Treatment Of Parkinson's Disease Research Articles

Diverse pathways for the treatment of Parkinson's disease: Integration and development of traditional and emerging therapies.

Parkinson's disease (PD) is the second most common central neurodegenerative disease in the world after Alzheimer's disease (AD), which mainly occurs in middle-aged and elderly people, and is increasing with the aging of the population. With the increasing incidence of PD, it is particularly important to explore its pathology and provide effective interventions and treatments. The pathogenesis of PD involves a variety of factors such as genetics, environment, and age, and is not yet fully understood. The main pathogenic mechanisms include neuronal degeneration, abnormal aggregation of α-synuclein, formation of Lewy bodies and oxidative stress, etc. In recent years, gene therapy, stem cell therapy, and immunotherapy, along with traditional drugs and surgical treatments, have become widely used. Currently, all treatments for PD are symptomatic and there is no radical cure. This paper reviews existing traditional and emerging treatments for PD to provide a theoretical basis for the in-depth study of PD pathogenesis and therapeutic approaches. Meanwhile, the application of gene editing and delivery, stem cell transplantation, immunotherapy and multi-target therapy laid the foundation for the development of safer, more effective and more comprehensive treatments for PD.

Multiomics approach identifies dysregulated lipidomic and proteomic networks in Parkinson’s disease patients mutated in TMEM175

Parkinson’s disease (PD) represents one of the most frequent neurodegenerative disorders for which clinically useful biomarkers remain to be identified and validated. Here, we adopted an untargeted omics approach to disclose lipidomic, metabolomic and proteomic alterations in plasma and in dermal fibroblasts of PD patients carrying mutations in TMEM175 gene. We revealed a wide dysregulation of lysosome, autophagy, and mitochondrial pathways in these patients, supporting a role of this channel in regulating these cellular processes. The most significant altered lipid classes were Fatty acyls, Glycerophospholipids and Phosphosphingolipids. The plasma level of Phosphatidylcholines (PC) and Phosphatidylinositol (PI) 34:1 significantly correlated with an earlier age at onset of the disease in TMEM175 patients (p = 0.008; p = 0.006). In plasma we also observed altered amino acids metabolic pathways in PD patients. We highlighted that increased level of L-glutamate strongly correlated (p < 0.001) with the severity of motor and non-motor symptoms in PD_TMEM175 patients. In dermal fibroblasts, we disclosed alterations of proteins involved in lipids biosynthesis (PAG15, PP4P1, GALC, FYV1, PIGO, PGPS1, PLPP1), in the insulin pathway (IGF2R), in mitochondrial metabolism (ACD10, ACD11, ACADS) and autophagy (RAB7L). Interestingly, we quantified 43 lysosomal or lysosomal-related proteins, which were differentially modulated between TMEM175 patients and controls. Integrative correlation analysis of proteome and lipidome of PD_TMEM175 cellular models identified a strong positive correlation of 13 proteins involved in biosynthetic processes with PC and Ceramides. Altogether, these data provide novel insights into the molecular and metabolic alterations underlying TMEM175 mutations and may be relevant for PD prediction, diagnosis and treatment.

IMMUnity Unveiled: A Translational NETwork for tackling PARKinson's Disease – IMMUPARKNET

Parkinson’s disease (PD) affects more than one million people in the EU. It currently has no definitive cure, meaning that patients rely only on symptomatic treatments, which themselves are burdened by side effects. The need for advancements in both knowledge and available treatments is thus strongly felt by patients, caregivers, and health operators. This unmet need sparked the idea of orchestrating a collaborative effort via a common network – IMMUPARKNET (The role of IMMUnity in tackling PARKinson’s disease through a Translational NETwork). The IMMUPARKNET COST Action focuses on challenges in PD and its related crosstalk with immune response. Although widely recognized, the role of immunity in the onset and development of PD is still unclear. The main goal of IMMUPARKNET is to fill this knowledge gap by establishing an innovative, interdisciplinary research network and fostering exchanges of expertise among specialists from different countries and institutions. As we gather scientists and clinicians who study immunity in PD and related fields, IMMUPARKNET will establish the first nucleus of a multidisciplinary ecosystem that aims to harmonize efforts and approaches, both in research and clinical practice, to boost the development of ground-breaking treatments for PD. Through meetings, training schools, webinars, position papers, and review manuscripts, IMMUPARKNET will lead fruitful exchanges of know-how among experts in the field. The IMMUPARKNET structure revolves around 5 working groups, with a total of 157 active members from 34 different countries. Of these active members, 58.5% are young researchers, while 67.5% come from Inclusiveness Target Countries (ITC - less research-intensive COST Members; https://www.cost.eu/about/members/). IMMUPARKNET output will facilitate the improved sharing and development of research resources, straightening the road to novel treatments and identifying where existing ones can be repurposed, all, ultimately and hopefully, finding a cure for PD.

MicroRNAs in Parkinson's disease: From pathogenesis to diagnostics and therapeutic strategies.

Parkinson's disease (PD) is a prevalent neurodegenerative disorder characterized by pathological changes, including the loss of dopaminergic neurons and abnormal aggregation of α-synuclein (α-syn). Certain cellular and molecular events are involved; however, the origin and significance of these events remain uncertain. The discovery of microRNAs (miRNAs) predicted to play a pivotal role in various regulatory processes has emerged. Studies on the dysregulation of miRNAs in PD pathogenesis, diagnosis, and treatment have recently gained attention. This review aims to encapsulate recent research developments concerning the function of miRNAs in the pathophysiology of PD and their prospective applications as diagnostic and therapeutic biomarkers, targets, and pharmaceuticals. The most effective drug delivery approach for the treatment of PD, transnasal-cerebral drug delivery, has also been briefly described. The advantage of this delivery strategy is its capacity to bypass the blood-brain barrier, enabling direct administration of medication to the brain, which improves therapeutic efficacy and minimizes side effects.

Large-scale genetic characterization of Parkinson's disease in the African and African admixed populations.

Elucidating the genetic contributions to Parkinson's disease (PD) etiology across diverse ancestries is a critical priority for the development of targeted therapies in a global context. We conducted the largest sequencing characterization of potentially disease-causing, protein-altering and splicing mutations in 710 cases and 11,827 controls from genetically predicted African or African admixed ancestries. We explored copy number variants (CNVs) and runs of homozygosity (ROHs) in prioritized early onset and familial cases. Our study identified rare GBA1 coding variants to be the most frequent mutations among PD patients, with a frequency of 4% in our case cohort. Out of the 18 GBA1 variants identified, ten were previously classified as pathogenic or likely pathogenic, four were novel, and four were reported as of uncertain clinical significance. The most common known disease-associated GBA1 variants in the Ashkenazi Jewish and European populations, p.Asn409Ser, p.Leu483Pro, p.Thr408Met, and p.Glu365Lys, were not identified among the screened PD cases of African and African admixed ancestry. Similarly, the European and Asian LRRK2 disease-causing mutational spectrum, including LRRK2 p.Gly2019Ser and p.Gly2385Arg genetic risk factors, did not appear to play a major role in PD etiology among West African-ancestry populations. However, we found three heterozygous novel missense LRRK2 variants of uncertain significance overrepresented in cases, two of which - p.Glu268Ala and p.Arg1538Cys - had a higher prevalence in the African ancestry population reference datasets. Structural variant analyses revealed the presence of PRKN CNVs with a frequency of 0.7% in African and African admixed cases, with 66% of CNVs detected being compound heterozygous or homozygous in early-onset cases, providing further insights into the genetic underpinnings in early-onset juvenile PD in these populations. Novel genetic variation overrepresented in cases versus controls among screened genes warrants further replication and functional prioritization to unravel their pathogenic potential. Here, we created the most comprehensive genetic catalog of both known and novel coding and splicing variants potentially linked to PD etiology in an underserved population. Our study has the potential to guide the development of targeted therapies in the emerging era of precision medicine. By expanding genetics research to involve underrepresented populations, we hope that future PD treatments are not only effective but also inclusive, addressing the needs of diverse ancestral groups.

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.

Transcutaneous 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. This review aimed to investigate the efficacy of tVNS on motor function, other potential clinical targets and its safety in various treatment conditions. We 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. 6 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. tVNS 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. https://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.