Treatment Of PD Research Articles

CTNI-36. THE FEASIBILITY OF USING BORTEZOMIB WITH CHEMOTHERAPY IN ATYPICAL TERATOID/RHABDOID TUMORS

Abstract Atypical teratoid/rhabdoid tumors (ATRTs) are highly aggressive pediatric brain tumors with sensitivity to proteasome inhibitors in preclinical models. We evaluated the feasibility of combining the proteasome inhibitor bortezomib with chemotherapy. Patients aged 0-20 years with newly diagnosed ATRT were enrolled from January 2022 through December 2023. A modified Medical University of Vienna (MUV)-ATRT regimen was used. They were treated with bortezomib of 1.3 mg/m2/dose given intravenously or subcutaneously twice a week for 2 weeks concurrently with 6 cycles of chemotherapy and 2 additional cycles after high-dose chemotherapy. Radiation therapy was given prior to or at the end of chemotherapy. A total of 36 chemotherapy cycles with bortezomib in 6 patients were evaluated. The primary endpoint was grade 3 or higher non-hematologic toxicities. Numbers of cycles with grade 3+ toxicities included: AST/ALT elevation (1), hypokalemia (2), peripheral neuropathy (1), subdural hemorrhage (2), vomiting (2), oral mucositis (3), lung infection (2), urinary tract infection (8), sepsis (3), febrile neutropenia (20). No grade 3+ toxicities were considered bortezomib-related. Three patients completed 8 cycles of bortezomib treatment; 2 patients discontinued the study due to progressive disease after 2 and 4 cycles respectively; 1 patient completed 6 cycles of bortezomib and died of septic shock in complete remission after high-dose chemotherapy. Two patients had a surgical complete resection. Three patients were evaluable for response after bortezomib: 1 partial response and 2 stable disease. Two patients had progression-free survival for 16+ and 22+ months after diagnosis, respectively. Among the 3 patients with progressive disease, 2 had metastatic relapse and 1 had primary and metastatic relapse. There were 4 deaths due to metastatic PD (n=2), septic shock after high-dose chemotherapy (n=1), and septic shock after 2nd line treatment for PD (n=1). We conclude that adding bortezomib to standard and high-dose chemotherapy of ATRT was feasible with the occurrence of grade 3/4 toxicities no more than what was expected with chemotherapy alone. Metastatic relapse remains the major challenge of ATRT treatment.

Application of Optogenetics in the Regulation of Neural Circuits in Parkinson’s Disease

This paper reviews the application of optogenetics in the study of Parkinson’s disease and discuss how optogenetics stimulates specific neural circuits to regulate the symptoms and behaviors of Parkinson’s disease. Optogenetics technology has a higher spatial resolution than traditional electrical stimulation, and optogenetics can accurately control specific neuron populations, providing a new perspective for studying PD and exploring potential treatments. The researchers found that selective optogenetic stimulation of the dorsal striatum was sufficient to induce levodopalike dyskinesia in 6-hydroxydopamine (6-OHDA)-induced PD rat models. In addition, the researchers found that transplanted dopamine neurons can correct some of the motor deficits through their neural activity, including dopamine release and synaptic transmission. Although the utility of optogenetic techniques in human patients is unclear, the precise control of neural circuits in animal models provides an important way to understand the mechanisms and side effects of DBS therapy. The study also suggests that optogenetic stimulation of glutamatergic neurons in the mesocerebellar nucleus may improve motor function in PD mouse models, providing a new potential target for PD treatment. Finally, the article discusses how optogenetic technology can be transformed from a research tool into a treatment for PD, and how to repair damaged neural circuits through optogenetic technology to provide a more durable and effective treatment.

CDK4/6 inhibition initiates cell cycle arrest by nuclear translocation of RB and induces a multistep molecular response

CDK4/6 inhibitors are standard of care in the treatment of metastatic breast cancer. Treatment regimen consists of a combination with endocrine therapy, since their therapeutic efficacy as monotherapy in most clinical trials was rather limited. Thus, understanding the molecular mechanisms that underlie response to therapy might allow for the development of an improved therapy design. We analyzed the response to the CDK4/6 inhibitor palbociclib in bladder cancer cells over a 48-hour time course using RNA sequencing and identified a multi-step mechanism of response. We next translated these results to the molecular mechanism in bladder cancer cells upon PD treatment. The initial step is characterized by translocation of the RB protein into the nucleus by activation of importin α/β, a mechanism that requires the NLS sequence. In parallel, RB is proteolyzed in the cytoplasm, a process regulated by gankyrin and the SCF complex. Only hypophosphorylated RB accumulates in the nucleus, which is an essential step for an efficient therapy response by initiating G1 arrest. This might explain the poor response in RB negative or mutated patients. At later stages during therapy, increased expression of the MiT/TFE protein family leads to lysosomal biogenesis which is essential to maintain this response. Lastly, cancer cells either undergo senescence and apoptosis or develop mechanisms of resistance following CDK4/6 inhibition.

Increasing Sensitivity in Patient-Reported MDS-UPDRS Items for Predicting Medication Initiation in Early PD.

The MDS-UPDRS Parts IB and II are self-reported items providing a direct patient voice to the experiences of PD. To determine the most sensitive combination of MDS-UPDRS Parts IB and II items that accurately predicted the clinically relevant target of dopaminergic therapy initiation. Utilizing a longitudinal cohort of de novo non-treated PD patients, we applied item response theory (IRT) and survival analysis to assess the relationship between baseline patient-reported symptoms and the later initiation of dopaminergic therapy. The 20 MDS-UPDRS Parts IB and II items were analyzed for their relationship to PD severity (discrimination) and the amount of information they provided in this determination (information). These parameters were used to develop models of predictive accuracy for initiation of dopaminergic therapy. A six-item version showed a significantly higher C-index as compared to the full 20 item model (P = 0.001). This shortened version of the MDS-UPDRS contained only Part II items and provided a predictive accuracy for initiation of dopaminergic therapy better than the total combined scale score or any other combination. A six-item "Baseline Outcome Voice" version of patient-reported MDS-UPDRS items significantly increases the sensitivity of predicting the key future clinical outcome of starting dopaminergic treatment in early PD. This study also demonstrates how IRT modeling can provide information useful to refining existing measures to identify the most sensitive combination of items honoring the voice of the patient in determining key clinically pertinent decisions. Further research is needed to validate these findings in underrepresented populations.

The therapeutic use of clonal neural stem cells in experimental Parkinson´s disease

BackgroundParkinson´s disease (PD), the second most common neurodegenerative disease in the world, is characterized by the death or impairment of dopaminergic neurons (DAn) in the substantia nigra pars compacta and dopamine depletion in the striatum. Currently, there is no cure for PD, and treatments only help to reduce the symptoms of the disease, and do not repair or replace the DAn damaged or lost in PD. Cell replacement therapy (CRT) seeks to relieve both pathological and symptomatic PD manifestations and has been shown to have beneficial effects in experimental PD models as well as in PD patients, but an apt cell line to be used in the treatment of PD has yet to be established. The purpose of this study was to examine the effects of the transplantation of hVM1 clone 32 cells, a bankable line of human neural stem cells (hNSCs), in a PD mouse model at four months post-transplant.MethodsAdult (five month-old) C57BL/6JRccHsd male mice were injected with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and subsequently transplanted with hVM1 clone 32 cells, or buffer, in the left striatum. Four months post-transplant, behavioral effects were explored using the open field and paw print tests, and histological analyses were performed.ResultsTransplantation of hVM1 clone 32 cells rescued dopaminergic nigrostriatal populations in adult Parkinsonian mice. Motor and neurological deterioration were observed in buffer-treated mice, the latter of which had a tendency to improve in hNSC-transplanted mice. Detection of mast cell migration to the superficial cervical lymph nodes in cell-transplanted mice denoted a peripheral effect. Transplantation of hNSCs also rescued neuroblast neurogenesis in the subgranular zone, which was correlated with dopaminergic recovery and is indicative of local recovery mechanisms.ConclusionsIn this proof-of-concept study, the transplantation of hVM1 clone 32 cells provided neuroprotection in adult Parkinsonian mice by restoring the dopaminergic nigrostriatal pathway and hippocampal neurogenesis, demonstrating the efficacy of cell replacement therapy as a treatment for PD.

Implication of nutrition in severity of symptoms and treatments in quality of life in Parkinson's disease: a systematic review.

Therefore, this review aims to evaluate whether nutritional alterations are related either to the severity of motor and non-motor symptoms through the gut-brain axis or to the different treatments for PD and whether all of this, in turn, impacts the QoL of patients. A systematic review was carried out in MEDLINE and EMBASE databases, and Mendeley from 2000 to June 2024, searching for articles related to nutritional alterations in PD that alter patients' QoL. A total of 14 articles (2,187 participants) of 924 records were included. Among the 14 studies examined, two investigated the relationship between nutritional status and QoL in patients with PD. Poor nutritional status was associated with lower QoL scores. Four studies explored the connection between nutritional status and its impact on both motor and non-motor symptoms (psychiatric disturbances, cognitive impairment, and fatigue), revealing a link between nutritional status, activities of daily living, and the severity of motor symptoms. Three studies identified changes in body weight associated with the severity of symptoms related to mobility issues in PD patients. Three studies investigated the relationship between different PD treatments and their interaction with changes in weight and energy metabolism, highlighting that weight loss in the early stages of PD needs adequate monitoring of different treatments, as well as the interaction between the central and peripheral nervous systems in regulating these processes. Finally, two studies investigated how gastrointestinal alterations and changes in the microbiota were related to cognitive status, thus identifying them as risk factors and early signs of PD. The systematic review highlighted the significant relationship between nutritional status and QoL in patients with PD, as well as how the PD treatments influenced their weight. An association was also observed in the gut-brain axis, where adequate nutritional status influenced the balance of intestinal microbiota, slowing cognitive decline, improving activities of daily living, and the QoL of PD patients. It is confirmed that the nutritional status of patients influenced both motor and non-motor symptoms of the disease, and therefore their QoL.

The QT interval in Parkinson's disease: a systematic review.

PD (PD) is associated with a twofold increase in the risk of death especially sudden death. A predisposing factor for cardiac sudden death is prolongation of the QT interval. This study evaluated the potential association between QT interval and PD. A systematic search was conducted of Medline and EMBASE using the search terms "PD" AND "QT interval" OR "Cardiac Repolarization" to identify articles. Seven studies with persons with PD (n = 981) and control groups were identified. There was a significant difference in QT interval comparing patients with PD and persons without PD. The odds ratio showed a significant (P < 0.001) 2.6-fold (random effect) greater QTc prolongation in PD compared to control. Overall, there was a significantly longer QT in patients with PD than controls of 10.7 ± 2.8 ms. Data analysis did not show much publication bias. Focusing only on studies that related the QT interval to the severity of PD as assessed by Hoehn-Yahr classification (n = 6), there was a significant (P = 0.004) overall correlation between QT interval and the severity of PD. There was little publication bias. The data directly examining patients with PD taking any drug than might prolong QT do not support an association between these mediations and QT prolongation. Individuals with PD have a longer QT interval than individuals without PD. The QT interval is associated with a greater severity of PD and a greater probability of developing more severe PD. The QT interval should be considered in assessment of PD and possibly as a target for the treatment of PD.

The treatment gap for deep brain stimulation in Parkinson's disease: a comparative analysis of cost and utilisation in high-income countries.

ObjectiveParkinson's disease (PD) is one of the most prevalent neurodegenerative disorders, globally affecting approximately 120 per 100,000 people by age 70. Deep brain stimulation (DBS) is a US Federal Drug Administration (FDA)-approved and highly effective treatment for late-stage PD. However, country-specific reimbursement regulations and health policies may affect access to PD-DBS. We aimed to evaluate the uptake rate and 'treatment gap' for DBS across high-income countries.MethodsWe reviewed previous literature to investigate the cost and utilisation of PD-DBS in high-income countries across Asia, Europe, Oceania, and North America (Australia, Canada, France, Germany, Hong Kong, Japan, Korea, the Netherlands, New Zealand, Norway, Spain, Switzerland, UK, and USA). Using previous estimates of DBS candidate eligibility rates, we calculated theoretical DBS uptake rates and treatment gaps nationally.ResultsPD-DBS utilisation was highest in Australia and the USA and lowest in Korea and New Zealand. The total cost of PD-DBS in the first 12months was highest in the USA and France and lowest in the UK and Germany. The utilisation rate (i.e. uptake rate) of PD-DBS (% DBS surgeries per PD case) was highest in Australia and the USA, and lowest in New Zealand and the UK, where the treatment gap reflected these trends.ConclusionsOur results highlight differences in access to DBS for PD patients among high-income countries, which we discuss in the context of health systems. Better access to effective PD treatments such as DBS is critical given the increasing prevalence of PD in an ageing world and the associated, avoidable morbidity.

Schisandra chinensis (Turcz.) Baill neutral polysaccharides alleviate Parkinson's disease via effectively activating MCL-1 expression regulation of autophagy signaling

The purified neutral polysaccharide fraction, namely SBP-1, was isolated and characterized from Schisandra chinensis (Turcz.) Baill crude polysaccharides, which have anti-Parkinson's disease activity were investigated in vivo and in vitro. Experiments have shown that the main chain of SBP-1 was Glcp-(1→, →4)-Glcp-(1→ and →4,6)-Glcp-(1→. We also revealed the effect of SBP-1 on the PD mice model and the potential underlying molecular mechanism. The results showed that SBP-1 administration improved behavioral deficits, increased tyrosine hydroxylase-positive cells, attenuated loss of dopaminergic neurons in MPTP-exposed mice, and reduced cell death induced by MPP+. The MCL-1 was identified as the target of SBP-1 by the combination of docking-SPR-ITC, WB, and IF experiments. Subsequently, the study showed that SBP-1 could target MCL-1 to enhance autophagy with a change in the apoptotic response, which was further demonstrated by a change in LC3/P62, PI3K/AKT/mTOR, and possesses a change in the expression of BCL2/BAX/Caspase3. These results demonstrate that SBP-1 may protect neurons against MPP+ or MPTP-induced damage in vitro and in vivo through enhancing autophagy. In summary, these findings indicate that SBP-1 and S. chinensis show potential as effective candidates for further investigation in the prevention and treatment of PD or associated illnesses, specifically through autophagy apoptotic-based mechanisms.

A comprehensive review and recent advancement in the application of tannins for treating Parkinson disease

IntroductionParkinson's disease (PD) is a neurodegenerative disorder characterized by progressive loss of dopaminergic neurons in the substantia nigra. Despite extensive research, the etiology of PD remains elusive, and current treatments focus primarily on symptomatic relief rather than disease modification. MethodsThe papers were searched in Web of Science, Scopus, PubMed, PubMed Prime, Cochrane library, Sciencedirect and Google Scholar as web resources. This article includes information about tannins research and reviews in the treatment of PD. However, other paper related to CNS have been avoided. ResultsIn recent years, there has been growing interest in exploring the therapeutic potential of natural compounds, such as tannins, for the management of PD. Tannins, polyphenolic compounds found abundantly in various plant species, have demonstrated neuroprotective effects through their antioxidant, anti-inflammatory, and metal chelating properties. This review provides a comprehensive overview of the current understanding of PD pathophysiology, existing treatment modalities, and the potential role of tannins in PD management. Additionally, recent advancements in the application of tannins, including in vitro and in vivo studies, clinical trials, and novel delivery systems, are discussed. Furthermore, challenges and future perspectives regarding the translation of tannin-based therapies into clinical practice are addressed. DiscussionOverall, this review highlights the promising therapeutic potential of tannins in the treatment of Parkinson's disease and underscores the need for further research to elucidate their mechanisms of action and optimize their clinical efficacy.

Variations in provider practices in remote patient monitoring on peritoneal dialysis in the USA and Canada.

Automation has allowed clinicians to program PD treatment parameters, all while obtaining extensive individual treatment data. This data populates in a centralized online platform shortly after PD treatment completion. Individual treatment data available to providers includes patients' vital signs, alarms, bypasses, prescribed PD treatment, actual treatment length, individual cycle fill volumes, ultrafiltration volumes, as well as fill, dwell, and drain times. However, there is no guidance about how often or if this data should be assessed by the clinical team members. We set out to determine current practice patterns by surveying members of the home dialysis team managing PD patients across the United States and Canada. A total of 127 providers completed the survey. While 91% of respondents reported having access to a remote monitoring platform, only 31% reported having a standardized protocol for data monitoring. Rating their perceived importance of having a standard protocol for remote data monitoring, on a scale of 0 (not important at all) to 10 (extremely important), the average response was 8 (physicians 7; nurses 9). Most nurses reported reviewing the data multiple times per week, whereas most physicians reported viewing the data only during regular/monthly visits. Although most of the providers who responded have access to remote monitoring data and feel that regular review is important, the degree of its utilization is variable, and the way in which the information is used is not commonly protocolized. Working to standardize data interpretation, testing algorithms, and educating providers to help process and present the data are important next steps.

Research on the mechanism of Ursolic acid for treating Parkinson's disease by network pharmacology and experimental verification

The objective of this study was to investigate the potential targets and mechanisms of UA in the treatment of PD. The efficacy of UA in PD was assessed through network pharmacology, molecular docking, and experimental methods. Common target protein-protein interaction (PPI) networks were constructed and visualized using Cytoscape. As a result, 9 key genes, namely CASP3, IL6, IL1B, PTGS2, CREB1, TNF, MAPK3, JUN, and CASP8, were selected. Molecular docking simulations were performed using Discovery Studio 2019 to validate the correlation between UA and the core targets. The results demonstrated a favorable binding affinity between UA and CASP8, IL1B, CASP3, TNF, MAPK3 and IL6. In vivo studies showed UA ameliorated motor dysfunction, and UA can significantly increase the protein expression of tyrosine hydroxylase (TH) in PD mice model. In addition, in vitro experiments confirmed that UA effectively reduced the protein expression of CASP8, CASP3 and MAPK3 in PD cell models and suppressed the gene expression of TNF-α, IL-6, and IL-1β. These findings indicate that the therapeutic effects of UA on PD could be due to its influence on various targets within both the apoptosis and neuroinflammatory signaling pathways. Consequently, this study provides a methodological and theoretical foundation for further elucidating the pharmacological mechanism of UA.

The Use of Nano-based Drug Delivery Systems for Neurodegenerative Disorders

ABSTRACT Blood–brain interfaces surrounding the central nervous system (CNS) present problems for targeted drug delivery, which limits the bioavailability of therapies for the diagnosis and treatment of neurological illnesses such as Alzheimer’s diseases and Parkinson’s diseases (AD/PD). Over the past 10 years, research has concentrated on creating novel approaches to get around these restrictions and effectively transport medications to the CNS. The protective barriers surrounding the CNS can be penetrated by nanoparticles (NPs), which have the ability to encapsulate medicines with prolonged drug release patterns and customizable physiochemical properties. To find out more about drug delivery systems, blood–brain barrier, NPs, neurodegenerative illnesses, AD and PD, and their treatment applications, a ScienceDirect, PubMed, and Google Scholar search was done. After analysis using the keywords/phrases, relevant articles were determined to be completed. Because nanotechnology is a potent substitute for traditional drug delivery systems, it thus offers new hope for the treatment of AD and PD for example. The possible use of techniques based on NPs in neurodegenerative disorders and their therapeutic implications are covered briefly in this work.

Identification of diagnose related therapeutic targets of Danggui buxue decoction in Parkinson’s disease

BackgroundParkinson’s disease (PD) is the fastest growing neurological disease. Currently, there is no disease-modifying therapy to slow the progression of the disease. Danggui buxue decoction (DBD) is widely used in the clinic because of its therapeutic effect. However, little is known about the molecular mechanism of DBD against PD. This study intends to explore the possible molecular mechanisms involved in DBD treatment of PD based on network pharmacology, and provide potential research directions for future research. MethodsFirstly, the active components and target genes of DBD were screened from the traditional Chinese medicine systems pharmacology (TCMSP), DrugBank and UniProt database. Secondly, target genes of PD were identified from the (GEO) dataset, followed by identification of common target genes of DBD and PD. Thirdly, analysis of protein–protein interaction (PPI), functional enrichment and diagnosis was performed on common target genes, followed by correlation analysis between core target genes, immune cell, miRNAs, and transcription factors (TFs). Finally, molecular docking between core target genes and active components, and real-time PCR were performed. ResultsA total of 72 common target genes were identified between target genes of DBD and target genes of PD. Among which, 11 target genes with potential diagnostic value were further identified, including TP53, AKT1, IL1B, MMP9, NOS3, RELA, MAPK14, HMOX1, TGFB1, NOS2, and ERBB2. The combinations with the best docking binding were identified, including kaempferol-AKT1/HMOX1/NOS2/NOS3, quercetin-AKT1/ERBB2/IL1B/HMOX1/MMP9/TP53/NOS3/TGFB1. Moreover, IL1B and NOS2 respectively positively and negatively correlated with neutrophil and Type 1 T helper cell. Some miRNA-core target gene regulatory pairs were identified, such as hsa-miR-185-5p-TP53/TGFB1/RELA/MAPK14/IL1B/ERBB2/AKT1 and hsa-miR-214-3p-NOS3. These core target genes were significantly enriched in focal adhesion, TNF, HIF-1, and ErbB signaling pathway. ConclusionDiagnostic TP53, AKT1, IL1B, MMP9, NOS3, RELA, MAPK14, HMOX1, TGFB1, NOS2, and ERBB2 may be considered as potential therapeutic targets of DBD in the treatment of PD.

MiR-142-3p alleviates neuronal apoptosis in Parkinson’s disease via negatively regulating C9orf72

Although microRNA (miRNA) have important clinical prospects in the early diagnosis and treatment of PD, the functions and mechanisms of miRNAs in PD models remain poorly defined. In this study, we screened 9 miRNAs that differently expressed in PD patients and found that miR-142-3p expression was downregulated in both animal and cell models of PD. We showed that overexpression of miR-142-3p significantly alleviates the neuronal damage induced by MPP+, while knockdown of miR-142-3p exacerbates the neuronal damage caused by MPP+. We further found that miR-142-3p targets and inhibits the expression of C9orf72. Knockdown of C9orf72 mitigated neuronal autophagy dysfunction by reducing excessive activation of the AKT/mTOR pathway after MPP+ stimulation, thereby exerted neuroprotective effects. This study reveals that miR-142-3p protects neuron in PD pathogenesis via negatively regulating C9orf72 and enhancing autophagy. Our findings provides an insight into the development of potential biomarkers and therapeutic targets for PD.

A Hybrid Deep Spatiotemporal Attention‐Based Model for Parkinson's Disease Diagnosis Using Resting State EEG Signals

ABSTRACTParkinson's disease (PD), a severe and progressive neurological illness, affects millions of individuals worldwide. For effective treatment and management of PD, an accurate and early diagnosis is crucial. This study presents a deep learning‐based model for the diagnosis of PD using a resting state electroencephalogram (EEG) signal. The objective of the study is to develop an automated model that can extract complex hidden nonlinear features from EEG and demonstrate its generalizability on unseen data. The model is designed using a hybrid model, consisting of a convolutional neural network (CNN), bidirectional gated recurrent unit (Bi‐GRU), and attention mechanism. The proposed method is evaluated on three public datasets (UC San Diego, PRED‐CT, and University of Iowa [UI] dataset), with one dataset used for training and the other two for evaluation. The proposed model demonstrated remarkable performance, attaining high accuracy scores of 99.4%, 84%, and 73.2% using UC San Diego, PRED‐CT, and UI datasets, respectively. These results justify the effectiveness and robustness of the proposed model across diverse datasets, highlighting its potential for versatile applications in data analysis and prediction tasks. Our proposed hybrid spatiotemporal attention‐based model has been developed with 10‐fold cross‐validation (CV) for UC San Diego dataset and 10‐fold CV and leave‐one‐out cross‐validation (LOOCV) strategies for PRED‐CT and UI datasets. Our results indicate that the proposed PD detection system is accurate and robust. The developed prototype can be used for other neurodegenerative diseases such as Alzheimer's disease, Huntington's disease, and so forth.

A simulation study of transcranial magnetoacoustic stimulation of the basal ganglia thalamic neural network to improve pathological beta oscillations in Parkinson's disease

BackgroundParkinson's disease (PD) is a common neurodegenerative disease. Transcranial magnetoacoustic stimulation (TMAS) is a new therapy that combines a transcranial focused acoustic pressure field with a magnetic field to excite or inhibit neurons in targeted area, which suppresses the abnormally elevated beta band amplitude in PD states, with high spatial resolution and non-invasively. ObjectiveTo study the effective stimulation parameters of TMAS mononuclear and multinuclear stimulation for the treatment of PD with reduced beta band energy, improved abnormal synchronization, and no thermal damage. MethodsThe TMAS model is constructed based on the volunteer's computed tomography, 128 arrays of phase-controlled transducers, and permanent magnets. A basal ganglia-thalamic (BG-Th) neural network model of the PD state was constructed on the basis of the Izhikevich model and the acoustic model. An ultrasound stimulation neuron model is constructed based on the Hodgkin-Huxley model. Numerical simulations of transcranial focused acoustic pressure field, temperature field and induced electric field at single and dual targets were performed using the locations of STN, GPi, and GPe in the human brain as the main stimulation target areas. And the acoustic and electric parameters at the focus were extracted to stimulate mononuclear and multinuclear in the BG-Th neural network. ResultsWhen the stimulating effect of ultrasound is ignored, TMAS-STN simultaneously inhibits the beta-band amplitude of the GPi nucleus, whereas TMAS-GPi fails to simultaneously have an inhibitory effect on the STN. TMAS-STN&GPi can reduce the beta band amplitude. TMAS-STN&GPi&GPe suppressed the PD pathologic beta band amplitude of each nucleus to a greater extent. When considering the stimulatory effect of ultrasound, lower sound pressures of ultrasound do not affect the neuronal firing state, but higher sound pressures may promote or inhibit the stimulatory effect of induced currents. ConclusionsAt 9 T static magnetic field, 0.5–1.5 MPa and 1.5–2.0 MPa ultrasound had synergistic effects on individual STN and GPi neurons. TMAS multinuclear stimulation with appropriate ultrasound intensity was the most effective in suppressing the amplitude of pathological beta oscillations in PD and may be clinically useful.

Subthalamic DBS does not restore deficits in corticospinal suppression during movement preparation in Parkinson’s disease

ObjectiveParkinson’s disease (PD) patients exhibit changes in mechanisms underlying movement preparation, particularly the suppression of corticospinal excitability – termed “preparatory suppression” – which is thought to facilitate movement execution in healthy individuals. Deep brain stimulation (DBS) of the subthalamic nucleus (STN) being an attractive treatment for advanced PD, we aimed to study the potential contribution of this nucleus to PD-related changes in such corticospinal dynamics. MethodsOn two consecutive days, we applied single-pulse transcranial magnetic stimulation to the primary motor cortex of 20 advanced PD patients treated with bilateral STN-DBS (ON vs. OFF), as well as 20 healthy control subjects. Motor-evoked potentials (MEPs) were elicited at rest or during movement preparation in an instructed-delay choice reaction time task including left- or right-hand responses. Preparatory suppression was assessed by expressing MEPs during movement preparation relative to rest. ResultsPD patients exhibited a deficit in preparatory suppression when it was probed on the responding hand side, particularly when this corresponded to their most-affected hand, regardless of their STN-DBS status. ConclusionsAdvanced PD patients displayed a reduction in preparatory suppression which was not restored by STN-DBS. SignificanceThe current findings confirm that PD patients lack preparatory suppression, as previously reported. Yet, the fact that this deficit was not responsive to STN-DBS calls for future studies on the neural source of this regulatory mechanism during movement preparation.

The TLR4/NF-κB/NLRP3 and Nrf2/HO-1 pathways mediate the neuroprotective effects of alkaloids extracted from Uncaria rhynchophylla in Parkinson's disease

Ethnopharmacological relevanceParkinson's disease (PD) is the second most common neurodegenerative disorder with limited therapeutic options available. Neuroinflammation plays an important role in the occurrence and development of PD. Alkaloids extracted from Uncaria rhynchophylla (URA), have emerged as a potential neuroprotective agent because of its anti-inflammatory and anti-oxidant properties. Nevertheless, the underlying mechanism by which URA exerts neuroprotective effects in PD remains obscure. Aim of the studyThe main aim of this study was to investigate the neuroprotective effects and underlying mechanism of URA in the treatment of PD through in vivo and in vitro models, focusing on the neuroinflammation and oxidative stress pathways. Materials and methodsThe protective effects of URA against PD were evaluated by neurobehavioral tests, immunohistochemistry, serum biochemical assays, and real-time quantitative polymerase chain reaction in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mice. The role of the TLR4/NF-κB/NLRP3 pathway and the Nrf2/HO-1 pathway in URA-mediated effects was examined in lipopolysaccharide (LPS)-stimulated BV-2 microglial cells and a microglia-neuron coculture system. ResultsURA significantly alleviated motor deficits and dopaminergic neurotoxicity, and reversed the abnormal secretion of inflammatory and oxidative stress factors in the serum of MPTP-induced mice. URA suppressed the gene expression of Toll-like receptor 4 (TLR4), NOD-like receptor protein 3, and cyclooxygenase 2 (COX2) in the striatum of PD mice. Further studies indicated that URA inhibited activation of the TLR4/NF-κB/NLRP3 pathway and enhanced activation of the Nrf2/HO-1 pathway, reduced reactive oxygen species (ROS) production, and reversed the secretion of inflammatory mediators in LPS-stimulated BV-2 microglial cells, thereby alleviating neuroinflammatory damage to SH-SY5Y neuronal cells. ConclusionURA exerted neuroprotective effects against PD mainly by the inhibition of the TLR4/NF-κB/NLRP3 pathway and activation of the Nrf2/HO-1 antioxidant pathway, highlighting URA as a promising candidate for PD treatment.

Integrated bioinformatics analysis for exploring potential biomarkers related to Parkinson’s disease progression

BackgroundParkinson’s disease (PD) is a progressive neurodegenerative disease with increasing prevalence. Effective diagnostic markers and therapeutic methods are still lacking. Exploring key molecular markers and mechanisms for PD can help with early diagnosis and treatment improvement.MethodsThree datasets GSE174052, GSE77668, and GSE168496 were obtained from the GEO database to search differentially expressed circRNA (DECs), miRNAs (DEMis), and mRNAs (DEMs). GO and KEGG enrichment analyses, and protein–protein interaction (PPI) network construction were implemented to explore possible actions of DEMs. Hub genes were selected to establish circRNA-related competing endogenous RNA (ceRNA) networks.ResultsThere were 1005 downregulated DECs, 21 upregulated and 21 downregulated DEMis, and 266 upregulated and 234 downregulated DEMs identified. The DEMs were significantly enriched in various PD-associated functions and pathways such as extracellular matrix organization, dopamine synthesis, PI3K-Akt, and calcium signaling pathways. Twenty-one hub genes were screened out, and a PD-related ceRNA regulatory network was constructed containing 31 circRNAs, one miRNA (miR-371a-3p), and one hub gene (KCNJ6).ConclusionWe identified PD-related molecular markers and ceRNA regulatory networks, providing new directions for PD diagnosis and treatment.