Treatment Of Parkinson's Disease Research Articles

Identification of high-affinity Monoamine oxidase B inhibitors for depression and Parkinson's disease treatment: bioinformatic approach of drug repurposing.

Depression and Parkinson's disease (PD) are devastating psychiatric and neurological disorders that require the development of novel therapeutic interventions. Drug repurposing targeting predefined pharmacological targets is a widely use approach in modern drug discovery. Monoamine oxidase B (MAO-B) is a critical protein implicated in Depression and PD. In this study, we undertook a systematic exploration of repurposed drugs as potential inhibitors of MAO-B. Exploring a library of 3,648 commercially available drug molecules, we conducted virtual screening using a molecular docking approach to target the MAO-B binding pocket. Two promising drug molecules, Brexpiprazole and Trifluperidol, were identified based on their exceptional binding potential and drug profiling. Subsequently, all-atom molecular dynamics (MD) simulations were performed on the MAO-B-ligand complexes for a trajectory of 300 nanoseconds (ns). Simulation results demonstrated that the binding of Brexpiprazole and Trifluperidol induced only minor structural alterations in MAO-B and showed significant stabilization throughout the simulation trajectory. Overall, the finding suggests that Brexpiprazole and Trifluperidol exhibit strong potential as repurposed inhibitors of MAO-B that might be explored further in experimental investigations for the development of targeted therapies for depression and PD.

Network pharmacology combined with experimental validation show that apigenin as the active ingredient of Campsis grandiflora flower against Parkinson's disease by inhibiting the PI3K/AKT/NF-κB pathway.

The exploration of novel natural products for Parkinson's disease (PD) is a focus of current research, as there are no definitive drugs to cure or stop the disease. Campsis grandiflora (Thunb.) K. Schum (Lingxiaohua) is a traditional Chinese medicine (TCM), and the exact active constituents and putative mechanisms for treating PD are unknown. Through data mining and network pharmacology, apigenin (APi) was identified as the main active ingredient of Lingxiaohua, and key targets (TNF, AKT1, INS, TP53, CASP3, JUN, BCL2, MMP9, FOS, and HIF1A) of Lingxiaohua for the treatment of PD were discovered. The primary routes implicated were identified as PI3K/AKT, Apoptosis, TNF, and NF-κB pathways. Subsequently, therapeutic potential of APi in PD and its underlying mechanism were experimentally evaluated. APi suppressed the release of mediators of inflammation and initiation of NF-κB pathways in MES23.5 cells induced by MPP+. APi suppressed caspase-3 activity and apoptosis and elevated p-AKT levels in MES23.5 cells. Pretreatment with LY294002, a PI3K inhibitor, resulted in APi treatment blocking the activation of NF-κB pathway and expression of inflammatory factors in MES23.5 cells by activating the PI3K/AKT pathway. In conclusion, APi protects dopaminergic neurons by controlling the PI3K/AKT/NF-κB pathway, giving novel insights into the pharmacological mechanism of Lingxiaohua in treating PD.

Neural effects of multisensory dance training in Parkinson's disease: evidence from a longitudinal neuroimaging single case study.

Dance is associated with beneficial outcomes in motor and non-motor domains in Parkinson's disease (PD) and regular participation may help delay symptom progression in mild PD. However, little is known about the neurobiological mechanisms of dance interventions for PD. The present case study explored potential neuroplastic changes in a 69-year-old male with mild PD participating in regular dance classes over 29 weeks. Functional MRI was performed at four timepoints (pre-training, 11 weeks, 18 weeks, 29 weeks), where the individual imagined a dance choreography while listening to the corresponding music. Neural activity was compared between dance-imagery and fixation blocks at each timepoint. Analysis of functionally defined regions revealed significant blood-oxygen-level-dependent (BOLD) signal activation in the supplementary motor area, right and left superior temporal gyri and left and right insula, with modulation of these regions observed over the training period except for the left insula. The results suggest the potential for dance to induce neuroplastic changes in people with PD in regions associated with motor planning and learning, auditory processing, rhythm, emotion, and multisensory integration. The findings are consistent with dance being a multimodal therapeutic activity that could provide long-term benefits for people with PD.

Exploring the hub Genes and Potential Mechanisms of Complement system-related Genes in Parkinson Disease: Based on Transcriptome Sequencing and Mendelian Randomization.

An accurate diagnosis of Parkinson's disease (PD) remains challenging and the exact cause of the disease is unclean. The aims are to identify hub genes associated with the complement system in PD and to explore their underlying molecular mechanisms. Initially, differentially expressed genes (DEGs) and key module genes related to PD were mined through differential expression analysis and WGCNA. Then, differentially expressed CSRGs (DE-CSRGs) were obtained by intersecting the DEGs, key module genes and CSRGs. Subsequently, MR analysis was executed to identify genes causally associated with PD. Based on genes with significant MR results, the expression level and diagnostic performance verification were achieved to yield hub genes. Functional enrichment and immune infiltration analyses were accomplished to insight into the pathogenesis of PD. qRT-PCR was employed to evaluate the expression levels of hub genes. After MR analysis and related verification, CD93, CTSS, PRKCD and TLR2 were finally identified as hub genes. Enrichment analysis indicated that the main enriched pathways for hub genes. Immune infiltration analysis found that the hub genes showed significant correlation with a variety of immune cells (such as myeloid-derived suppressor cell and macrophage). In the qRT-PCR results, the expression levels of CTSS, PRKCD and TLR2 were consistent with those we obtained from public databases. Hence, we mined four hub genes associated with complement system in PD which provided novel perspectives for the diagnosis and treatment of PD.

Therapies Using Anti-Diabetics to Prevent and Manage Progression of Parkinson's Disease

<p>Currently, a significant proportion of older individuals have demonstrated connections between Parkinson's disease (PD) and type 2 diabetes mellitus (T2DM). Emerging evidence from cohort studies, clinical data, and preclinical meta-analyses reveals that T2DM patients have an increased risk of developing PD, often accompanied by more severe disease progression. These two chronic conditions are believed to share common pathways. The pathways that likely connect the neurodegenerative process of PD include autophagy, mitochondrial dysfunction, dysregulated insulin signaling, inflammation, and insulin resistance. Preclinical PD models highlight the importance of cerebral insulin signaling, which confers numerous neuroprotective benefits. Several ongoing phase II and phase III trials are being conducted in PD-affected populations. These trials reflect the potential of existing anti-diabetic medications to improve PD motor symptoms and halt the progression of neurodegeneration. Brain insulin resistance plays a crucial role in the pathophysiology of PD. The insulin signaling pathway represents a promising novel target for disease modification in both diabetic and non-diabetic PD. Incretin receptors in the brain have emerged as the most promising targets for repurposing existing drugs in PD treatment. Targeting these receptors mitigates inflammation, apoptosis, toxic protein aggregation, long-term potentiation, autophagy, and insulin signaling failure. </p><p> Presently, various novel anti-diabetic targets are available that can regulate the insulin signaling pathway in dopaminergic neurons, suggesting improvements in cognitive function and significant neuroprotective effects in PD. Throughout neurodegenerative processes, insulin and incretins exert therapeutic effects in multiple manners. Preclinical studies have demonstrated that glucagon-- like peptide 1 (GLP-1) receptor agonists reduce neuroinflammation, tau phosphorylation, and amyloid deposition while increasing synaptic function and enhancing memory formation. Incretin mimetics may act through the restoration of insulin signaling pathways, inducing further neuroprotective effects. </p><p> This review examined the reported shared cellular and molecular pathologies between PD and T2DM, and explored the repurposing of anti-diabetic drugs for the prevention of PD progression through the regulation of insulin signaling pathways.</p>

Missed Insights for Earlier Management of Parkinson's Disease and the Value of Dopamine Transporter (DAT) Scans.

Background/Objectives: This retrospective study focused on the role of Dopamine Transporter (DAT) scans in diagnosing Parkinson's Disease (PD) in older adults with cognitive impairment (CI). Methods: We retrospectively analyzed brain imaging of 6483 individuals aged 60 and above with CI. Among these, 297 underwent a DAT scan, with 189 testing positive and 89 starting dopamine therapy. In contrast, 173 patients exhibited PD-associated structural changes on CT or MRI without receiving DAT scans or treatment. Results: Of these patients, 50 (29%) experienced falls. This points towards a potential missed diagnosis of PD, which can respond to therapy in the early stages. Conclusions: Our results suggest that providers may overlook subtle signs of parkinsonism in patients with CI, resulting in symptoms worsening and treatment delay. Since CI is often first brought to the attention of PCPs, our findings call for an increased effort to inform PCPs of the role of DAT scans in aiding the diagnosis of dopamine deficiency states. By understanding PD-related structural changes seen on brain imaging and using a DAT scan to confirm dopamine deficiency, treatment for PD or related states might be started earlier or a timely referral made to a specialist, reducing patient disability and improving their quality of life.

Continuous Subcutaneous Foslevodopa-Foscarbidopa in Parkinson's Disease: A Mini-Review of Current Scope and Future Outlook.

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by motor and non-motor symptoms, primarily because of the impairment of dopaminergic neurons. Long-term use of levodopa, the standard PD treatment, often results in fluctuating therapeutic effects and dyskinesia, necessitating alternative therapies. This review aims to synthesize current insights and clinical experiences with foslevodopa-foscarbidopa, focusing on its pharmacokinetics, efficacy, and safety profile, to evaluate its potential in transforming PD therapy. A systematic literature search was conducted up to November 2023 using databases PubMed, Web of Science, and Cochrane Library. The search yielded eight eligible articles, including pharmacological studies, case reports, observational studies, and controlled trials. No language restrictions were applied. Foslevodopa and foscarbidopa, as prodrugs of levodopa and carbidopa, exhibited excellent chemical stability and solubility, facilitating continuous subcutaneous infusion. Clinical trials demonstrated that these prodrugs maintain stable levodopa levels, thereby addressing the limitations of oral levodopa therapy. Phase 1 and 3 studies indicated significant improvements in motor function and quality of life in advanced PD patients. However, a higher incidence of treatment-emergent adverse events, mainly infusion site reactions, was observed compared to oral therapies. Foslevodopa-foscarbidopa emerges as a promising alternative for advanced PD treatment, offering sustained symptom control. Its efficacy in managing motor fluctuations and dyskinesia makes it a viable option in the PD therapeutic spectrum. Future research should focus on long-term safety, economic impact, and broader accessibility. Foslevodopa-foscarbidopa is now commercially distributed in many countries in Europe and in Japan.

LRRK2; Communicative Role in the Treatment of Parkinson's Disease and Ulcerative Colitis Overlapping.

Involvement of gastrointestinal inflammation in Parkinson's disease (PD) pathogenesis and movement have progressively emerged. Inflammation is involved in the etiology of both PD and inflammatory bowel disease (IBD). Transformations in leucine-rich recurrent kinase 2 (LRRK2) are among the best hereditary supporters of IBD and PD. Elevated levels of LRRK2 have been reported in stimulated colonic tissue from IBD patients and peripheral invulnerable cells from irregular PD patients; thus, it is thought that LRRK2 directs inflammatory cycles. Since its revelation, LRRK2 has been seriously linked in neurons, albeit various lines of proof affirmed that LRRK2 is profoundly communicated in invulnerable cells. Subsequently, LRRK2 might sit at a junction by which stomach inflammation and higher LRRK2 levels in IBD might be a biomarker of expanded risk for inconsistent PD or potentially may address a manageable helpful objective in incendiary sicknesses that increment the risk of PD. Here, we discuss how PD and IBD share covering aggregates, especially regarding LRRK2 and present inhibitors, which could be a helpful objective in ongoing treatments. English data were obtained from Google Scholar, PubMed, Scopus, and Cochrane library studies published between 1990-December 2022. Inhibitors of the LRRK2 pathway can be considered as the novel treatment approaches for IBD and PD treatment. Common mediators and pathways are involved in the pathophysiology of IBD and PD, which are majorly correlated with inflammatory situations. Such diseases could be used for further clinical investigations.

Direct conversion of human umbilical cord mesenchymal stem cells into dopaminergic neurons for Parkinson's disease treatment

Parkinson's disease (PD) is a neurodegenerative disorder characterized by motor deficits due to the depletion of nigrostriatal dopamine. Stem cell differentiation therapy emerges as a promising treatment option for sustained symptom relief. In this study, we successfully developed a one-step differentiation system using the YFBP cocktail (Y27632, Forskolin, SB431542, and SP600125) to effectively convert human umbilical cord mesenchymal stem cells (hUCMSCs) into dopaminergic neurons without genetic modification. This approach addresses the challenge of rapidly and safely generating functional neurons on a large scale. After a 7-day induction period, over 80 % of the cells were double-positive for TUBB3 and NEUN. Transcriptome analysis revealed the dual roles of the cocktail in inducing fate erasure in mesenchymal stem cells and activating the neuronal program. Notably, these chemically induced cells (CiNs) did not express HLA class II genes, preserving their immune-privileged status. Further study indicated that YFBP significantly downregulated p53 signaling and accelerated the differentiation process when Pifithrin-α, a p53 signaling inhibitor, was applied. Additionally, Wnt/β-catenin signaling was transiently activated within one day, but the prolonged activation hindered the neuronal differentiation of hUCMSCs. Upon transplantation into the striatum of mice, CiNs survived well and tested positive for dopaminergic neuron markers. They exhibited typical action potentials and sodium and potassium ion channel activity, demonstrating neuronal electrophysiological activity. Furthermore, CiNs treatment significantly increased the number of tyrosine hydroxylase-positive cells and the concentration of dopamine in the striatum, effectively ameliorating movement disorders in PD mice. Overall, our study provides a secure and reliable framework for cell replacement therapy for Parkinson's disease.

Chondroitin sulfate modulates oxidative stress and inflammation in the substantia nigra via gut microbiota regulation: Mechanistic insights into Parkinson's disease treatment

Hydrogen sulfide (H2S) is a bioactive gas with potential neuroprotective properties. This study explores the therapeutic efficacy of chondroitin sulfate (CS) in a Parkinson's disease (PD) mouse model by evaluating its impact on behavior, gut microbiota composition, substantia nigra (SN) pathology, oxidative stress, and inflammation. Behavioral tests indicate that CS improves cognitive function and learning abilities in PD mice. Gut microbiota analysis and fecal H2S content measurement reveal that CS fosters the growth of Desulfovibrio and boosts H2S production, respectively. Further examination shows that CS treatment enhances antioxidant defenses, reduces inducible nitric oxide synthase (iNOS)-mediated inflammation, and alleviates PD-related pathology and α-synuclein overexpression in the SN. These findings suggest that CS modulates the gut microbiota and its metabolic product, H2S, potentially improving PD symptoms through the gut-brain axis.

Resveratrol and ceftriaxone encapsulated in hybrid nanoparticles to prevent dopaminergic neurons from degeneration for Parkinson's disease treatment

The purpose of this study is to evaluate the influence of phospholipid-polymer nanoparticles (PNPs) on mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) signaling of dopaminergic neurons in degenerated brain. Resveratrol (RES)- and ceftriaxone (CEF)-entrapped PNPs with surface leptin (Lep) and transferrin (Tf) were fabricated to rescue both 1-methyl-4-phenylpyridinium (MPP+)-insulted SH-SY5Y cells and Wistar rats. Based on PNPs, anti-apoptosis of RES and CEF, and targeting of Lep and Tf were investigated. Experimental results revealed that 20–30 % alginic acid (Alg) yielded the maximal particle size, physical stability and entrapment efficiency of CEF, and the minimal release percentage of CEF. Increasing Alg content in PNPs decreased the entrapment efficiency of RES, and facilitated the release of RES. Optimized PNP composition was about 40 % Alg, 15 % phosphatidylserine and 45 % poly-ε-caprolactone. Lep-Tf-PNPs ameliorated brain permeability of RES and CEF without jeopardizing the blood-brain barrier, and promoted the viability of MPP+-insulted SH-SY5Y cells. Immunofluorescence images and western blots of MPP+-insulted SH-SY5Y cells showed that Lep-Tf-RES-CEF-PNPs upregulated dopamine transporter, tyrosine hydroxylase, B-cell lymphoma 2 (Bcl-2), cyclic AMP response element-binding protein and ERK5 expressions, and downregulated Bcl-2-associated X protein (Bax), α-synuclein (α-syn), phosphorylated tau protein (p-tau), c-Jun N-terminal kinase and ERK1/2 expressions. Lep-Tf-RES-CEF-PNPs unveiled a strong capacity to recover Bcl-2, Bax, α-syn and p-tau levels from MPP+ injury in the substantia nigra of rats. Hence, Lep-Tf-RES-CEF-PNPs can retard α-syn fibril formation, prevent tau protein from phosphorylation, and moderate MAPK/ERK and phosphatidylinositol 3-kinase/protein kinase B, and are promising for brain- and neuron-targeted pharmacotherapy to manage Parkinson's disease.

Application of multimodal deep learning and multi-instance learning fusion techniques in predicting STN-DBS outcomes for Parkinson's disease patients

Parkinson's Disease (PD) is a progressive neurodegenerative disorder with substantial impact on patients' quality of life. Subthalamic nucleus deep brain stimulation (STN-DBS) is an effective treatment for advanced PD, but patient responses vary, necessitating predictive models for personalized care. Recent advancements in medical imaging and machine learning offer opportunities to enhance predictive accuracy, particularly through deep learning and multi-instance learning (MIL) techniques. This retrospective study included 127 PD patients undergoing STN-DBS. Medical records and imaging data were collected, and patients were categorized based on treatment outcomes. Advanced segmentation models were trained for automated region of interest (ROI) delineation. A novel 2.5D deep learning approach incorporating multi-slice representation was developed to extract detailed ROI features. Multi-instance learning fusion techniques integrated predictions across multiple slices, combining radiomics and deep learning features to enhance model performance. Various machine learning algorithms were evaluated, and model robustness was assessed using cross-validation and hyperparameter optimization. The MIL model achieved an area under the curve (AUC) of 0.846 for predicting STN-DBS outcomes, surpassing the radiomics model's AUC of 0.825. Integration of MIL and radiomics features in the DLRad model further improved discriminative ability to an AUC of 0.871. Calibration tests showed good model reliability, and decision curve analysis demonstrated clinical utility, affirming the model's predictive advantage. This study demonstrates the efficacy of integrating MIL, radiomics, and deep learning techniques to predict STN-DBS outcomes in PD patients. The multimodal fusion approach enhances predictive accuracy, supporting personalized treatment planning and advancing patient care.

Multiomics approach discloses lipids and metabolites profiles associated to Parkinson's disease stages and applied therapies

Profiling circulating lipids and metabolites in Parkinson's disease (PD) patients could be useful not only to highlight new pathways affected in PD condition but also to identify sensitive and effective biomarkers for early disease detection and potentially effective therapeutic interventions. In this study we adopted an untargeted omics approach in three groups of patients (No L-Dopa, L-Dopa and DBS) to disclose whether long-term levodopa treatment with or without deep brain stimulation (DBS) could reflect a characteristic lipidomic and metabolomic signature at circulating level. Our findings disclosed a wide up regulation of the majority of differentially regulated lipid species that increase with disease progression and severity. We found a relevant modulation of triacylglycerols and acyl-carnitines, together with an altered profile in adiponectin and leptin, that can differentiate the DBS treated group from the others PD patients. We found a highly significant increase of exosyl ceramides (Hex2Cer) and sphingoid bases (SPB) in PD patients mainly in DBS group (p < 0.0001), which also resulted in a highly accurate diagnostic performance. At metabolomic level, we found a wide dysregulation of pathways involved in the biosynthesis and metabolism of several amino acids. The most interesting finding was the identification of a specific modulation of L-glutamic acid in the three groups of patients. L-glutamate levels increased slightly in No L-Dopa and highly in L-Dopa patients while decreased in DBS, suggesting that DBS therapy might have a beneficial effect on the glutamatergic cascade. All together, these data provide novel insights into the molecular and metabolic alterations underlying PD therapy and might be relevant for PD prediction, diagnosis and treatment.

Astrocytic lactoferrin deficiency augments MPTP-induced dopaminergic neuron loss by disturbing glutamate/calcium and ER-mitochondria signaling

Increased levels of lactoferrin (Lf) are present in the aged brain and in the lesions of various neurodegenerative diseases, including Parkinson's disease (PD), and may contribute to the cascade of events involved in neurodevelopment and neuroprotection. However, whether Lf originates from astrocytes and functions within either the normal or pathological brain are unknown. Here, we employed mice with specific knockout of the astrocyte lactoferrin gene (named Lf-cKO) to explore its specific roles in the pathological process of PD. We observed a decrease in tyrosine hydroxylase-positive cells, mitochondrial dysfunction of residual dopaminergic neurons, and motor deficits in Lf-cKO mice, which were significantly aggravated after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment. To further explore how astrocytic lactoferrin deficiency exacerbated PD-like manifestation in MPTP-treated mice, the critical molecules involved in endoplasmic reticulum (ER)-mitochondria contacts and signaling pathways were investigated. In vitro and in vivo models, we found an aberrant level of effects implicated in glutamate and calcium homeostasis, mitochondrial morphology and functions, mitochondrial dynamics, and mitochondria-associated ER membranes, accompanied by signs of oxidative stress and ER stress, which increase the fragility of dopaminergic neurons. These findings confirm the existence of astrocytic Lf and its influence on the fate of dopaminergic neurons by regulating glutamate/calcium metabolism and ER-mitochondria signaling. Our findings may be a promising target for the treatment of PD.

Effectiveness of physiotherapy rehabilitation approaches for Parkinson's disease: A Durrës case study.

The article's significance lies in the substantial rise in the risk of developing Parkinson's disease (PD), necessitating the exploration of various approaches to rehabilitation and medical treatment. The purpose of the article is to detect the direct effect of physiotherapy for patients with PD and to identify how it helps in slowing down cardio-pulmonary failure, improving the posture, balance, bradykinesia and tremor. The research utilised clinical data from 407 PD patients aged 30-100 years at the Central Polyclinic of Durrës, spanning 2011-2022, and included a systematic literature review and statistical analysis comparing physiotherapy outcomes with European Union standards. The research demonstrates the efficiency of physiotherapy in the short and long term in the treatment of PD for patients and medical personnel. All information can be used to increase the functional abilities of patients and minimise complications after physiotherapy and to estimate the effectiveness of different exercises in delaying PD. Older adults, particularly those aged 71-80, are most affected by PD, with males more likely to be diagnosed. Physiotherapy rehabilitation improves motor symptoms, posture, and balance in 30-80-year-olds, but its effectiveness declines with age. Advanced rehabilitation methods in Italy lead to better outcomes, suggesting the potential for improvement in Durres disease. The study emphasises the need for improved rehabilitation strategies for older patients by recommending tailored programs, advanced methods, standardisation, training, and long-term monitoring. Further research should concentrate on the long-term sustainability of physiotherapy benefits, the development of targeted interventions for older patients, and the integration of innovative therapeutic approaches.

Vagus nerve stimulation with a small total charge transfer improves motor behavior and reduces neuroinflammation in a mouse model of Parkinson's disease

Parkinson's disease (PD) is a common neurodegenerative disease characterized by the loss of dopaminergic (DA) neurons in the substantia nigra (SN). Conventional treatments are ineffective in reversing disease progression. Recently, the therapeutic and rehabilitation potential of vagus nerve stimulation (VNS) in PD has been explored. However, the underlying mechanisms remain largely unknown. In this study, we investigated the neuroprotective effects of VNS in a lateral lesioned mice model of PD. Excluding controls, experimental mice received cuff electrode implantation on the left vagus nerve and 6-hydroxydopamine administration into the bilateral striatum. After ten days, electrical stimulation was delivered for 11 consecutive days onto PD animals. Behavioral tests were performed after stimulation. The expression of TH, Iba-1, GFAP, adrenergic receptors and cytokines in the SN and striatum was detected by immunofluorescence or western blotting. The activity of noradrenergic neurons in the locus coeruleus (LC) was also measured. Our results suggest that VNS improved behavioral performance in rod rotation, open field tests and pole-climbing tests in PD mice, accompanied by a decrease in the loss of dopaminergic neurons in the SN and increased TH expression in the striatum. Neuroinflammation-related factors, such as GFAP, Iba-1, TNF-α and IL-1β were also suppressed in PD mice after VNS compared to those without treatment. Furthermore, the proportion of c-Fos-positive noradrenergic neurons in the LC increased when animals received VNS. Additionally, the expression of the adrenergic receptor of α1BR was also upregulated after VNS compared to PD mice. In conclusion, VNS has potential as a novel PD therapy for neuroprotective effects, and indicate that activation of norepinephric neurons in LC may plays an important role in VNS treatment for PD.

Trends and hotspots on the relationship between gut microbiota and Parkinson's Disease: a bibliometric analysis.

Parkinson's disease (PD) is a neurodegenerative disorder that significantly impacts patients' quality of life. Recent evidence has highlighted a complex relationship between the gut microbiota (GM) and PD. Understanding this relationship is crucial for potentially targeting GM in PD treatment and expanding therapeutic options. This study aimed to comprehensively analyze the global landscape, trends, and research focus on GM and PD using bibliometric analysis. Utilizing publications from the Web of Science Core Collection (WsSCC), bibliometric tools such as the R package 'Bibliometrix,' VOS viewer, and CiteSpace software were employed to assess parameters like yearly publications, countries/regions, institutions, and authors. Research trends and hotspots were identified through keyword analysis. The results revealed 1,161 articles published between 2013-2023, with China leading in publications (n=352, 30.31% of total), while the United States had a higher influence (H-index=58). The University of California System was the top institution in terms of publications (n=35), with the National Natural Science Foundation of China funding the most projects (n=172). Keshavarzian A and Sampson TR were the authors with the highest publication and co-citation counts, respectively. The International Journal of Molecular Sciences had the most articles published (n=48). Keyword analysis identified parkinson's disease, gut microbiota, short-chain fatty acids, inflammation, and probiotics as main research topics. Biomarkers, ketogenic diet, and NF-κB were recent research hotspots and trends (2021-2023). The current study conducts an objective and comprehensive analysis of these publications, identifying trends and hotspots in the field of research. The findings offer valuable insights to scholars globally and in-vestigate potential therapeutic strategies for Parkinson's Disease.

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.

Nanoparticle Formulations for the Improvement of Symptomatic Treatments of Neurodegenerative Disorders

Neuronanomedicine merges nanotechnology and neuroscience in the pursuit of engineering therapeutic interventions for neurological disorders, including Alzheimer’s disease (AD) and Parkinson’s disease (PD). While no nanoparticle‐based drug delivery systems (NDDSs) are yet approved for use for targeting the central nervous system, this review critically analyses the development of NDDSs for the improvement of currently approved therapeutics for the symptomatic treatment of AD and PD. It showcases how NDDSs can help therapeutic payloads overcome existing limitations, such as insufficient drug accumulation in the brain and limited effectiveness, by enhancing their pharmacokinetics, bioavailability, brain penetration and accumulation, and overall therapeutic efficacy through drug encapsulation, manipulation of nanoparticle properties, and nanoparticle surface functionalisation. However, we also draw attention to widespread issues in the field that impede progress, including the poor selection of in vitro models and the inadequate design of pre‐clinical in vivo studies. We further advocate for greater standardisation of study design and reporting requirements in the future, which would likely enhance outcomes and expedite the translation of neuronanomedicines.

Reassessing kinetin's effect on PINK1 and mitophagy.

Substantial evidence indicates that a decline in mitochondrial health contributes to the development of Parkinson disease. Accordingly, therapeutic stimulation of mitophagy, the autophagic turnover of dysfunctional mitochondria, is a promising approach to treat Parkinson disease. An attractive target in such a setting is PINK1, a protein kinase that initiates the mitophagy cascade. Previous reports suggest that PINK1 kinase activity can be enhanced by kinetin triphosphate (KTP), an enlarged ATP analog that acts as an alternate phosphate donor for PINK1 during phosphorylation. However, the mechanism of how KTP could exert such an effect on PINK1 was unclear. In a recent study, we demonstrate that contrary to previous thinking, KTP cannot be used by PINK1. Nucleotide-bound PINK1 structures indicate that KTP would clash with the back of PINK1's ATP binding pocket, and enlarging this pocket by mutagenesis is required to enable PINK1 to use KTP. Strikingly, mutation shifts PINK1's nucleotide preference from ATP to KTP. Similar results could be demonstrated in cells with kinetin, a membrane-permeable precursor of KTP. These results overturn the previously accepted mechanism of how kinetin enhances mitophagy and indicate that kinetin and its derivatives instead function through a currently unidentified mechanism.