermedad de Parkinson/terapia , Australia , Levodopa/uso terapéutico , Levodopa/economía , Masculino , Femenino , Anciano , Persona de Mediana Edad , Encuestas y Cuestionarios , Antiparkinsonianos/uso terapéutico , Antiparkinsonianos/economía , Investigación Cualitativa , Entrevistas como AsuntoRESUMEN
Interspecies pathways in the gut microbiome have been shown to metabolize levodopa, the primary treatment for Parkinson's disease, and reduce its bioavailability. While the enzymatic reactions have been identified, the ability to establish the resulting macromolecules as biomarkers of microbial metabolism remains technically challenging. In this study, we leveraged an untargeted mass spectrometry-based approach to investigate volatile organic compounds (VOCs) produced during levodopa metabolism by Enterococcus faecalis, Clostridium sporogenes, and Eggerthella lenta. We cultured these organisms with and without their respective bioactive metabolites and detected levodopa-induced shifts in VOC profiles. We then utilized bioinformatics to identify significant differences in 2,6-dimethylpyrazine, 4,6-dimethylpyrimidine, and 4,5-dimethylpyrimidine associated with its biotransformation. Supplementing cultures with inhibitors of levodopa-metabolizing enzymes revealed specific modulation of levodopa-associated diazines, verifying their relationship to its metabolism. Furthermore, functional group analysis depicts strain-specific VOC profiles that reflect interspecies differences in metabolic activity that can be leveraged to assess microbiome functionality in individual patients. Collectively, this work identifies previously uncharacterized metabolites of microbe-mediated levodopa metabolism to determine potential indicators of this activity and further elucidate the metabolic capabilities of different gut bacteria.
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Enterococcus faecalis , Microbioma Gastrointestinal , Levodopa , Compuestos Orgánicos Volátiles , Levodopa/metabolismo , Compuestos Orgánicos Volátiles/metabolismo , Enterococcus faecalis/metabolismo , Humanos , Bacterias/metabolismo , Bacterias/clasificación , Bacterias/genética , Bacterias/aislamiento & purificación , Clostridium/metabolismo , Clostridium/clasificación , Espectrometría de Masas , BiotransformaciónRESUMEN
Parkinson's disease (PD) is a gradually worsening neurodegenerative disorder affecting the nervous system, marked by a slow progression and varied symptoms. It is the second most common neurodegenerative disease, affecting over six million people in the world. Its multifactorial etiology includes environmental, genomic, and epigenetic factors. Clinical symptoms consist of non-motor and motor symptoms, with motor symptoms being the classic presentation. Therapeutic approaches encompass pharmacological, non-pharmacological, and surgical interventions. Traditional pharmacological treatment consists of administering drugs (MAOIs, DA, and levodopa), while emerging evidence explores the potential of antidiabetic agents for neuroprotection and gene therapy for attenuating parkinsonian symptoms. Non-pharmacological treatments, such as exercise, a calcium-rich diet, and adequate vitamin D supplementation, aim to slow disease progression and prevent complications. For those patients who have medically induced side effects and/or refractory symptoms, surgery is a therapeutic option. Deep brain stimulation is the primary surgical option, associated with motor symptom improvement. Levodopa/carbidopa intestinal gel infusion through percutaneous endoscopic gastrojejunostomy and a portable infusion pump succeeded in reducing "off" time, where non-motor and motor symptoms occur, and increasing "on" time. This article aims to address the general aspects of PD and to provide a comparative comprehensive review of the conventional and the latest therapeutic advancements and emerging treatments for PD. Nevertheless, further studies are required to optimize treatment and provide suitable alternatives.
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Enfermedad de Parkinson , Humanos , Enfermedad de Parkinson/terapia , Levodopa/uso terapéutico , Estimulación Encefálica Profunda/métodos , Antiparkinsonianos/uso terapéutico , Terapia Genética/métodos , AnimalesRESUMEN
Monotherapy is the recommended initial treatment for early Parkinson's disease. The pharmacological options for initial treatment include dopaminergic agonists, monoamine oxidase B inhibitors, and levodopa formulations. Several factors should be considered when selecting the optimal treatment, such as disease severity, disease duration, age, activity level, and the risk of developing motor and non-motor complications. Early evidence on the potential role of levodopa formulations in the risk of dyskinesia led to levodopa aversion in the late 1990s and early 2000s, favoring the use of levodopa-sparing options like dopamine agonists. This shift resulted in an increase in behavioral adverse effects, such as impulse control disorders, leading to a subsequent dopamine agonist aversion in the mid-2000s. This review aims to provide a comprehensive evaluation of the existing literature regarding the benefits and drawbacks of levodopa versus levodopa-sparing strategies in drug-naive early-stage Parkinson's disease.
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Antiparkinsonianos , Agonistas de Dopamina , Levodopa , Enfermedad de Parkinson , Humanos , Levodopa/administración & dosificación , Levodopa/uso terapéutico , Levodopa/efectos adversos , Enfermedad de Parkinson/tratamiento farmacológico , Antiparkinsonianos/uso terapéutico , Antiparkinsonianos/farmacología , Antiparkinsonianos/administración & dosificación , Agonistas de Dopamina/uso terapéutico , Agonistas de Dopamina/administración & dosificación , Índice de Severidad de la EnfermedadRESUMEN
INTRODUCTION: Early, simple predictors for long-term survival in Parkinson's disease (PD) may help identify patients at elevated risk and are crucial for more personalized treatment. METHODS: This large, retrospective study examined whether higher levodopa equivalent daily dose (LEDD) a year after diagnosis predicts long-term survival. RESULTS: Mortality risk was increased among 292 patients receiving ≥ 600 mg LEDD versus 2233 patients receiving < 600 mg LEDD (hazard ratio 1.5; 95% confidence interval 1.3-1.7), particularly among patients aged < 75 years (1.8; 1.4-2.4). CONCLUSION: In PD, higher LEDD can be an early risk marker of increased mortality, probably because it reflects more severe disease.
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Antiparkinsonianos , Levodopa , Enfermedad de Parkinson , Humanos , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/mortalidad , Masculino , Femenino , Anciano , Antiparkinsonianos/uso terapéutico , Antiparkinsonianos/administración & dosificación , Estudios Retrospectivos , Levodopa/uso terapéutico , Levodopa/administración & dosificación , Persona de Mediana Edad , Relación Dosis-Respuesta a Droga , Factores de Riesgo , Anciano de 80 o más AñosRESUMEN
Psychotic symptoms and delusional beliefs have been linked to dopamine transmission in both healthy and clinical samples and are assumed to result at least in part from perceiving illusory patterns in noise. However, the existing literature on the role of dopamine in detecting patterns in noise is inconclusive. To address this issue, we assessed the effect of manipulating dopaminergic neurotransmission on illusory pattern perception in healthy individuals (n = 48, n = 19 female) in a double-blind placebo-controlled within-subjects design (see preregistration at https://osf.io/a4k9j/). We predicted individuals on versus off Ê-DOPA to be more likely to perceive illusory patterns, specifically objects in images containing only noise. Using a signal detection model, however, we found no credible evidence that Ê-DOPA compared with placebo increased false alarm rates. Further, Ê-DOPA did not reliably modulate measures of accuracy, discrimination sensitivity, and response bias. In all cases, Bayesian statistics revealed strong evidence in favor of the null hypothesis. The task design followed previous work on illusory pattern perception and comprised a limited number of items per condition. The results therefore need to be interpreted with caution, as power was limited. Future studies should address illusory pattern perception using more items and take into account potential dose-dependent effects and differential effects in healthy versus clinical samples.
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Dopamina , Ilusiones , Levodopa , Humanos , Femenino , Masculino , Método Doble Ciego , Adulto , Ilusiones/fisiología , Ilusiones/efectos de los fármacos , Dopamina/metabolismo , Adulto Joven , Levodopa/farmacología , Levodopa/administración & dosificación , Transmisión Sináptica/efectos de los fármacos , Transmisión Sináptica/fisiología , Dopaminérgicos/farmacología , Reconocimiento Visual de Modelos/fisiología , Reconocimiento Visual de Modelos/efectos de los fármacos , Teorema de BayesRESUMEN
Brain organoids are being recognized as valuable tools for drug evaluation in neurodegenerative diseases due to their similarity to the human brain's structure and function. However, a critical challenge is the lack of selective and sensitive electrochemical sensing platforms to detect the response of brain organoids, particularly changes in the neurotransmitter concentration upon drug treatment. This study introduces a 3D concave electrode patterned with a mesoporous Au nanodot for the detection of electrochemical signals of dopamine in response to drugs in brain organoids for the first time. The mesoporous Au nanodot-patterned film was fabricated using laser interference lithography and electrochemical deposition. Then, the film was attached to a polymer-based 3D concave mold to obtain a 3D concave electrode. Midbrain organoids generated from Parkinson's disease (PD) patient-derived iPSCs with gene mutations (named as PD midbrain organoid) or normal midbrain organoids were positioned on the developed 3D concave electrode. The 3D concave electrode showed a 1.4 times higher electrochemical signal of dopamine compared to the bare gold electrode. And the dopamine secreted from normal midbrain organoids or PD midbrain organoids on the 3D concave electrode could be detected electrochemically. After the treatment of PD midbrain organoids with levodopa, the drug for PD, the increase in dopamine level was detected due to the activation of dopaminergic neurons by the drug. The results suggest the potential of the proposed 3D concave electrode combined with brain organoids as a useful tool for assessing drug efficacy. This sensing system can be applied to a variety of organoids for a comprehensive drug evaluation.
Asunto(s)
Dopamina , Electrodos , Oro , Mesencéfalo , Organoides , Enfermedad de Parkinson , Humanos , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/patología , Organoides/patología , Oro/química , Mesencéfalo/citología , Dopamina/análisis , Porosidad , Levodopa/farmacología , Técnicas Electroquímicas/métodos , Técnicas Electroquímicas/instrumentación , Evaluación Preclínica de Medicamentos , Nanopartículas del Metal/químicaRESUMEN
In the present study, we explored the development of a novel noninvasive liposomal drug delivery material for use in intranasal drug delivery applications in human diseases. We used drug entrapment into liposomal nanoparticle assembly to efficiently deliver the drugs to the nasal mucosa to be delivered to the brain. The naturally occurring flavonoid 7,8-dihydroxyflavone (7,8-DHF) has previously been shown to have beneficial effects in ameliorating Parkinson's disease (PD). We used both naturally occurring 7,8-DHF and the chemically modified form of DHF, the DHF-ME, to be used as a drug candidate for the treatment of PD and l-DOPA induced dyskinesia (LID), which is the debilitating side effect of l-DOPA therapy in PD. The ligand-protein interaction behavior for 7,8-DHF and 6,7-DHF-ME was found to be more effective with molecular docking and molecular stimulation studies of flavonoid compounds with TrkB receptor. Our study showed that 7,8-DHF delivered via intranasal route using a liposomal formulation ameliorated LID in hemiparkinsonian mice model when these mice were chronically administered with l-DOPA, which is the only current medication for relieving the clinical symptoms of PD. The present study also demonstrated that apart from reducing the LID, 7,8-DHF delivery directly to the brain via the intranasal route also corrected some long-term signaling adaptations involving ΔFosB and α Synuclein in the brain of dopamine (DA) depleted animals.
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Administración Intranasal , Flavonoides , Levodopa , Liposomas , Animales , Liposomas/química , Levodopa/administración & dosificación , Flavonoides/administración & dosificación , Flavonoides/farmacología , Ratones , Masculino , Enfermedad de Parkinson/tratamiento farmacológico , Ratones Endogámicos C57BL , Discinesia Inducida por Medicamentos/tratamiento farmacológico , Simulación del Acoplamiento Molecular , Receptor trkB/metabolismo , Sistemas de Liberación de Medicamentos , FlavonasRESUMEN
The gene product of ocular albinism 1 (OA1)/G-protein-coupled receptor (GPR)143 is a receptor for L-3,4-dihydroxyphenylanine (l-DOPA), the most effective agent for Parkinson's disease. When overexpressed, human wild-type GPR143, but not its mutants, inhibits neurite outgrowth in PC12 cells. We investigated the downstream signaling pathway for GPR143-induced inhibition of neurite outgrowth. Nifedipine restored GPR143-induced neurite outgrowth inhibition to the level of control transfectant but did not affect outgrowth in GPR143-knockdown cells. Cilnidipine and flunarizine also suppressed the GPR143-induced inhibition, but their effects at higher concentrations still occurred even in GPR143-knockdown cells. These results suggest that GPR143 regulates neurite outgrowth via L-type calcium channel(s).
Asunto(s)
Canales de Calcio Tipo L , Proyección Neuronal , Nifedipino , Receptores Acoplados a Proteínas G , Células PC12 , Animales , Ratas , Canales de Calcio Tipo L/metabolismo , Canales de Calcio Tipo L/genética , Nifedipino/farmacología , Proyección Neuronal/efectos de los fármacos , Receptores Acoplados a Proteínas G/metabolismo , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/fisiología , Humanos , Proteínas del Ojo/genética , Proteínas del Ojo/metabolismo , Proteínas del Ojo/farmacología , Flunarizina/farmacología , Transducción de Señal/efectos de los fármacos , Levodopa/farmacología , Técnicas de Silenciamiento del Gen , Neuritas/efectos de los fármacos , Bloqueadores de los Canales de Calcio/farmacología , Glicoproteínas de MembranaRESUMEN
Parkinson's is a progressive neurodegenerative disease of the nervous system. It has no cure, but its symptoms can be managed by supplying dopamine artificially to the brain.This work aims to engineer tricompartmental polymeric microcarriers by electrohydrodynamic cojetting technique to encapsulate three PD (Parkinson's disease) drugs incorporated with high encapsulation efficiency (â¼100%) in a single carrier at a fixed drug ratio of 4:1:8 (Levodopa (LD): Carbidopa(CD): Entacapone (ENT)). Upon oral administration, the drug ratio needs to be maintained during subsequent release from microparticles to enhance the bioavailability of primary drug LD. This presents a notable challenge, as the three drugs vary in their aqueous solubility (LD > CD > ENT). The equilibrium of therapeutic release was achieved using a combination of FDA-approved polymers (PLA, PLGA, PCL, and PEG) and the disc shape of particles. In vitro studies demonstrated the simultaneous release of all the three therapeutics in a sustained and controlled manner. Additionally, pharmacodynamics and pharmacokinetics studies in Parkinson's disease rats induced by rotenone showed a remarkable improvement in PD conditions for the microparticles-fed rats, thereby showing a great promise toward efficient management of PD.
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Carbidopa , Catecoles , Preparaciones de Acción Retardada , Portadores de Fármacos , Levodopa , Enfermedad de Parkinson , Carbidopa/farmacocinética , Carbidopa/administración & dosificación , Carbidopa/uso terapéutico , Carbidopa/farmacología , Animales , Levodopa/farmacocinética , Levodopa/administración & dosificación , Levodopa/uso terapéutico , Levodopa/farmacología , Enfermedad de Parkinson/tratamiento farmacológico , Preparaciones de Acción Retardada/química , Catecoles/química , Catecoles/uso terapéutico , Catecoles/farmacología , Catecoles/farmacocinética , Portadores de Fármacos/química , Ratas , Masculino , Nitrilos/farmacocinética , Nitrilos/uso terapéutico , Nitrilos/farmacología , Antiparkinsonianos/farmacocinética , Antiparkinsonianos/uso terapéutico , Antiparkinsonianos/administración & dosificación , Antiparkinsonianos/farmacología , Liberación de Fármacos , Ratas Sprague-Dawley , Rotenona/farmacologíaRESUMEN
We report the gelation propensity of three gelators derived from l-dihydroxyphenylalanine (l-Dopa), where the amino group is derivatized with three different fatty acids (lauric acid, palmitic acid, and azelaic acid). The long aliphatic side chains should introduce additional van der Waals interactions among the molecules, contributing to the self-assembly process. The hydrogels have been prepared with the pH change method, and both the hydrogels and the corresponding aerogels have been analyzed using several techniques. In any case, Lau-Dopa provides stronger hydrogels compared with the other gelators. This property may be ascribed to its tendency to efficiently form supramolecular ß-sheet structures, as outlined by the ECD, IR, and SEM analyses. Moreover, the preliminary measurement of the apparent pKa displays for Lau-Dopa two plateaux, as previously observed for, one at about pH 12 and a second one at pH 7.5. Thus, its pKa results in two apparent pKa shifts of â¼8.5 and â¼4 pH units above the theoretical pKa, as a consequence of a multistep self-assembly pathway that correlates, in the final ß-sheet-based hydrogel, with a high degree of order and stability.
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Hidrogeles , Levodopa , Hidrogeles/química , Levodopa/química , Concentración de Iones de HidrógenoRESUMEN
It is crucial to accurately and rapidly monitor the levodopa (LD) concentration for accurate classification and treatment of dyskinesia in Parkinson's disease. In this paper, 3D graphene foam (GF) with a highly conductive network is obtained by chemical vapor deposition. 3D GF serves as the substrate for hydrothermal in situ growth of tapered cross-linked ZnO nanowire bundle arrays (ZnO NWBAs), enabling the development of a highly sensitive detection platform for LD. The formation mechanism of a tapered cross-linked ZnO nanowire bundle arrays on 3D GF is put forward. The integration of 3D GF and ZnO NWBAs can accelerate the electron transfer rate and increase the contact area with biomolecules, resulting in high electrochemical properties. The electrode composed of ZnO NWBAs on 3D GF exhibits significant sensitivity (1.66 µA·µM-1·cm-2) for LD detection in the concentration range 0-60 µM. The electrode is able to rapidly and specifically determine LD in mixed AA or UA solution. The selectivity mechanism of the electrode is also explained by the bandgap model. Furthermore, the successful detection of LD in serum demonstrates the practicality of the electrode and its great potential for clinical application.
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Técnicas Electroquímicas , Grafito , Levodopa , Límite de Detección , Nanocables , Óxido de Zinc , Grafito/química , Óxido de Zinc/química , Nanocables/química , Levodopa/sangre , Levodopa/análisis , Levodopa/química , Técnicas Electroquímicas/métodos , Técnicas Electroquímicas/instrumentación , Electrodos , HumanosRESUMEN
Background and Objectives: Currently, no tool exists to predict clinical outcomes in patients with advanced Parkinson's disease (PD) under levodopa-carbidopa intestinal gel (LCIG) treatment. The aim of this study was to develop a novel deep neural network model to predict the clinical outcomes of patients with advanced PD after two years of LCIG therapy. Materials and Methods: This was a longitudinal, 24-month observational study of 59 patients with advanced PD in a multicenter registry under LCIG treatment from September 2019 to September 2021, including 43 movement disorder centers. The data set includes 649 measurements of patients, which make an irregular time series, and they are turned into regular time series during the preprocessing phase. Motor status was assessed with the Unified Parkinson's Disease Rating Scale (UPDRS) Parts III (off) and IV. The NMS was assessed by the NMS Questionnaire (NMSQ) and the Geriatric Depression Scale (GDS), the quality of life by PDQ-39, and severity by Hoehn and Yahr (HY). Multivariate linear regression, ARIMA, SARIMA, and Long Short-Term Memory-Recurrent NeuralNetwork (LSTM-RNN) models were used. Results: LCIG significantly improved dyskinesia duration and quality of life, with men experiencing a 19% and women a 10% greater improvement, respectively. Multivariate linear regression models showed that UPDRS-III decreased by 1.5 and 4.39 units per one-unit increase in the PDQ-39 and UPDRS-IV indexes, respectively. Although the ARIMA-(2,0,2) model is the best one with AIC criterion 101.8 and validation criteria MAE = 0.25, RMSE = 0.59, and RS = 0.49, it failed to predict PD patients' features over a long period of time. Among all the time series models, the LSTM-RNN model predicts these clinical characteristics with the highest accuracy (MAE = 0.057, RMSE = 0.079, RS = 0.0053, mean square error = 0.0069). Conclusions: The LSTM-RNN model predicts, with the highest accuracy, gender-dependent clinical outcomes in patients with advanced PD after two years of LCIG therapy.
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Carbidopa , Combinación de Medicamentos , Geles , Levodopa , Redes Neurales de la Computación , Enfermedad de Parkinson , Humanos , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/fisiopatología , Levodopa/uso terapéutico , Levodopa/administración & dosificación , Carbidopa/uso terapéutico , Carbidopa/administración & dosificación , Masculino , Femenino , Anciano , Persona de Mediana Edad , Estudios Longitudinales , Antiparkinsonianos/uso terapéutico , Antiparkinsonianos/administración & dosificación , Factores Sexuales , Calidad de Vida , Resultado del Tratamiento , Índice de Severidad de la EnfermedadRESUMEN
The loss of midbrain dopaminergic (DA) neurons is the fundamental pathological feature of Parkinson's disease (PD). PD causes chronic pain in two-thirds of patients. Recent studies showed that the activation of the pedunculopontine tegmental nucleus (PPTg) can effectively relieve inflammatory pain and neuropathic pain. The PPTg is located in the pontomesencephalic tegmentum, a target of deep brain stimulation (DBS) treatment in PD, and is involved in motor control and sensory integration. To test whether the lesion of midbrain DA neurons induced pain hypersensitivity, and whether the chemogenetic activation of the PPTg could modulate the pain, the AAV-hM3Dq receptor was transfected and expressed into the PPTg neurons of 6-hydroxydopamine-lesioned mice. In this study, von Frey, open field, and adhesive tape removal tests were used to assess animals' pain sensitivity, locomotor activity, and sensorimotor function and somatosensory perception, respectively. Here, we found that the lesion of midbrain DA neurons induced a minor deficit in voluntary movement but did not affect sensorimotor function and somatosensory perception in the tape removal test. The results showed that lesion led to pain hypersensitivity, which could be alleviated both by levodopa and by the chemogenetic activation of the PPTg. Activating the PPTg may be a potential therapeutic strategy to relieve pain phenotypes in PD.
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Neuronas Dopaminérgicas , Mesencéfalo , Núcleo Tegmental Pedunculopontino , Animales , Núcleo Tegmental Pedunculopontino/metabolismo , Neuronas Dopaminérgicas/metabolismo , Ratones , Mesencéfalo/metabolismo , Masculino , Enfermedad de Parkinson/terapia , Enfermedad de Parkinson/fisiopatología , Dolor/etiología , Dolor/metabolismo , Ratones Endogámicos C57BL , Estimulación Encefálica Profunda/métodos , Modelos Animales de Enfermedad , Levodopa/farmacología , OxidopaminaRESUMEN
This study presents the effects of treating polystyrene (PS) cell culture plastic with oxidoreductase enzyme laccase and the catechol substrates caffeic acid (CA), L-DOPA, and dopamine on the culturing of normal human epidermal melanocytes (NHEMs) and human embryonal carcinoma cells (NTERA-2). The laccase-substrate treatment improved PS hydrophilicity and roughness, increasing NHEM and NTERA-2 adherence, proliferation, and NHEM melanogenesis to a level comparable with conventional plasma treatment. Cell adherence dynamics and proliferation were evaluated. The NHEM endpoint function was quantified by measuring melanin content. PS surfaces treated with laccase and its substrates demonstrated the forming of polymer-like structures. The surface texture roughness gradient and the peak curvature were higher on PS treated with a combination of laccase and substrates than laccase alone. The number of adherent NHEM and NTERA-2 was significantly higher than on the untreated surface. The proliferation of NHEM and NTERA-2 correspondingly increased on treated surfaces. NHEM melanin content was enhanced 6-10-fold on treated surfaces. In summary, laccase- and laccase-substrate-modified PS possess improved PS surface chemistry/hydrophilicity and altered roughness compared to untreated and plasma-treated surfaces, facilitating cellular adherence, subsequent proliferation, and exertion of the melanotic phenotype. The presented technology is easy to apply and creates a promising custom-made, substrate-based, cell-type-specific platform for both 2D and 3D cell culture.
Asunto(s)
Ácidos Cafeicos , Proliferación Celular , Dopamina , Lacasa , Melaninas , Melanocitos , Poliestirenos , Humanos , Lacasa/metabolismo , Melanocitos/metabolismo , Melanocitos/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Poliestirenos/química , Ácidos Cafeicos/farmacología , Ácidos Cafeicos/química , Dopamina/metabolismo , Melaninas/metabolismo , Adhesión Celular/efectos de los fármacos , Levodopa/farmacología , Levodopa/metabolismo , Levodopa/química , Propiedades de Superficie , Línea Celular Tumoral , Células Madre de Carcinoma Embrionario/metabolismo , Células Madre de Carcinoma Embrionario/efectos de los fármacosRESUMEN
BACKGROUND: The gut microbiota has been implicated in Parkinson's disease (PD), with alterations observed in microbial composition and reduced microbial species richness, which may influence gastrointestinal symptoms in PD patients. It remains to be determined whether the severity of gastrointestinal symptoms correlates with microbiota variations in PD patients treated pharmacologically or with subthalamic nucleus deep brain stimulation (STN-DBS) therapy. This study aims to explore how these treatments affect gut microbiota and gastrointestinal symptoms in PD, identifying specific microbial differences associated with each treatment modality. METHODS: A total of 42 individuals diagnosed with PD, along with 38 age-matched household control participants, contributed stool samples for microbiota characterization. Differences in the gut microbiota across various groups of PD patients and their households were identified through comprehensive sequencing of the 16S rRNA gene amplicon sequencing. KEY RESULTS: Differences in microbial communities were observed between PD patients and controls, as well as between PD patients receiving pharmacological treatment and those with STN-DBS. Pharmacologically treated advanced PD patients have higher gastrointestinal dysfunctions. Gut microbiota profile linked to STN-DBS and reduced levodopa consumption, characterized by its anti-inflammatory properties, might play a role in diminishing gastrointestinal dysfunction relative to only pharmacological treatments. CONCLUSIONS & INFERENCES: Advanced PD patients on medication exhibit more gastrointestinal issues, despite relatively stable microbial diversity, indicating a complex interaction between gut microbiota, PD progression, and treatment effects. An imbalanced gut-brain axis, particularly due to reduced butyrate production, may lead to constipation by affecting the enteric nervous system, which emphasizes the need to incorporate gut microbiome insights into treatment strategies.
Asunto(s)
Estimulación Encefálica Profunda , Microbioma Gastrointestinal , Enfermedad de Parkinson , Humanos , Enfermedad de Parkinson/microbiología , Enfermedad de Parkinson/terapia , Microbioma Gastrointestinal/efectos de los fármacos , Microbioma Gastrointestinal/fisiología , Masculino , Femenino , Persona de Mediana Edad , Anciano , Antiparkinsonianos/uso terapéutico , Levodopa/uso terapéutico , Levodopa/farmacología , Enfermedades Gastrointestinales/microbiología , Núcleo SubtalámicoRESUMEN
Parkinson's disease (PD) is a debilitating condition that affects 1.8% of people 65 years of age and older. Patients with PD often require hospitalization and are frequently admitted through the emergency department (ED). Notably, their hospital durations tend to be lengthier compared with patients without PD. The primary outcome of this research was to compare the length of stay (LOS) of patients who received carbidopa-levodopa (CL) in the ED with those who did not. Secondary outcomes included 30-day-readmission rates and administration of injectable for agitation. In addition, the percentage of patients receiving CL before and after an information management technology (IMT) alert implementation was compared in a sub-analysis. Patients that received CL during their inpatient stay were identified by a database report in this retrospective study. Patients were excluded if they were not admitted through the ED, younger than 65 years of age, or admitted to the intensive care unit after the ED. There was a total of 266 in the control group and 217 patients in the intervention group. The intervention group had a significantly shorter LOS than the control group (3.29 vs 5.37 days; P = 0.002), significantly less frequent 30-day readmissions (P = 0.032), and used fewer injectables for agitation (P = 0.035). The sub-analysis of the IMT alert revealed that prior to the alert's implementation, 28.5% of patients received CL in the ED; whereas post-alert, this percentage increased to 91.4% (P < 0.001). The results of this study found that the group of PD patients who received CL in the ED had shorter LOS, lower 30-day readmissions, and used less injectables for agitation compared with the group that did not receive CL in the ED. This improvement is possibly due to continuity of CL supply considering its short half-life and clinical importance for PD.