Search Results (388)

Brucella abortus is an intracellular pathogen that must withstand oxidative stress and other hostile conditions encountered within host cells. Here, we investigated the contribution of BAB2_0534, a gene encoding a putative multicopper oxidase, to bacterial adaptation and persistence. Deletion of BAB2_0534 impaired pigment production in the presence of the melanin precursors L-DOPA and homogentisic acid, supporting a role for BAB2_0534 in phenolic substrate oxidation and melanin-like pigment biosynthesis. The mutant also exhibited increased susceptibility to oxidative stress and reduced survival with macrophages, indicating that BAB2_0534 contribute to intracellular adaptation. In vivo, mice infected with the ΔBAB2_0534 mutant showed significantly reduced splenic bacterial burdens compared with animals infected with the wild-type or complemented strains, demonstrating impaired persistence during infection. Consistently, Fontana–Masson-positive pigment was detected in tissues from wild-type-infected animals but was markedly reduced following infection with the mutant. Collectively, these findings support a model in which BAB2_0534-associated multicopper oxidase activity and pigment production contribute to oxidative stress resistance and intracellular persistence of B. abortus. This study characterizes BAB2_0534 as a previously unrecognized component of the adaptive mechanisms underlying Brucella persistence. Full article

This study investigated non-conventional crops as raw materials for plant-based fermented functional products with potential neuromodulatory properties, assessing antioxidant activity, amino acid composition, neuroactive metabolites, and aroma profile. Antioxidant activity depended not only on total phenolic content but also on the composition and extractability of other bioactive and reducing constituents released during processing. Free amino acid and γ-aminobutyric acid (GABA) profiles differed markedly from the raw grains, reflecting the effects of enzymatic hydrolysis, formulation, and microbial fermentation. The naked oat fermented product (NOFP) had the highest total, essential and branched-chain free amino acid contents and contained serotonin (811 µg/kg). The triticale fermented product (TFP) showed high phenylethylamine (440 µg/kg), proline and glutamine, and the highest diacetyl content (502 ng/g), potentially contributing to its nutritional and sensory properties. The amaranth fermented product (AFP) was distinguished by high GABA (648.9 mg/kg DW) and L-DOPA (15,272 µg/kg). Kynurenine, kynurenic acid, indole-3-lactic acid, tryptamine, and other tryptophan and tyrosine metabolites were also detected. Volatile profiles were strongly matrix-dependent; AFP was the most diverse, with high levels of aldehydes, pyrazines, furans, and sulfur-containing compounds. Overall, the grain matrix and the processing and formulation sequence strongly influence the nutritional, antioxidant, neuroactive, and aroma characteristics of the products. Full article

Current Parkinson’s disease (PD) therapies like Levodopa (L-DOPA) only provide symptomatic relief, highlighting the need for multi-target neuroprotective agents. This study investigates the mechanisms and preclinical effects of trans-vitisin B (tVB), an oligomeric stilbene, in PD models. In LPS-stimulated HMC3 and RAW 264.7 cells, tVB (0.1–10.0 µM) significantly suppressed reactive oxygen species (ROS), nitric oxide (NO), COX-2, and pro-inflammatory cytokines (IL-1β, TNF-α), while restoring HSP70 chaperone levels to normalize proteostasis. These findings were validated in vivo using C57BL/6 mice with rotenone-induced chronic PD. Administration of tVB attenuated motor deficits (Cylinder test) and reduced pathological freezing (Open Field) and working memory impairments (Y-maze) in this model, without inducing the dyskinesia-like side effects of L-DOPA treatment in rodents. Histologically, tVB mitigated the loss of dopaminergic neurons (TH⁺) in the substantia nigra, reduced microglial activation (IBA-1⁺) and neuronal NO synthase, and suppressed pathological phosphorylated Tau protein (p-TauSer202) accumulation. Unlike L-DOPA’s direct dopaminergic stimulation, tVB’s neuroprotective efficacy is mediated through multilevel regulation of key PD pathogenetic pathways, including neuroinflammation, oxidative stress, and impaired proteostasis. Full article

Background: COVID-19 vaccines have proven effective in reducing severe disease and mortality from SARS CoV-2 infection. The underlying molecular mechanisms and alterations in the human serum metabolome influencing the effectiveness and development of immunity remain unclear. Methods: Serum samples were collected from 29 healthy individuals at three time points: prior to vaccination (A), post-first dose (B), and post-second dose (C). Untargeted high-resolution (HR) liquid chromatography coupled with mass spectrometry (LC-MS) was performed on these samples. Metabolites showing significant differential abundance at each time point were identified, and both multivariate and univariate statistical analyses were performed to determine changes associated with the pairwise comparisons, priming (A vs. B), booster (B vs. C), and the overall vaccine effect (A vs. C). Vaccination-specific features were determined after excluding metabolites associated with SARS-CoV-2 IgG seropositivity to better isolate vaccine-driven metabolic changes. Bioinformatics, pathway, and network analyses were conducted using Ingenuity Pathway Analysis (IPA) to identify relevant pathways. Results: Our study identified significant metabolic changes across the three time points. A total of 377 metabolites were identified, of which 59 metabolites, including prostaglandins, eicosanoids, and lipids, were shared across all three groups. The majority of these metabolites showed an initial decrease after the first dose, followed by broad upregulation after the second dose. We identified 1 (downregulated), 34 (26 upregulated and 8 downregulated), and 18 (2 upregulated and 16 downregulated) unique metabolites in the priming, booster, and the overall vaccine effect groups, respectively. L-3-hydroxykynurenine was observed to be significantly reduced by the priming dose effect. By contrast, the booster effect showed decreased myo-inositol 1,3,4,5-tetrakisphosphate, while levels of DL-DOPA, 3-methoxytyrosine, and prostaglandin-esterified phospholipids, including PC(P-16:0/PGF1α) and PE(PGF1α/18:0), increased. On the other hand, the overall vaccine effect revealed decreased cyclic AMP and increased 3′-O-methyladenosine levels. These changes were associated with perturbations in arachidonic acid metabolism, glycerophospholipid metabolism, arginine biosynthesis, and steroid hormone biosynthesis. IPA network analysis identified AKT, TP53, EGFR, and cAMP as key dysregulated nodes. Conclusions: Longitudinal metabolomic profiling demonstrated that COVID-19 vaccination induced distinct but interrelated biochemical changes throughout the vaccination course. The priming dose induced a limited set of early metabolic changes, whereas the booster was associated with more significantly changed metabolites that were involved in lipid, bile acid, steroid, amino acid, and nucleotide pathways. Together, these findings indicate that sequential vaccination is associated with dose-dependent systemic metabolic adaptation, with the booster dose having the largest number of dysregulated metabolites. Full article

Dysregulation of the microbiota–gut–brain axis has been implicated in Parkinson’s disease (PD), and modulation of the intestinal microbiota may offer a complementary nutritional approach. This study evaluated the preventive attenuation of MPTP-induced PD-like abnormalities by Lactiplantibacillus plantarum SHOU LAC-1 and examined associated microbiota–gut–brain axis-related changes. Forty male C57BL/6J mice were allocated to Control, MPTP, L-DOPA, and SHOU LAC-1 groups (n = 10 per group). SHOU LAC-1 was orally administered at 1 × 10⁹ CFU per mouse per day for 42 days, with MPTP administered during the final 14 days; L-DOPA was administered during the MPTP-treatment period as a positive control. Motor performance and defecatory parameters, nigrostriatal TH and α-SYN immunoreactivity, neurotrophic-support-related gene expression, inflammatory markers, glial-cell-related gene expression, Nrf2-related antioxidant gene expression, colonic histopathology and tight-junction-related gene expression, gut microbiota composition, and serum metabolic profiles were assessed. Compared with MPTP-treated mice, SHOU LAC-1-treated mice showed better motor and defecatory performance, partial preservation of nigrostriatal TH immunoreactivity, reduced α-SYN immunoreactivity, increased neurotrophic-support-related gene expression, lower central and colonic inflammatory markers and glial-cell-related gene expression, increased Nrf2/HO-1/NQO1-related antioxidant gene expression, and comparatively better-preserved colonic morphology with higher tight-junction-related gene expression. 16S rRNA sequencing and untargeted serum metabolomics further showed that SHOU LAC-1 administration was accompanied by changes in gut microbial diversity and composition and serum metabolic profiles. Overall, under this preventive experimental design, SHOU LAC-1 administration was associated with attenuation of multiple MPTP-induced PD-like abnormalities, accompanied by changes in gut microbial and serum metabolic profiles. These preclinical findings are predominantly associative; causal relationships among microbial, metabolic, intestinal, and neurological changes remain to be established, and the translational relevance of SHOU LAC-1 requires further validation. Full article

Tilia americana var. mexicana is a medicinal species whose reported pharmacological effects primarily target the central nervous system, including anxiolytic, antidepressant, and anticonvulsant activities, attributed in part to flavonoids such as tiliroside (8). In this study, 14 compounds were isolated and identified from the methanolic extract (Ta-MeOH) and evaluated by molecular docking against the monoamine oxidases MAO-A and MAO-B, enzymes implicated in Parkinson’s disease (PD) due to their involvement in dopamine metabolism. Chemical analysis identified six terpenes: α- and β-amyrine (1–2), β-sitosterol (3), stigmasterol (4), ursolic acid (5), and β-sitosterol glucoside (6); the novel diglycosylated monoterpene 4α-terpineol sambubioside (7), characterized through its hexaacetate derivative (7a); the flavonoids tiliroside (8) and rutin (9); sucrose (10); and four phenolic compounds: scopoletin (11), caffeic acid (12), coumaric acid (13), and chlorogenic acid (14). Molecular docking against monoamine oxidases A and B (MAO-A and MAO-B) was used as a computational strategy to prioritize isolated metabolites for biological evaluation. β-Sitosterol glucoside (6), 4α-terpineol sambubioside (7), tiliroside (8) and rutin (9) exhibited the most favorable docking scores toward MAO-B, with predicted binding energies of −10.8733, −11.1434, −12.16986 and −12.9474 kcal/mol, respectively. Considering the docking results together with phytochemical and experimental criteria, (6) and (8) (1 mg/kg) were prioritized for biological evaluation, together with Ta-MeOH extract (100 mg/kg) and selected fractions (25 mg/kg), in a reserpine-induced mouse model of parkinsonism using L-DOPA (150 mg/kg) as a positive control. In the open field test, spontaneous locomotor activity was assessed by total crossings and expressed as AUC. Ta-MeOH significantly increased locomotor activity compared with the reserpine-treated group (AUC: 1281.8 vs. 551.7, respectively; p < 0.05). Tiliroside (8) also increased locomotor activity (AUC: 858). In the Rota-Rod test, fine motor coordination was assessed by latency to fall and expressed as AUC. Ta-MeOH showed the greatest recovery, with AUC values of 431, 89, and 34 at 4, 10, and 20 rpm, respectively. In addition, treatments derived from T. americana attenuated behavioral alterations induced by reserpine in the Irwin test. Overall, this study demonstrates that integrating phytochemical isolation, molecular docking, and in vivo pharmacological evaluation provides a useful strategy for prioritizing bioactive metabolites from T. americana. These findings support further pharmacological investigation of this medicinal species and its isolated metabolites, while additional studies are required to establish their molecular targets and mechanisms of action. Full article

Mucuna pruriens (Linn.) DC. var. pruriens is used as a traditional medication to enhance male sexual function, yet integrated evidence linking vascular-cell mechanisms to in vivo efficacy and safety of a standardized extract remains limited. This study evaluated the ethanolic seed extract of M. pruriens var. pruriens (MPSE) on erectile function-related mechanisms, addressing the nitric oxide (NO)–cyclic guanosine monophosphate (cGMP)–phosphodiesterase type 5 (PDE5) pathway in vitro, together with mounting frequency, anxiety-like behavior, locomotor activity, and cardiovascular safety in vivo. Soxhlet extraction with 80% ethanol yielded a dark brown, syrupy extract (12.28% w/w), which was standardized by high-performance thin-layer chromatography to contain 278 mg/g extract (27.8% w/w) of L-DOPA (Rf 0.38). Mechanistic effects were assessed in human umbilical vein endothelial cells (HUVECs), pulmonary artery smooth muscle cells (PASMCs), and a PDE5A1 enzyme assay. Male Wistar rats received MPSE (50, 100, and 200 mg/kg) orally for 15 days, with hemodynamic assessment in normotensive and Nω-nitro-L-arginine methyl ester (L-NAME)-induced hypertensive rats. MPSE significantly increased eNOS expression and NO production in HUVECs, elevated intracellular cGMP in PASMCs, and directly inhibited PDE5A1 enzymatic activity. Repeated administration significantly increased mounting frequency relative to baseline without altering serum testosterone levels, anxiety-like behavior, locomotor activity, mean arterial pressure, or heart rate. These findings indicate that MPSE modulates erectile function-related mechanisms, primarily through peripheral vascular effects on the NO–cGMP–PDE5 pathway, and suggest a favorable safety profile. Erectile function itself was not directly assessed and warrants confirmation in models of erectile response. MPSE nevertheless represents a promising plant-derived candidate for erectile dysfunction. Full article

Background: Parkinson’s disease (PD) is characterized by a complex interplay of dopaminergic degeneration, glial activation, and lipid metabolic dysregulation. However, accurately describing how natural product interventions remodel these pathologies across distinct brain regions and cellular microenvironments remains a critical challenge. Methods: We established an integrated multi-omics framework to decode the neuroprotective mechanisms of solanesol (Sol) in an MPTP-induced PD mouse model. We combined single-cell eQTL-based Mendelian randomization (scMR), transcriptomic localization, and virtual knockout analyses to prioritize cell-type-specific regulatory nodes across neuronal, glial, and vascular populations, avoiding the limitations of traditional bulk targeting. In vivo behavioral assays were conducted, alongside orthogonal validation via airflow-assisted desorption electrospray ionization mass spectrometry imaging (AFADESI-MSI) and gene–metabolite co-enrichment analysis, to map regional metabolic networks and structural spatial reprogramming. Results: Computational prioritization highlighted cell-type-specific regulatory nodes including PRKCB, PRKCE, PDGFRB, and FABP3/5. In vivo, Sol attenuated motor and cognitive deficits and largely restored the highly compartmentalized spatial distributions of striatal dopamine, L-DOPA, and acetylcholine. Crucially, AFADESI-MSI and co-enrichment analysis revealed that Sol specifically reversed MPTP-induced spatial disruptions by rescuing key neuromodulatory metabolites—including cervonoyl ethanolamide, phosphatidylcholine species, taurine, and NADHX—which were tightly coupled to sphingolipid signaling, fatty-acid transport, mitochondrial translation, and cell-adhesion pathways. Conclusions: Sol ameliorates PD-like pathology not through a singular target, but by choreographing a spatially and cellularly compartmentalized restoration of lipid–inflammatory homeostasis. Furthermore, our integrated single-cell and spatial metabolomic blueprint sets a new methodological paradigm for elucidating the precise execution programs of natural neurotherapeutics. Full article

Parkinson’s disease (PD), impacting millions worldwide, leads to motor deficits and various non-motor symptoms. Although there is no cure, treatment primarily involves dopamine replacement therapy, especially L-dopa for motor symptoms, and additional drugs are required to address non-motor effects. This underscores the increasing demand for dual-acting drugs that can effectively target both symptom types in PD. This study explored the potential effects of a standardised Mesembryanthemum tortuosum extract, Zembrin^®, in treating PD, utilising in vivo and in silico models. Zebrafish larvae were subjected to pre-treatment with reserpine, followed by exposure to Zembrin^®, with selegiline and L-dopa as positive controls. The in vivo component of this study monitored locomotion and oxidative stress, while the in silico component identified potential drug targets for the treatment of PD. Reserpine induced hypolocomotion and oxidative stress in zebrafish larvae, and Zembrin^® (12.5 µg/mL) effectively enhanced locomotion and reduced oxidative stress. The molecular docking, molecular dynamics simulations, and binding free energy calculations revealed that four mesembrine alkaloids (mesembranol, mesembrenol, mesembrenone, and mesembrine) form stable and energetically favourable complexes with monoamine oxidase B (MAO-B) and dopamine transporter (DAT), which are significant targets for addressing both the motor and non-motor effects of PD. Full article

Levodopa-induced dyskinesia (LID) is a severe motor complication associated with long-term levodopa (L-DOPA) treatment for Parkinson’s disease (PD). Its underlying mechanisms remain unclear, and candidate biomarkers lack consistency. To investigate cortico-striatal network alterations associated with LID, we simultaneously recorded single-neuron spikes and local field potentials (LFPs) from the dorsolateral striatum (DLS) and the primary motor cortex (M1) in LID rats. Our results showed that in the DLS, the LID group had a greater number of putative fast-spiking interneurons (FSIs) with lower firing rates, and fewer putative medium spiny neurons (MSNs) with higher firing rates. In M1, pyramidal neurons were fewer but fired faster, while interneurons were more numerous with no change in firing rate. Although gamma power increased and delta power decreased in both regions in LID rats, delta-gamma phase-amplitude coupling (PAC) was present in the DLS but absent in M1. Furthermore, cross-regional PAC analysis revealed significantly stronger coupling between the low-frequency phase of M1 and the high-frequency amplitude of the DLS than in the opposite direction, indicating an asymmetric pattern of cortico-striatal coupling in LID. These findings demonstrate region-specific alterations in neuronal activity and oscillatory coupling associated with LID and suggest that asymmetric cortico-striatal PAC may serve as a promising electrophysiological marker for characterizing abnormal network dynamics underlying dyskinesia. Full article

Background/Objectives: Aromatic L-amino acid decarboxylase deficiency (AADC-D; OMIM #608643) is a rare autosomal recessive neurometabolic disorder caused by pathogenic variants in the DDC gene, leading to impaired of monoamine neurotransmitter biosynthesis. AADC, a pyridoxal-5′-phosphate (PLP)-dependent enzyme, catalyzes the conversion of L-dopa and 5-hydroxytryptophan (5-HTP) to dopamine and serotonin, respectively. Early diagnosis remains challenging due to the limited specificity of current biochemical approaches. This study aimed to evaluate plasma AADC enzyme activity using these physiological substrates by High-Performance Liquid Chromatography (HPLC)-based method and assess its potential utility in the biochemical diagnosis of AADC deficiency. Methods: Plasma AADC activity was quantified using physiological substrates (L-dopa and 5-HTP) by HPLC with electrochemical and fluorescence detection. Sanger sequencing of the DDC gene was performed in two suspected patients to identify pathogenic variants. Results: Two genetically confirmed AADC-D patients demonstrated reduced enzyme activity. Using L-dopa as substrate, enzyme activity in patients was 12.4 and 26.1 pmol/min/mL, both below the published reference interval (36–129 pmol/min/mL). Using 5-HTP as substrate, enzyme activity was 1.5 and 5.1 pmol/min/mL; Patient 1 showed activity below the reference interval (2.0–7.1 pmol/min/mL), while Patient 2 demonstrated activity within the lower range of reported values. Reduced enzyme activity was consistent with the clinical features and molecular findings with identification of pathogenic variants in the DDC gene (c.175G>A and c.714+4A>T). Conclusions: Plasma AADC activity measurement demonstrates potential as a functional biochemical biomarker that augments molecular genetic testing in the biochemical evaluation of AADC deficiency. Further studies involving larger patient cohorts are required to further evaluate its diagnostic performance and broader clinical applicability. Full article

Metanephrine (MN) and normetanephrine (NMN) are critical biomarkers for neuroendocrine tumors (pheochromocytoma and paraganglioma). Following our previous development of a molecularly imprinted solid-phase extraction (MISPE) sorbent for urine analysis, this study evaluated MISPE coupled with HILIC-MS/MS for determining metanephrines in human plasma. Unlike conventional phases, the novel polymer selectively binds analytes as in situ-generated anions via quaternary alkylammonium groups in hydroxide form, ensuring accurate extraction from just 25 µL of plasma. Validated per U.S. FDA guidelines, the assay showed good intra- and interday precision (CV < 10.8%), accuracy (bias < −10.6%) and excellent linearity (R² > 0.99) across pathological ranges (184.3–877.8 ng/L for MN; 174.8–923.0 ng/L for NMN), with low relative standard errors (<6.9%). Excellent selectivity was demonstrated in the presence of structurally close analogs (catecholamines, DOPA and its derivatives). Compared with commercial WCX, the sorbent yielded cleaner extracts, significantly reducing the phospholipid interference. Although lower limits of quantification (92.2 ng/L MN; 87.4 ng/L NMN) slightly exceeded healthy upper thresholds, the method has potential for use in specific clinical scenarios with pronounced biomarker elevations: diagnosis of pheochromocytoma/paraganglioma, monitoring post-treatment metanephrine decline, and tracking tumor-induced hypertensive crises in emergencies. This accessible protocol forms a solid foundation for advanced diagnostics. Full article

The effects of antidepressants on limbic structures, important in the context of the treatment of Parkinson’s disease (PD)-associated depression, are relatively poorly explored in animal models. The present study investigated the impact of the tricyclic antidepressant amitriptyline (AMI), administered chronically alone or in combination with L-DOPA, on anhedonia, monoamine levels, and the binding of radioligands to their transporters in the limbic structures of unilaterally 6-OHDA-lesioned rats. Anhedonia, as a core symptom of depression, was evaluated using the sucrose preference test. Tissue concentrations of noradrenaline (NA), dopamine (DA) and serotonin (5-HT) and their metabolites in the prefrontal cortex (PFC) and hippocampus (HIP) were assayed by HPLC method. Bindings of [³H]nisoxetine to noradrenaline transporter (NET), [³H]GBR 12,935 to dopamine transporter (DAT), and [³H]citalopram to serotonin transporter (SERT) in the nucleus accumbens (NAcc), PFC, and HIP were analyzed by autoradiography. Three weeks of treatment of unilaterally 6-OHDA-lesioned rats with AMI alone significantly reduced the intake of sucrose solution compared to the sham-operated control, but the combined administration of AMI+L-DOPA enhanced sucrose consumption. Administration of AMI+L-DOPA increased tissue DA concentrations in the lesioned and intact PFC and HIP more distinctly than L-DOPA alone. L-DOPA alone significantly decreased tissue 5-HT content in the lesioned PFC and HIP, while the addition of AMI reversed this effect. 6-OHDA administered unilaterally into the MFB drastically decreased DAT binding in the lesioned NAcc while increasing it on the intact side. Neither AMI nor L-DOPA, given alone or jointly, affected DAT binding in the lesioned NAcc. SERT binding was significantly reduced in the PFC, NAcc and HIP on both sides of the brain in the AMI- or AMI+L-DOPA-treated groups. NET binding decreased in the PFC and NAcc in the AMI-treated group, but no such effect was observed in the AMI+L-DOPA-treated group. The obtained results are discussed in relation to the impaired psychiatric functions in PD. Full article

Background/Objectives: Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by dopaminergic neuronal loss, oxidative stress, and mitochondrial dysfunction. Although levodopa (L-Dopa) remains the main symptomatic treatment, prolonged administration can lead to adverse effects. Safranal, a bioactive constituent of Crocus sativus, has antioxidant and anti-apoptotic properties. This study evaluated the neuroprotective potential of L-Dopa and safranal, individually and in combination, in an in vitro cell-culture PD model. Methods: SH-SY5Y human neuroblastoma cells were treated with 6-hydroxydopamine (6-OHDA, 50 µM) to induce cytotoxicity. Cells were pretreated with L-Dopa (5–500 µM) and safranal (1–500 µM and 1–5 mM) for 4 or 24 h. Cell viability was assessed using 3-(4, 5-dimethylthiazol-2-yl)2,5-diphenyl-tetrazolium bromide (MTT) and lactate dehydrogenase (LDH) assays. Mitochondrial membrane potential (MMP), caspase-3/7 activity, and autophagy markers were also evaluated. Synergy was analyzed using Combination Index (CI) analysis. Furthermore, mRNA levels of circadian rhythm associated genes were also evaluated. Results: 6-OHDA significantly impaired cell viability and mitochondrial function. Pretreatment with low doses of L-Dopa and safranal partially improved cell viability and reduced apoptosis and showed a tendency to decrease autophagy-associated marker levels. Higher L-Dopa concentrations caused mild cytotoxicity, while high-dose safranal exhibited pronounced concentration-dependent toxicity. CI analysis confirmed synergistic interaction between both drugs in mitigating 6-OHDA-induced toxicity. Combined treatment markedly improved cell survival preserved mitochondrial function, and reduced caspase-3/7 activity compared with monotherapy. A significant increase in the mRNA levels of Per1, Clock, Bmal1 and Cry1 genes was observed in groups treated with L-Dopa and safranal together. Conclusions: L-Dopa and safranal exerted concentration-dependent neuroprotective effects in SH-SY5Y cells. Their combination enhanced cytoprotection, which was associated with modulation of mitochondrial function, oxidative stress, apoptosis, and autophagy-related responses. Full article

Background: The term dyskinesia describes involuntary movements of the face, body and extremities. Frequently, they appear following and in relation with prior oral long-lasting and high-dose levodopa therapy in Parkinson’s disease patients. Onset of these motion sequences causes patient distress and caregiver embarrassment with declined quality of life. Continuity of nigrostriatal postsynaptic dopamine receptor stimulation delays occurrence of dyskinesia. A pulsatile pattern with temporary too high dopamine receptor excitation promotes manifestation of dyskinesia. Methods: This narrative review describes past pharmacologic approaches for therapy of dyskinesia, such as the principle of continuous dopamine receptor stimulation. Discussion and Conclusions: Novel concepts were tested. They influenced neurotransmission of serotonin and altered stimulation of dopamine receptor subtypes. The translation of successful experimental research outcomes into valuable clinical trial results with consecutive approval of drugs with a new mode of action under the indication “antidyskinetic” repeatedly failed. An exception is the open-channel blocker of the N-methyl-D-aspartate receptor and dopamine reuptake inhibitor amantadine with its moderate dyskinesia-reducing effects, particularly in its extended-release formulation. This antiviral compound also improves impaired motor behavior and reduces “OFF” intervals. Therefore, amantadine is currently experiencing a certain resurgence in regions where its extended-release formulations are marketed for therapy of levodopa-induced dyskinesia. Full article