Treatment Of Parkinson's Disease Research Articles

Modulation of Intestinal Inflammation and Protection of Dopaminergic Neurons in Parkinson’s Disease Mice through a Probiotic Formulation Targeting NLRP3 Inflammasome

Emerging evidence highlights the significance of peripheral inflammation in the pathogenesis of Parkinson’s disease (PD) and suggests the gut as a viable therapeutic target. This study aimed to explore the neuroprotective effects of the probiotic formulation VSL#3® and its underlying mechanism in a PD mouse model induced by MPTP. Following MPTP administration, the striatal levels of dopamine and its metabolites, as along with the survival rate of dopaminergic neurons in the substantia nigra, were significantly reduced in PD mice. MPTP also significantly increased the mRNA expression of pro-inflammatory cytokines TNF-α and IL-1β, while reducing anti-inflammation mediators, like glia cell line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF) in the striatum. These pathological changes were notably mitigated by VSL#3® treatment, suggesting its neuroprotective and anti-inflammatory effects in the brain. Additionally, VSL#3® significantly lowered the circulating levels of pro-inflammatory cytokines, and reduced TNF-α and IL-1β mRNA expression in the liver, indicating an inhibition of cytokine transfer. In the intestine, the probiotic treatment markedly decreased the mRNA expression of pro-inflammatory cytokines, (TNF-α, IL-1β, IL-6 and IL-17), and the other two key components of the NLRP3 inflammasome, caspase-1 and NLRP3, demonstrating an inhibition of VSL#3® on gut NLRP3 inflammasome. VSL#3® exerts neuroprotective effects in PD mice through the suppression of intestinal inflammation, particularly inhibiting the intestinal NLRP3 inflammasome. This study supports the therapeutic potential of targeting intestinal inflammation and utilizing probiotics in PD treatment.

Integrating network pharmacology with molecular docking and dynamics to uncover therapeutic targets and signaling mechanisms of vitamin D3 in Parkinson's disease.

Parkinson's disease (PD) is a chronic neurodegenerative disorder marked by dopaminergic neuron degeneration in the substantia nigra. Emerging evidence suggests vitamin D3 (VD) plays a therapeutic role in PD, but its precise molecular mechanisms remain unclear. This study employed network pharmacology and bioinformatics to identify VD's hub targets and related pathways. We identified 24 VD's anti-PD targets, with estrogen receptor 1, estrogen receptor 2 (ESR2), sodium-dependent norepinephrine transporter, and insulin-like growth factor 1 receptor emerging as hub targets. Gene enrichment analysis elucidated that VD's anti-PD mechanism is closely related to the estrogen signaling pathway. Additionally, two-sample Mendelian randomization suggested a positive causal relationship between 25-hydroxyvitamin D and estrogen levels in vivo. To verify the interaction between VD and the hub drug targets, we performed molecular docking and kinetic simulations, finding the strongest interaction between VD and ESR2. Further Mendelian randomization analysis of drug targets confirmed the significant effect of the ESR2 drug target on PD risk. Single-cell nuclear sequencing of dopaminergic neurons, coupled with GSEA analysis, indicated that ESR2 activation upregulates the neuroactive ligand-receptor interaction signaling pathway and downregulates the Parkinson's disease pathway, thereby exerting a neuroprotective effect. In summary, our findings suggest that VD supplementation can not only elevate estradiol levels in humans but also directly activate ESR2, thereby modulating the estrogen signaling pathway in PD patients and providing neuroprotection. These predictive biological targets offer promising avenues for future clinical applications in Parkinson's disease treatment.

Gut Microbiota-Based Interventions for Parkinson's Disease: Neuroprotective Mechanisms and Current Perspective.

Recent evidence links gut microbiota alterations to neurodegenerative disorders, including Parkinson's disease (PD). Replenishing the abnormal composition of gut microbiota through gut microbiota-based interventions "prebiotics, probiotics, synbiotics, postbiotics, and fecal microbiota transplantation (FMT)" has shown beneficial effects in PD. These interventions increase gut metabolites like short-chain fatty acids (SCFAs) and glucagon-like peptide-1 (GLP-1), which may protect dopaminergic neurons via the gut-brain axis. Neuroprotective effects of these interventions are mediated by several mechanisms, including the enhancement of neurotrophin and activation of the PI3K/AKT/mTOR signaling pathway, GLP-1-mediated gut-brain axis signaling, Nrf2/ARE pathway, and autophagy. Other pathways, such as free fatty acid receptor activation, synaptic plasticity improvement, and blood-brain and gut barrier integrity maintenance, also contribute to neuroprotection. Furthermore, the inhibition of the TLR4/NF-кB pathway, MAPK pathway, GSK-3β signaling pathway, miR-155-5p-mediated neuroinflammation, and ferroptosis could account for their protective effects. Clinical studies involving gut microbiota-based interventions have shown therapeutic benefits in PD patients, particularly in improving gastrointestinal dysfunction and some neurological symptoms. However, the effectiveness in alleviating motor symptoms remains mild. Large-scale clinical trials are still needed to confirm these findings. This review emphasizes the neuroprotective mechanisms of gut microbiota-based interventions in PD as supported by both preclinical and clinical studies.

Strategies for Real-time Adjustment of Stimulation Patterns in Closed-loop Deep Brain Stimulation for Parkinsons Disease: A Comprehensive Review

Parkinsons disease (PD) is a prevalent neurodegenerative disorder that poses significant healthcare challenges worldwide. Deep brain stimulation (DBS) has proven effective for managing PD, particularly for patients with inadequate medication response. However, traditional high-frequency DBS systems lack the capability to adjust stimulation patterns in real time based on patient responses. In contrast, closed-loop DBS systems, which adjust stimulation based on recorded biomarkers, present a promising alternative that allows more flexible, on-demand electrical pulses delivery, offering possibility of achieving better therapeutic outcomes with less invasive stimulus. This review article explored various strategies for real-time adjustment of stimulation parameters in closed-loop DBS primarily based on electrophysiological biomarkers, particularly local field potentials (LFPs). We categorize these strategies into four categories: simple on-demand methods, control methods in systems theory, optimization or machine learning algorithms, and desynchronization approaches. By synthesizing existing literature, we provide a comprehensive overview of these strategies, highlighting contributions from multiple disciplines and the prospect of optimizing treatment for Parkinsons disease using closed-loop approach.

Feasibility of Simon 2-Stage Futility Trials in Early Parkinson Disease: Analysis of the PRECEPT and DATATOP Trial Datasets.

Disease-modifying treatments (DMTs) are a major unmet need in Parkinson disease (PD). To date, trials investigating DMT candidates in PD most often used a randomized controlled trial (RCT) design. Unfortunately, RCTs to date have not led to a breakthrough, in part because of the large sample sizes and length of follow-up required. In the interest of testing DMT candidates in a more efficient manner, it may be worthwhile to perform futility trials, which are smaller clinical trials that have originally been developed as phase 2 trials in oncology and more recently been used in progressive multiple sclerosis. In this investigation, we used original, patient-level data from DATATOP and PRECEPT, 2 large RCTs in early PD, to explore the feasibility of using the Simon 2-Stage futility trial design in early PD. This is a post hoc analysis of original, patient-level data from the DATATOP and PRECEPT RCTs in early PD. In our analyses, we use descriptive statistics, survival analysis, and binary logistic regression to explore thresholds of change in the Unified Parkinson Disease Rating Scale (UPDRS) motor score as the primary outcome measure, length of follow-up, inclusion and exclusion criteria, and projected sample sizes for Simon 2-Stage futility trials in early PD. We also performed bootstrapping experiments to illustrate the ability of trials using the Simon 2-Stage futility design to identify selegiline as nonfutile and tocopherol as futile. PRECEPT included 806 participants (mean age 59.7 years, SD 10.3, 64.4% male), and DATATOP included 800 participants (mean age 61.1 years, SD 9.5, 64.4% male). Our analyses suggest that futility trials using the Simon 2-Stage methodology are feasible in PD. We propose a 5-point worsening on the UPDRS motor score as the primary outcome measure and a length of follow-up of 12 months. Trial simulations based on these data suggest the required sample size for such clinical trials to be lower than 200 participants. Based on our analysis of DATATOP and PRECEPT, phase 2 clinical trials using the Simon 2-Stage methodology are feasible in PD and may offer an opportunity to expedite the discovery of promising treatments in early PD.

Transcutaneous vagus nerve stimulation for Parkinson’s disease: a systematic review and meta-analysis

BackgroundTranscutaneous vagus nerve stimulation (tVNS) has emerged as a novel noninvasive adjunct therapy for advanced Parkinson’s disease (PD), yet no quantitative analysis had been conducted to assess its therapeutic effect.ObjectivesThis review aimed to investigate the efficacy of tVNS on motor function, other potential clinical targets and its safety in various treatment conditions.MethodsWe searched six databases for randomized controlled trials (RCTs) that involved treating PD patients with tVNS. Primary outcome was motor functions, including severity of motor signs, functional mobility and balance, and gait parameters. Secondary outcomes were cognition, emotion, sleep related impairments, patient reported non-motor outcomes, and any adverse events. All outcomes were classified and analyzed according to the treatment duration and medication condition of an included study. Risk of bias was evaluated by referencing Cochrane risk of bias tool 1.0. Data was analyzed by Revman 5.4.Results6 RCTs with 176 PD patient were included. Several motor functions and non-motor functions measured during on-medication condition (severity of motor signs −0.48 [95% CI −0.93, −0.04], gait −0.48 [95% CI −0.85, −0.1], patients reported non-motor outcomes −0.4 [95% CI −0.78, −0.03]), improved significantly. However, verbal fluency, sleep-related impairment, and fatigue were negatively impacted by tVNS during on-medication condition. No distinct adverse events were reported.ConclusiontVNS is a relatively safe adjunct treatment for PD. It has small to moderate therapeutic effects on motor functions and may negatively impact on a few other outcomes. Quality level of the evidence is low and further research is warranted.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/#recordDetails, identifier CRD42024503322 (PROSPERO).

An Integrative Computational Approach for the Identification of C-Abl Kinase Inhibitors from Anti-Parkinson Plant-Derived Bioactive.

Oxidative stress is strongly linked to neurodegeneration through the activation of c-Abl kinase, which arrests α-synuclein proteolysis by interacting with parkin interacting substrate (PARIS) and aminoacyl tRNA synthetase complex-interacting multifunctional protein 2 (AIMP2). This activation, triggered by ataxia-telangiectasia mutated (ATM) kinase, leads to dopaminergic neuron loss and α-synuclein aggregation, a critical pathophysiological aspect of Parkinson's disease (PD). To halt PD progression, pharmacological inhibition of c-Abl kinase is essential. Despite three generations of tyrosine kinase inhibitors (TKIs) being explored for PD treatment, they present significant concerns including poor blood-brain barrier penetration, off-target effects, and severe side effects. Notably, there are currently no FDA-approved c-Abl kinase inhibitors in clinical usage for PD treatment, highlighting the urgent need for potent, safe, and cost-effective alternatives. This study aims to identify potential c-Abl kinase inhibitors from plant-derived compounds with reported anti-Parkinson's potential and their derivatives using molecular docking, molecular dynamics simulations (MDS), and in silico pharmacokinetics and toxicity profiling. Seventy-eight compounds sourced from literature were docked against c-Abl kinase using Maestro 12.5. The top three hit compounds, along with nilotinib (control drug), were subjected to drug-likeness, ADMET profiling using the AI Drug Lab server and 100 ns MDS using Desmond. Amburoside A, diarylheptanoid MS13, and dimethylaminomethyl-substituted-curcumin showed binding affinities close to nilotinib, with values of -12.615, -12.556, and -11.895 kcal/mol respectively, compared to nilotinib's -16.826 kcal/mol. The three plant-derived compounds exhibited excellent structural stability and favorable ADMET profiles, including optimal blood-brain barrier permeation Conclusion: The three hit compounds identified in this study show potential as c-Abl kinase inhibitors. Given the absence of FDA-approved c-Abl kinase inhibitors for PD, these findings are significant as they could contribute new therapeutic options for the treatment and management of PD. However, further in vitro and in vivo experiments are necessary to validate these findings.

HDAC4/5 Inhibitor, LMK-235 Improves Animal Voluntary Movement in MPTP-Induced Parkinson's Disease Model.

Oxidation of dopamine can cause various side effects, which ultimately leads to cell death and contributes to Parkinson's disease (PD). To counteract dopamine oxidation, newly synthesized dopamine is quickly transported into vesicles via vesicular monoamine transporter 2 (VMAT2) for storage. VMAT2 expression is reduced in patients with PD, and studies have shown increased accumulation of dopamine oxidation byproducts and α-synuclein in animals with low VMAT2 expression. Conversely, animals that overexpress VMAT2 show better protection for dopamine neurons. Based on these findings, this study used histone deacetylase inhibitors (HDACi) to increase VMAT2 expression, reduce dopamine-induced oxidative stress, and evaluate the resulting behavioral improvements in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD animal model. LMK-235 not only increased VMAT2 expression at various concentrations in the SH-SY5Y cell line differentiated into dopaminergic cells but also demonstrated effective cytoprotective properties in several toxicity assays. It significantly raised VMAT2 expression in both the striatum and the ventral tegmental area of an MPTP-induced PD model, supporting its role in reversing behavioral abnormalities linked to PD. In addition to these results, coadministration of LMK-235 with L-DOPA, a standard therapy for PD, restored typical behavioral patterns, highlighting the potential of HDACi in alleviating PD symptoms. The expression of VMAT2 induced by LMK-235, an inhibitor of Class IIa histone deacetylases primarily found in the nervous system, aids in sequestering dopamine into vesicles, potentially enhancing cell survival by inhibiting dopamine oxidation. Additionally, upregulation of VMAT2 has been shown to offer effective protection against MPTP-induced toxicity and significantly improve behavioral abnormalities associated with PD. Coadministration with L-DOPA produced the most notable improvement in behavioral outcomes. Altogether, these findings suggest that the overexpression of VMAT2 may offer a promising strategy for developing treatments for PD by mitigating dopaminergic neuron death resulting from dopamine oxidation.

Amyotrophic Lateral Sclerosis and Parkinson's Disease: Brain Tissue Transcriptome Analysis Reveals Interactions.

This study utilises amyotrophic lateral sclerosis (ALS) and Parkinson's disease (PD) human brain samples from the GEO database and employs differential expression gene (DEG) analysis to identify genes that are pivotal in both neurodegenerative diseases. Through in depth GO and KEGG enrichment analyses, we elucidated the biological functions and potential pathways associated with these DEGs. Furthermore, by constructing protein‒protein interaction networks, we highlight the significance of shared DEGs in both cellular physiology and disease contexts. Analysis of drug‒gene associations revealed potential therapeutic compounds linked to ALS and PD treatment. Additionally, we explored the interactions between transcription factors, miRNAs, and common DEGs, revealing aspects of gene regulatory networks. This study provides insights into the molecular mechanisms of ALS and PD, offering valuable contributions to ongoing research and potential therapeutic avenues.

Long-term effect and reasons for switching and combining device-aided therapies in Parkinson's Disease.

In the advanced stages of Parkinson's disease (PD), when standard drug adjustments fail to sufficiently improve patients' quality of life, device-aided therapies (DATs) such as deep brain stimulation (DBS), continuous subcutaneous apomorphine infusion (CSAI), levodopa-carbidopa intestinal gel infusion (LCIG), levodopa-carbidopa-entacapone intestinal gel infusion, or continuous subcutaneous foslevodoa-foscarbidopa infusion are beneficial in the long run. However, sometimes patients need to switch or combine DATs due to either adverse events or loss of efficacy. The aim of this article was to summarise the existing data on the long-term efficacy and adverse events of DATs, and to review the data on the rationale and efficacy for switching or combining DATs in advanced PD. A total of 50 studies on the long-term efficacy of DBS (N = 28), LCIG (N = 12), CSAI (N = 10) and 13 studies on switching and combining DATs were included in this review. Although the DATs show a favourable long-term effect on the main motor and non-motor symptoms of PD they all feature specific adverse events that need to be considered when deciding which DAT to offer to a particular patient. Occasionally, switching or combining DATs is recommended, e.g. if the first DAT shows inadequate symptom control, or due to adverse events. The choice of the second DAT depends above all on the main problems of the first DAT being correctly recognised. DATs are a safe and long-term effective option for the treatment of advanced PD. Switching and/or combining DATs is recommended for patients in whom the first treatment option is not optimal. Future studies are warranted to address the unresolved issues related to long-term efficacy, side effect profile and switching and combination of DATs in multicentric studies and using advanced analytical approaches such as machine learning.

Loureirin C inhibits ferroptosis and apoptosis in 6-OHDA-induced Parkinson's model.

Parkinson's disease (PD) is a type of chronic neurodegenerative disorder. There is an ongoing need for the development of new medications to address this illness. Loureirin C is known to have a protective impact on neurological disorders. Nonetheless, its specific function in Parkinson's Disease (PD) has yet to be fully understood. In this study, we examined the effects of Loureirin C in a cellular model of PD. The PD cell model was established by treating PC-12 cells with 6-hydroxydopamine (6-OHDA). We revealed that Loureirin C promoted the growth of 6-OHDA-treated PC-12 cells. In addition, Loureirin C suppressed the apoptosis of 6-OHDA-treated PC-12 cells and alleviated ferroptosis. Further, Loureirin C improved mitochondrial membrane potential in 6-OHDA-treated PC-12 cells. Mechanically, Loureirin C mediated Nrf2 pathway. Accordingly, Loureirin C not only inhibits ferroptosis but also apoptosis in the 6-OHDA-induced PD cell model, leading us to consider the potential value of Loureirin C in the treatment of PD.

Revolutionizing Parkinson's treatment: Harnessing the potential of intranasal nanoemulsions for targeted therapy.

Parkinson's disease (PD) is the most prominent and highly prevalent chronic neuro-degenerative disease generally recognized by classical motor symptoms which are linked with genetic mutation, Lewy bodies, and subsequently selective loss of nigrostriatal dopaminergic neurons. The blood-brain barrier (BBB) and blood-cerebrospinal fluid barrier protect the central nervous system against toxins and are the most significant barriers to effectivebrain drug delivery in managing Parkinsonism. In recent years, intranasal delivery has attracted remarkable attention for brain targeting as the drug can be administered to the brain directly from the nose employing the trigeminal and olfactory pathways. For brain targeting through nasal delivery, several advanced and promising formulation techniques have been investigated globally. Nanoemulsions are regarded as an innovative carrier approach for PD, where these provide targeted administration and enhanced bioavailability of neurotherapeutics. This manuscript provides deeper insight into the pathophysiology of PD, various drug delivery strategies to overcome BBB, and the potential role of nanoemulsions via the intranasal route. Various research findings on the intranasal administration of nanoemulsions and their pivotal applications in the treatment of PD have also been embarked. The potential role of phytoconstituents and surface-modified nanoemulsions for the effective treatment of PD has also been reflected along with current challenges and future perspectives in this avenue.

Potential Biomarkers and Treatment of Neuroinflammation in Parkinson's Disease.

Parkinson's disease (PD) is a degenerative disease of the central nervous system primarily affecting middle-aged and elderly individuals, significantly compromising their quality of life. Neuroinflammation is now recognized as a key feature in the pathogenesis of PD. This study reviews recent advances in the identification of potential biomarkers associated with neuroinflammation in PD and their significance for therapeutic strategies. These findings suggest that inflammatory factors play a pivotal role in PD treatment, and interventions involving anti-inflammatory drugs, physical exercise, and dietary modifications have shown promising results in mitigating disease progression.

Comparative Safety of Istradefylline Among Parkinson Disease Adjunctive Therapies: A Systematic Review and Meta-analysis of Randomized Controlled Studies

Introduction Adjunctive therapies to treat OFF episodes resulting from long-term levodopa treatment in Parkinson disease (PD) are hampered by safety and tolerability issues. Istradefylline offers an alternative mechanism (adenosine A2A receptor antagonist) and therefore potentially improved tolerability. Methods A systematic review of PD adjuncts published in 2011 was updated to include randomized controlled trials published from January 1, 2010–April 15, 2019. Pairwise meta-analyses were updated, and Bucher indirect comparisons were used to generate estimates of relative safety, presented as odds ratio (OR) and 95% confidence interval (CI) for comparators versus istradefylline. Results Fifty-seven randomized controlled trials involving 11,517 patients were included in the meta-analysis. Relative to istradefylline, dopamine agonists and catechol-O-methyl transferase (COMT) inhibitors had statistically significant higher odds of dyskinesia and somnolence. Monoamine oxidase-B inhibitors had significantly higher odds of hypotension. Amantadine extended-release (ER) had statistically significant higher odds of hallucination, orthostatic hypotension, insomnia, and withdrawals due to adverse events. All interventions combined had significantly higher odds of dyskinesia versus istradefylline 20 mg and somnolence versus istradefylline 40 mg. Considering overall incidence of adverse events, COMT inhibitors and amantadine ER had statistically significant higher odds versus both istradefylline doses (COMT versus istradefylline 40 mg, OR: 1.33; 95% CI: 1.03, 1.75; versus istradefylline 20 mg, OR: 1.32; 95% CI: 1.01, 1.72; amantadine ER versus istradefylline 40 mg, OR: 3.45; 95% CI: 1.85, 6.25; versus istradefylline 20 mg, OR: 3.33; 95% CI: 1.82, 6.25). Conclusion Istradefylline was associated with a generally favorable safety profile relative to other adjunct medications in this study.

Hydroxycinnamic acids mediated modulation of α-Synuclein fibrillation: Biophysical insights.

The fibrillation of α-synuclein (α-Syn) is considered a major contributor to Parkinson's disease (PD). Recent therapeutic measures have focused on inhibiting the fibrillation of α-Syn using various small molecules. We report here the effects of two different hydroxycinnamic acids; chlorogenic acid and sinapic acid on α-Syn fibrillation and have also discussed the mechanistic insights into their mode of modulation. The fluorescence spectroscopy shows that the two hydroxycinnamic acids bind with α-Syn with moderate affinity. Molecular docking studies provide a detailed insights into binding at the residue level and isothermal titration calorimetry reveals specific interactions, like hydrogen bonding, hydrophobic interactions, and van der Waals forces involved in the binding process. Fibrillation kinetics and transmission microscopic studies demonstrated that both chlorogenic acid and sinapic acid attenuate α-Syn fibrillation in a concentration dependent manner. Circular dichroism spectroscopy shows that these compounds bind with α-Syn and delay its structural transition in β-sheet containing fibrillar structures. Both the compounds are also effective even if added after the onset of fibrillation and the fibrillar species formed in the presence of these acids are unable to induce secondary nucleation in monomeric α-Syn. Such kind of structural and mechanistic insights are extremely crucial for designing therapeutic intervention in PD and other neurodegenerative diseases.

Bromocriptine mesylate-loaded nanoparticles co-modified with low molecular weight protamine and lactoferrin for enhanced nose-to-brain delivery in Parkinson's disease treatment.

Parkinson's disease confronts challenges in drug delivery due to the blood-brain barrier. Intranasal delivery bypasses the blood-brain barrier for improved drug bioavailability, yet narrow nasal space and brief retention time hinder clinical applicability. We conducted a Bromocriptine Mesylate-loaded PLGA nanoparticles co-modified with low molecular weight protamine (LMWP) and lactoferrin (Lf) (LMWP/Lf-BCM-NPs) for nose-to-brain delivery. The resulting LMWP/Lf-BCM-NPs were uniform spheres with an average size of 248.53±16.25nm and zeta potential of -2.63±0.74mV. Fourier transform infrared spectroscopy confirmed LMWP and Lf attachment. The co-modified nanoparticles showed improving cellular transport and good viability. The LMWP/Lf-BCM-NPs showed increased brain targeting efficiency in mice. In haloperidol-induced Parkinson mouse models, the LMWP/Lf-BCM-NPs showed increased brain targeting efficiency, enhanced behavioral regulatory effects, enhanced antioxidant effects and neuroprotection effects. This study paves the way for a novel, non-invasive brain-targeted therapy, offering a promising avenue for Parkinson's disease clinical treatment.

Enhancements in Parkinson's Disease Management: Leveraging Levodopa Optimization and Surgical Breakthroughs.

Parkinson's disease (PD) is a complex neurological condition caused due to inheritance, environment, and behavior among various other parameters. The onset, diagnosis, course of therapy, and future of PD are thoroughly examined in this comprehensive review. This review also insights into pathogenic mechanisms of reactive microgliosis, Lewy bodies, and their functions in the evolution of PD. It addresses interaction complexity with genetic mutations, especially in genes such as UCH-L1, parkin, and α-synuclein, which illuminates changes in the manner dopaminergic cells handle proteins and use proteases. One of the emerging therapeutic routes that are being investigated is neuroprotective medicines that aim to prevent the aggregation of α-synuclein and interventions that modify the progression of diseases. The review concludes by stressing the dynamic nature of PD research and the potential game-changing impact of precision medicines on current approaches to therapy. This raises the improved outcomes and life quality for those with PD. Potential treatments for severe PD include new surgical methods like Deep Brain Stimulation (DBS). Further, exploration of non-motor manifestations, such as cognitive impairment, autonomic dysfunction, and others, is covered in this review article. These symptoms have a significant impact on patients' quality of life. One of the emerging therapeutic routes that are being investigated is neuroprotective medicines that aim to prevent the aggregation of α-synuclein and interventions that modify the progression of diseases. The review concludes by stressing the dynamic nature of PD research and the potential game-changing impact of precision medicines on current approaches to therapy.

Fast Fourier Transform in Assessing the Effect of Parkinson Disease Progression on Sympathetic Oscillation

The complex relationship between sympathetic oscillation and the progression of Parkinson disease (PD) is still under active investigation. This study examines the influence of PD on sympathetic activity by examining heart rate variability derived from electrocardiogram recordings. The peak frequency within the low-frequency band of heart rate variability, which is primarily associated with sympathetic modulation, was extracted and compared across various phases of PD severity. As PD advanced, the results revealed a significant and progressive decline in peak frequency, indicating a reduction in sympathetic responsiveness. This observation corresponds with the recognized autonomic dysfunction that accompanies PD progression. Furthermore, a significant negative correlation was observed between peak frequency and disease severity, suggesting its potential utility as a biomarker for monitoring PD advancement and treatment efficacy. The findings emphasize the clinical relevance of autonomic dysfunction in PD and highlight the potential of peak frequency analysis as an effective method for adding to the diagnosis, prognosis, and management of this complex neurodegenerative disorder.

Delivery of small interfering RNA by hydrogen sulfide-releasing nanomotor for the treatment of Parkinson's disease

Small interfering RNA (siRNA) that inhibit the formation of α-synuclein (α-syn) aggregates is considered very promising therapeutic agents for the treatment of Parkinson's disease (PD). However, the low stability and the difficulty in crossing the blood-brain barrier (BBB) of free siRNA has severely limited their therapeutic effects. Here, we developed an H2S donor nanomotor that can encapsulate siRNA, which can both protect the activity of siRNA and help siRNA to be effectively targeted to the mitochondria of damaged neuronal cells, in order to promote the effective therapeutic effect of siRNA for PD. Specifically, the cysteine monomer-modified polyethylene glycol (PEG-Cys) and the amphiphilic ionic monomer 2-methacryloyloxyethylphosphorylcholine (MPC) that can effectively penetrate the BBB, were selected to form a polymer protective layer on the surface of siRNA in a free-radical polymerization reaction, to construct the H2S donor nanomotor encapsulating siRNA (PCM@siRNA). Among them, MPC can help PCM@siRNA to break through the BBB by interacting with nicotinic acetylcholine receptor or choline transporter on the surface of cerebrovascular endothelial cells, while PEG-Cys can undergo chemotactic effect by specifically recognizing 3-thiopyruvate thioltransferase and thus achieve effective targeting of damaged mitochondria in neuronal cells. PCM@siRNA that reached neuronal cells can not only be utilized to play the role of silencing the α-syn gene to inhibit the formation of α-syn aggregates by siRNA, but also to degrade the formed α-syn aggregates by using the H2S produced by its chemotaxis process to achieve an effective treatment for PD. This therapeutic modality, which can simultaneously inhibit the formation of α-syn aggregates and promote their degradation, has the therapeutic potential to reverse the pathological state of α-syn, which is important for the treatment of PD.

Neuroprotective potential of isofraxidin: Alleviating parkinsonian symptoms, inflammation and microglial activation.

Parkinson's disease (PD) is one of the most common neurodegenerative disorders. Previous research has confirmed that isofraxidin can reduce macrophage expression and inhibit peripheral inflammation. However, its effects on the central nervous system remain underexplored. This study aims to determine whether isofraxidin offers protective effects against PD. To assess the effects of isofraxidin, motor performance changes in LPS-induced PD mice were evaluated using rotarod, pole-climbing, and beam-walking tests. Striatal damage was examined through [18F]fluorodeoxyglucose ([18F]FDG) positron emission tomography (PET) imaging, and dopaminergic neurotoxicity was assessed using tyrosine hydroxylase (TH) staining. Microglial accumulation and activation were monitored with Iba-1 staining, while LPS-induced inflammation was examined via TNF-α and IL-1β staining. Isofraxidin pre-treatment significantly improved LPS-induced motor dysfunction, as evidenced by better performance in the rotarod, pole-climbing, and beam-walking tests. [18F]FDG PET imaging showed that isofraxidin restored glucose uptake in the striatum, countering LPS-induced damage. Furthermore, Iba-1 staining revealed that isofraxidin markedly inhibited LPS-induced microglial activation and accumulation. TNF-α and IL-1β staining indicated a reduction in inflammation with isofraxidin treatment. Additionally, TH staining supported the neuroprotective role of isofraxidin on dopaminergic neurons. Isofraxidin exhibits notable neuroprotective properties by mitigating LPS-induced parkinsonian behaviors, microglial activation, inflammation, and dopaminergic neuron damage. These results highlight isofraxidin's potential as a therapeutic intervention for PD.