Search Results (32)

The microbiota–gut–brain axis (MGBA) comprises a complex bidirectional communication network integrating neural, immune, metabolic, and endocrine pathways. Dopamine, traditionally viewed as a central neurotransmitter, also plays essential roles in the gastrointestinal (GI) tract, where it regulates motility, secretion, barrier homeostasis, and mucosal immunity. Growing evidence indicates that the gut microbiota significantly contributes to intestinal dopamine metabolism through specialized enzymatic pathways, particularly tyrosine decarboxylase in Enterococcus species and catechol dehydroxylase in Eggerthella species. These microbial reactions compete with host processes, alter dopaminergic tone, and degrade orally administered levodopa (L-DOPA), providing a mechanistic explanation for the variability in treatment response in Parkinson’s disease (PD). Beyond PD, microbially mediated alterations in dopaminergic signaling have been implicated in mood disorders, neurodevelopmental conditions, metabolic dysfunction, and immune-mediated diseases. This review synthesizes current mechanistic and translational evidence on the dopamine–microbiota interface, outlines microbial pathways shaping dopaminergic activity, and highlights therapeutic opportunities including microbiota modulation, dietary strategies, fecal microbiota transplantation, and targeted inhibitors of microbial dopamine metabolism. Understanding this interface offers a foundation for developing personalized approaches in neurogastroenterology and neuromodulatory therapies. Full article

Dopamine (DA) replacement by L-DOPA administration is the most common and effective treatment for Parkinson’s disease (PD). However, its chronic use leads to important side effects at advanced stages of the disease. Levodopa-induced dyskinesia (LID), characterized by involuntary, abnormal movements, is the main challenge of L-DOPA treatment. Although the causes underlying LID are not fully understood, abnormal plasticity in corticostriatal synapses and dysregulated DA release from serotonin terminals play a crucial role. In recent years, several studies have suggested the involvement of neuroinflammation and oxidative stress in the pathophysiology of LID. Interestingly, different evidence has shown that blocking these pathways reduces LID in experimental animal PD models, pointing to the use of antioxidant/anti-inflammatory agents as a potential therapy for LID. Numerous studies have shown the role of the brain renin–angiotensin system (RAS) and the ROCK pathway in neuroinflammation and oxidative stress. Compounds acting through these routes have strong neuroprotective properties in PD models. Additionally, the use of ROCK inhibitors, such as fasudil, and RAS blockers has shown potent anti-dyskinetic effects. Therefore, compounds acting on the RAS and ROCK pathways could have a dual role, slowing down the degeneration of dopaminergic neurons and reducing the development of LID. Full article

Emerging evidence highlights the gut microbiota as a pivotal determinant of pharmacological efficacy. While Enterococcus faecalis (E. faecalis)-derived tyrosine decarboxylases (tyrDCs) are known to decarboxylate levodopa (L-dopa), compromising systemic bioavailability, the causal mechanisms underlying microbiota-mediated pharmacodynamic variability remain unresolved. In our study, we employed antibiotic-induced microbiota depletion and fecal microbiota transplantation (FMT) to interrogate microbiota-L-dopa interactions in MPTP-induced Parkinson’s disease (PD) mice. The study demonstrated that antibiotic-mediated microbiota depletion enhances L-dopa bioavailability and striatal dopamine (DA) level, correlating with improved motor function. To dissect clinical heterogeneity in the L-dopa response, PD patients were stratified into moderate responders and good responders following standardized L-dopa challenges. In vitro bioconversion assays revealed greater L-dopa-to-DA conversion in fecal samples from moderate responders versus good responders. FMT experiments confirmed mice receiving good-responder microbiota exhibited enhanced L-dopa bioavailability, higher striatal DA concentrations, and a heightened therapeutic effect of L-dopa relative to moderate-responder recipients. Collectively, our study provided evidence that the gut microbiota directly modulates L-dopa metabolism and microbial composition determines interindividual therapeutic heterogeneity. Targeted microbial modulation—through precision antibiotics or donor-matched FMT—is a viable strategy to optimize PD pharmacotherapy, supporting the potential for microbiota-targeted adjuvant therapies in PD management. Full article

A challenge to contemporary medicine is still the discovery of an effective and safe therapy for symptomatic control, if not cure, of Parkinson’s disease. While the potential century’s break-through is sought and foreseen by many scientists in gene therapy, immunotherapy, new drug combinations, and neurosurgical approaches, the not-yet-conventional intranasal administration of “classic” levodopa (L-DOPA) also stands out as a perspective from which Parkinson’s patients may benefit in the short term. With the main drawbacks of the standard oral L-DOPA treatment being the extremely low systemic and cerebral bioavailability, it is widely recognized that the nasal route may turn out to be the better administration site, for it offers the alternative of direct brain delivery via the olfactory bulb (the so-called nose-to-brain axis). However, such advancement would be unthinkable without the current progress in nano-scaled drug carriers which are needed to ensure drug stability, mucosal retention and permeation, olfactory uptake, and harmlessness to the sensory neurons and respiratory cilia. This study aims to review the most significant results and achievements in the field of nano-particulate nose-to-brain delivery of L-DOPA. Full article

Acrylamide (ACR) is a low-molecular weight, non-aromatic reagent, widely used in industry, such as in the manufacture of paper, textiles, plastics, cosmetics, and dyes. ACR is formed during the cooking of starchy food and its toxicity results mainly by conferring oxidative stress by elevating reactive oxygen species (ROS). To identify potential antidotes for ACR toxicity, we evaluated the efficacy of several thiol-based molecules known for ROS-scavenging, disulfide-reducing properties, and inhibition of oxidative stress-induced activation of the mitogen-activated protein kinases (MAPKs): the extracellular-signal-regulated-kinases (ERK1/2), p38-mitogen-activated-protein-kinases (p38^MAPK), and c-Jun-N-terminal-kinases (JNKs). We established a reproducible assay testing N-acetylcysteine (NAC), AD4/NACA, and the N-and C-blocked tri- and tetra-thioredoxin-mimetic (TXM) peptides, in PC12 cells. Our results demonstrate that these compounds exhibited high efficacy in suppressing ACR-induced MAPK activation, either prior to or subsequent to ACR exposure. The inhibition by single cysteine (Cys) residue, NAC and AD4/NACA (NAC-amide), 2 Cys peptides TXM-CB30, AcDCys-Gly-DCysNH₂, TXM-CB20, AcCys-Gly-CysNH₂, SuperDopa (SD, Ac-CysL-Levodopa-CysNH₂, TXM-CB13, AcCys-Met-Lys-CysNH₂, and a 3-Cys peptide, TXM-CB16, AcCys-γGlu-Cys-CysNH₂ was dose-dependent and potency displayed a direct correlation with the number of Cys residues. Cellular proteolysis of SD, which consists of levodopa flanked by two Cys, may suppress the manifestation of Parkinson’s disease (PD)-like symptoms mediated by chronic ACR exposure not only through lowering oxidative stress but also by replenishing cellular levels of dopamine. Overall, these results could advance the clinical application of TXM peptides as potential treatments for acute and/or chronic exposure to ACR and show promise as antidotes for preventing ACR-triggered PD-like neurotoxic symptoms. Full article

Parkinson’s disease (PD) is the second leading neurodegenerative disease after Alzheimer’s disease. Mucuna pruriens (L.) DC. (MP) is a plant that contains Levodopa (L-DOPA) and has been known to improve the symptoms of PD. In this preliminary study, we investigated the anti-parkinsonian potential of MP to compare the effects of L-DOPA. We first developed an in vivo model of the PD in C57BL/6 male mice using rotenone. A total of twelve mice were used for this experiment. Nine mice were injected with rotenone (28 mg/kg) daily for 28 days. The mice experiments were performed to validate the effectiveness of MP to treat PD. Synthetic L-DOPA in a ratio of 1:20 with MP was used as MP contains 5% L-DOPA by weight in it. MP and L-DOPA were injected for 19 days on a daily basis. Cognitive function was evaluated using beam balance and olfactory tests. Serum analysis was performed using serum enzyme-linked immunosorbent assay (ELISA) analysis test. IL-12, IL-6, and TGF-$\beta$ 1 were evaluated to validate the PD inducement and treatment. The levels of IL-12, IL-6, and TGF-$\beta$1 (p < 0.0001) in the PD mice group were significantly higher than those in the control group. The PD mice also showed higher latencies in beam balance and olfactory tests (p < 0.0001) compared to the control group. Both MP and L-DOPA-treated groups showed alleviation in latencies in beam balance and olfactory tests and decreased neuroinflammation in ELISA analysis (p < 0.001). The results treated by MP and L-DOPA showed insignificant differences in their values (p > 0.05). This proved that the MP and L-DOPA had similar effects in improving the symptoms of PD when used in the ratio of 1:20. Furthermore, both MP and L-DOPA reduced the level of IL-6 and TGF-$\beta 1$ in this study. It may be inferred that a reduction in the level of IL-6 and TGF-$\beta 1$ eventually leads to a reduction in the Th17 cells. The pathogenic Th17 is thought to be present in virtually all chronic inflammatory disorders. This can be an interesting area of research in further understanding the immunological effect of MP in ameliorating PD symptoms. Full article

Levodopa (L-DOPA) treatment represents the gold standard therapy for Parkinson’s disease (PD) patients. L-DOPA therapy shows many side effects, among them, L-DOPA-induced dyskinesias (LIDs) remain the most problematic. Several are the mechanisms underlying these processes: abnormal corticostriatal neurotransmission, pre- and post-synaptic neuronal events, changes in gene expression, and altered plasticity. In recent years, researchers have also suggested non-neuronal mechanisms as a possible cause for LIDs. We reviewed recent clinical and pre-clinical studies on neuroinflammation contribution to LIDs. Microglia and astrocytes seem to play a strategic role in LIDs phenomenon. In particular, their inflammatory response affects neuron-glia communication, synaptic activity and neuroplasticity, contributing to LIDs development. Finally, we describe possible new therapeutic interventions for dyskinesia prevention targeting glia cells. Full article

Parkinson’s disease (PD) is one of the most unremitting and dynamic neurodegenerative human diseases. Various wearable IoT devices have emerged for detecting, diagnosing, and quantifying PD, predominantly utilizing inertial sensors and computational algorithms. However, their proliferation poses novel challenges concerning security, privacy, connectivity, and power optimization. Clinically, continuous monitoring of patients’ motor function is imperative for optimizing Levodopa (L-dopa) dosage while mitigating adverse effects and motor activity decline. Tracking motor function alterations between visits is challenging, risking erroneous clinical decisions. Thus, there is a pressing need to furnish medical professionals with an ecosystem facilitating comprehensive Parkinson’s stage evaluation and disease progression monitoring, particularly regarding tremor and bradykinesia. This study endeavors to establish a holistic ecosystem centered around an energy-efficient Wi-Fi-enabled wearable bracelet dubbed A-WEAR. A-WEAR functions as a data collection conduit for Parkinson’s-related motion data, securely transmitting them to the Cloud for storage, processing, and severity estimation via bespoke learning algorithms. The experimental results demonstrate the resilience and effectiveness of the suggested technique, with 86.4% accuracy for bradykinesia and 90.9% accuracy for tremor estimation, along with good sensitivity and specificity for each scoring class. The recommended approach will support the timely determination of the severity of PD and ongoing patient activity monitoring. The system helps medical practitioners in decision making when initially assessing patients with PD and reviewing their progress and the effects of any treatment. Full article

Background: Loss of substantia nigra dopaminergic cells and alpha-synuclein (α-syn)-rich intraneuronal deposits within the central nervous system are key hallmarks of Parkinson’s disease (PD). Levodopa (L-DOPA) is the current gold-standard treatment for PD. This study aimed to evaluate in vivo retinal changes in a transgenic PD model of α-syn overexpression and the effect of acute levodopa (L-DOPA) treatment. Methods: Anaesthetised 6-month-old mice expressing human A53T alpha-synuclein (HOM) and wildtype (WT) control littermates were intraperitoneally given 20 mg/kg L-DOPA (50 mg levodopa, 2.5 mg benserazide) or vehicle saline (n = 11–18 per group). In vivo retinal function (dark-adapted full-field ERG) and structure (optical coherence tomography, OCT) were recorded before and after drug treatment for 30 min. Ex vivo immunohistochemistry (IHC) on flat-mounted retina was conducted to assess tyrosine hydroxylase (TH) positive cell counts (n = 7–8 per group). Results: We found that photoreceptor (a-wave) and bipolar cell (b-wave) ERG responses (p < 0.01) in A53T HOM mice treated with L-DOPA grew in amplitude more (47 ± 9%) than WT mice (16 ± 9%) treated with L-DOPA, which was similar to the vehicle group (A53T HOM 25 ± 9%; WT 19 ± 7%). While outer retinal thinning (outer nuclear layer, ONL, and outer plexiform layer, OPL) was confirmed in A53T HOM mice (p < 0.01), L-DOPA did not have an ameliorative effect on retinal layer thickness. These findings were observed in the absence of changes to the number of TH-positive amacrine cells across experiment groups. Acute L-DOPA treatment transiently improves visual dysfunction caused by abnormal alpha-synuclein accumulation. Conclusions: These findings deepen our understanding of dopamine and alpha-synuclein interactions in the retina and provide a high-throughput preclinical framework, primed for translation, through which novel therapeutic compounds can be objectively screened and assessed for fast-tracking PD drug discovery. Full article

Levodopa (L-DOPA) treatment, combined with the administration of dopa-decarboxylase inhibitors (DDCIs), is still the most effective symptomatic treatment of Parkinson’s disease (PD). Although its efficacy in the early stage of the disease has been confirmed, its complex pharmacokinetics (PK) increases the variability of the intra-individual motor response, thus amplifying the risk of motor/non-motor fluctuations and dyskinesia. Moreover, it has been demonstrated that L-DOPA PK is strongly influenced by several clinical, therapeutic, and lifestyle variables (e.g., dietary proteins). L-DOPA therapeutic monitoring is therefore crucial to provide personalized therapy, hence improving drug efficacy and safety. To this aim, we have developed and validated an ultra-high performance liquid chromatography–tandem mass spectrometry (UHPLC-MS/MS) method to quantify L-DOPA, levodopa methyl ester (LDME), and the DDCI carbidopa in human plasma. The compounds were extracted by protein precipitation and samples were analyzed with a triple quadrupole mass spectrometer. The method showed good selectivity and specificity for all compounds. No carryover was observed, and dilution integrity was demonstrated. No matrix effect could be retrieved; intra-day and inter-day precision and accuracy values met the acceptance criteria. Reinjection reproducibility was assessed. The described method was successfully applied to a 45-year-old male patient to compare the pharmacokinetic behavior of an L-DOPA-based medical treatment involving commercially available Mucuna pruriens extracts and an LDME/carbidopa (100/25 mg) formulation. Full article

Background and aims: Although the distinction between vascular parkinsonism (VP) and idiopathic Parkinson’s disease (IPD) is widely described, it is not uncommon to find parkinsonisms with overlapping clinical and neuroimaging features even in response to levodopa treatment. In addition, several treatments have been described as possible adjuvants in VP. This study aims to update and analyze the different treatments and their efficacy in VP. Methods: A literature search was performed in PubMed, Scopus and Web of Science for studies published in the last 15 years until April 2022. A systematic review was performed. No meta-analysis was performed as no new studies on response to levodopa in VP were found since the last systematic review and meta-analysis in 2017, and insufficient studies on other treatments were located to conduct it in another treatment subgroup. Results: Databases and other sources yielded 59 publications after eliminating duplicates, and a total of 12 original studies were finally included in the systematic review. The treatments evaluated included levodopa, vitamin D, repetitive transcranial magnetic stimulation (rTMS) and intracerebral transcatheter laser photobiomodulation therapy (PBMT). The response to levodopa was lower in patients with VP with respect to IPD. Despite this, there has been described a subgroup of patients with good response, it being possible to identify them by means of neuroimaging techniques and the olfactory identification test. Other therapies showed encouraging results in studies with some risk of bias. Conclusions: The response of VP to different therapeutic strategies is modest. However, there is evidence that a subgroup of patients can be identified as more responsive to L-dopa based on clinical and neuroimaging criteria. This subgroup should be treated with L-dopa at appropriate doses. New therapies such as vitamin D, rTMS and PBMT warrant further studies to demonstrate their efficacy. Full article

Levodopa (L-dopa) and catechol-O-methyltransferase (COMT) inhibition are widely used therapeutics in Parkinson’s disease (PD). Despite their therapeutic effects, it was raised that nutrients involved in one-carbon metabolism can be deteriorated by PD therapies. The aim of this meta-analysis was to investigate the impact of L-dopa and COMT inhibitors on levels of homocysteine (Hcy), vitamin B₁₂ and folate in patients with PD. A total of 35 case-control studies from 14 different countries were selected through PubMed, MEDLINE and Google Scholar and were meta-analyzed. In the L-dopa group, the Hcy level was higher compared to the PD without L-dopa group (SMD: 5.11 μmol/L, 95% CI: 3.56 to 6.66). Moreover, vitamin B₁₂ and folate levels in the L-dopa group were lower compared to the healthy control (SMD: −62.67 pg/mL, 95% CI: −86.53 to −38.81; SMD: −0.89 ng/mL, 95% CI: −1.44 to −0.33, respectively). The COMT inhibitor group showed lower levels of Hcy (SMD: −3.78 μmol/L, 95% CI: −5.27 to −2.29) and vitamin B₁₂ (SMD: −51.01 pg/mL, 95% CI: −91.45 to −10.57), but higher folate levels (SMD: 1.78 ng/mL, 95% CI: −0.59 to 4.15) compared to the L-dopa group. COMT inhibitors may ameliorate L-dopa-induced hyper-homocysteine and folate deficiency but exacerbate vitamin B₁₂ deficiency. Full article

Levodopa (L-DOPA) is an essential drug for the treatment of Parkinson’s disease. Currently, L-DOPA can be produced by chemical synthesis and can also be found naturally in many herbs, especially Mucuna Pruriens (MP). According to clinical research, the MP extract containing L-DOPA for the treatment of Parkinson’s disease could reduce side effects more than the synthetic one. Unfortunately, MP extracts can be easily degraded. Changes in physical and chemical properties such as the appearance (color, melt, solid lump) and the reduction of L-DOPA content in the extract were commonly observed. Therefore, it is necessary to develop an extraction procedure to stabilize the extract of L-DOPA. This study attempted to enhance the extraction process by modifying the traditional acidification approach using hydrochloric acid, citric acid, or ascorbic acid. According to the stability test results, using Phyllanthus emblica water (PEW) as a solvent improved the preservative properties more than other solvents. The color of the PEW-MP powder changed slightly after 12 months of accelerated storage, but the amount of L-DOPA remained the highest (73.55%). Moreover, L-DOPA was only detected in MP and PEW-MP, but not PEW alone (the HPTLC chromatogram at Rf 0.48 and the HPLC chromatogram at Rt 6.0 min). The chemical profiles of PEW and L-DOPA observed in the chromatograms indicated that they are independently separated. As a result, they can be applied to a quality control process. Therefore, PEW was proven to be a powerful solvent for L-DOPA herbal extract that could be readily used as a raw material for herbal products. Full article

The primary treatment for Parkinson’s disease (PD) is supplementation of levodopa (L-dopa). With disease progression, people may experience motor and non-motor fluctuations, whereby the PD symptoms return before the next dose of medication. Paradoxically, in order to prevent wearing-off, one must take the next dose while still feeling well, as the upcoming off episodes can be unpredictable. Waiting until feeling wearing-off and then taking the next dose of medication is a sub-optimal strategy, as the medication can take up to an hour to be absorbed. Ultimately, early detection of wearing-off before people are consciously aware would be ideal. Towards this goal, we examined whether or not a wearable sensor recording autonomic nervous system (ANS) activity could be used to predict wearing-off in people on L-dopa. We had PD subjects on L-dopa record a diary of their on/off status over 24 hours while wearing a wearable sensor (E4 wristband^®) that recorded ANS dynamics, including electrodermal activity (EDA), heart rate (HR), blood volume pulse (BVP), and skin temperature (TEMP). A joint empirical mode decomposition (EMD) / regression analysis was used to predict wearing-off (WO) time. When we used individually specific models assessed with cross-validation, we obtained > 90% correlation between the original OFF state logged by the patients and the reconstructed signal. However, a pooled model using the same combination of ASR measures across subjects was not statistically significant. This proof-of-principle study suggests that ANS dynamics can be used to assess the on/off phenomenon in people with PD taking L-dopa, but must be individually calibrated. More work is required to determine if individual wearing-off detection can take place before people become consciously aware of it. Full article

There are ten million people in the world who have Parkinson’s disease. The most potent medicine for Parkinson’s disease is levodopa (L-DOPA). However, long-term consumption of L-DOPA leads to the appearance of side effects, as a result of which the control and monitoring of its concentrations are of great importance. In this work, we have designed a new electrochemical sensor for detecting L-DOPA using a carbon paste electrode (CPE) modified with Eu₂O₃@Cr₂O₃ composite nanoparticles. Rare earth elements, including Eu, are increasingly used to design new electrode nanocomposites with enhanced electrocatalytic properties. Europium has been considered a significant lanthanide element with greater redox reaction behavior. We conducted a hydrothermal synthesis of Eu₂O₃@Cr₂O₃ and, for the first time, the acquired nanoparticles were used to modify CPE. The proposed Eu₂O₃@Cr₂O₃/CPE electrode was investigated in terms of its electrocatalytic properties and then used to develop an analytical method for detecting and quantifying L-DOPA. The proposed sensor offers a wide linear range (1–100 µM), high sensitivity (1.38 µA µM⁻¹ cm⁻²) and a low detection limit (0.72 µM). The practical application of the proposed sensor was investigated by analyzing commercially available pharmaceutical tablets of L-DOPA. The corresponding results indicate the excellent potential of the Eu₂O₃@Cr₂O₃/CPE sensor for application in real-time L-DOPA detection. Full article