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Pharmaceutics May 2024Neurodegenerative diseases (NDs) are a set of progressive, chronic, and incurable diseases characterized by the gradual loss of neurons, culminating in the decline of... (Review)
Review
Neurodegenerative diseases (NDs) are a set of progressive, chronic, and incurable diseases characterized by the gradual loss of neurons, culminating in the decline of cognitive and/or motor functions. Alzheimer's disease (AD) and Parkinson's disease (PD) are the most common NDs and represent an enormous burden both in terms of human suffering and economic cost. The available therapies for AD and PD only provide symptomatic and palliative relief for a limited period and are unable to modify the diseases' progression. Over the last decades, research efforts have been focused on developing new pharmacological treatments for these NDs. However, to date, no breakthrough treatment has been discovered. Hence, the development of disease-modifying drugs able to halt or reverse the progression of NDs remains an unmet clinical need. This review summarizes the major hallmarks of AD and PD and the drugs available for pharmacological treatment. It also sheds light on potential directions that can be pursued to develop new, disease-modifying drugs to treat AD and PD, describing as representative examples some advances in the development of drug candidates targeting oxidative stress and adenosine A2A receptors.
PubMed: 38931832
DOI: 10.3390/pharmaceutics16060708 -
Sensors (Basel, Switzerland) Jun 2024Parkinson's Disease (PD) is a complex neurodegenerative disorder characterized by a spectrum of motor and non-motor symptoms, prominently featuring the freezing of gait... (Meta-Analysis)
Meta-Analysis Review
Parkinson's Disease (PD) is a complex neurodegenerative disorder characterized by a spectrum of motor and non-motor symptoms, prominently featuring the freezing of gait (FOG), which significantly impairs patients' quality of life. Despite extensive research, the precise mechanisms underlying FOG remain elusive, posing challenges for effective management and treatment. This paper presents a comprehensive meta-analysis of FOG prediction and detection methodologies, with a focus on the integration of wearable sensor technology and machine learning (ML) approaches. Through an exhaustive review of the literature, this study identifies key trends, datasets, preprocessing techniques, feature extraction methods, evaluation metrics, and comparative analyses between ML and non-ML approaches. The analysis also explores the utilization of cueing devices. The limited adoption of explainable AI (XAI) approaches in FOG prediction research represents a significant gap. Improving user acceptance and comprehension requires an understanding of the logic underlying algorithm predictions. Current FOG detection and prediction research has a number of limitations, which are identified in the discussion. These include issues with cueing devices, dataset constraints, ethical and privacy concerns, financial and accessibility restrictions, and the requirement for multidisciplinary collaboration. Future research avenues center on refining explainability, expanding and diversifying datasets, adhering to user requirements, and increasing detection and prediction accuracy. The findings contribute to advancing the understanding of FOG and offer valuable guidance for the development of more effective detection and prediction methodologies, ultimately benefiting individuals affected by PD.
Topics: Humans; Parkinson Disease; Machine Learning; Gait Disorders, Neurologic; Gait; Wearable Electronic Devices; Algorithms; Quality of Life
PubMed: 38931743
DOI: 10.3390/s24123959 -
Pharmaceuticals (Basel, Switzerland) Jun 2024The enduring relationship between humanity and the cannabis plant has witnessed significant transformations, particularly with the widespread legalization of medical... (Review)
Review
The enduring relationship between humanity and the cannabis plant has witnessed significant transformations, particularly with the widespread legalization of medical cannabis. This has led to the recognition of diverse pharmacological formulations of medical cannabis, containing 545 identified natural compounds, including 144 phytocannabinoids like Δ9-THC and CBD. Cannabinoids exert distinct regulatory effects on physiological processes, prompting their investigation in neurodegenerative diseases. Recent research highlights their potential in modulating protein aggregation and mitochondrial dysfunction, crucial factors in conditions such as Alzheimer's Disease, multiple sclerosis, or Parkinson's disease. The discussion emphasizes the importance of maintaining homeodynamics in neurodegenerative disorders and explores innovative therapeutic approaches such as nanoparticles and RNA aptamers. Moreover, cannabinoids, particularly CBD, demonstrate anti-inflammatory effects through the modulation of microglial activity, offering multifaceted neuroprotection including mitigating aggregation. Additionally, the potential integration of cannabinoids with vitamin B12 presents a holistic framework for addressing neurodegeneration, considering their roles in homeodynamics and nervous system functioning including the hippocampal neurogenesis. The potential synergistic therapeutic benefits of combining CBD with vitamin B12 underscore a promising avenue for advancing treatment strategies in neurodegenerative diseases. However, further research is imperative to fully elucidate their effects and potential applications, emphasizing the dynamic nature of this field and its potential to reshape neurodegenerative disease treatment paradigms.
PubMed: 38931480
DOI: 10.3390/ph17060813 -
Pharmaceuticals (Basel, Switzerland) Jun 2024Parkinson's disease (PD) is a prevalent neurodegenerative disorder among the elderly population. The pathogenesis of PD encompasses genetic alterations, environmental... (Review)
Review
Parkinson's disease (PD) is a prevalent neurodegenerative disorder among the elderly population. The pathogenesis of PD encompasses genetic alterations, environmental factors, and age-related neurodegenerative processes. Numerous studies have demonstrated that aberrant functioning of the ubiquitin-proteasome system (UPS) plays a crucial role in the initiation and progression of PD. Notably, E3 ubiquitin ligases serve as pivotal components determining substrate specificity within UPS and are intimately associated with the regulation of various proteins implicated in PD pathology. This review comprehensively summarizes the mechanisms by which E3 ubiquitin ligases and deubiquitinating enzymes modulate PD-associated proteins and signaling pathways, while exploring the intricate relationship between UPS dysfunctions and PD etiology. Furthermore, this article discusses recent research advancements regarding inhibitors targeting PD-related E3 ubiquitin ligases.
PubMed: 38931449
DOI: 10.3390/ph17060782 -
Pharmaceuticals (Basel, Switzerland) Jun 2024Bromocriptine (BCR) presents poor bioavailability when administered orally because of its low solubility and prolonged first-pass metabolism. This poses a significant...
Bromocriptine (BCR) presents poor bioavailability when administered orally because of its low solubility and prolonged first-pass metabolism. This poses a significant challenge in its utilization as an effective treatment for managing Parkinson's disease (PD). The utilization of lipid nanoparticles can be a promising approach to overcome the limitations of BCR bioavailability. The aim of the research work was to develop and evaluate bromocriptine-loaded solid lipid nanoparticles (BCR-SLN) and bromocriptine-loaded nanostructured lipid carriers (BCR-NLC) employing the Box-Behnken design (BBD). BCR-SLNs and BCR-NLCs were developed using the high-pressure homogenization method. The prepared nanoparticles were characterized for particle size (PS), polydispersity index (PDI), and entrapment efficiency (EE). In vitro drug release, cytotoxicity studies, in vivo plasma pharmacokinetic, and brain distribution studies evaluated the optimized lipid nanoparticles. The optimized BCR-SLN had a PS of 219.21 ± 1.3 nm, PDI of 0.22 ± 0.02, and EE of 72.2 ± 0.5. The PS, PDI, and EE of optimized BCR-NLC formulation were found to be 182.87 ± 2.2, 0.16 ± 0.004, and 83.57 ± 1.8, respectively. The in vitro release profile of BCR-SLN and BCR-NLC showed a biphasic pattern, immediate release, and then trailed due to the sustained release. Furthermore, a pharmacokinetic study indicated that both the optimized BCR-SLN and BCR-NLC formulations improve the plasma and brain bioavailability of the drug compared to the BCR solution. Based on the research findings, it can be concluded that the BCR-loaded lipid nanoparticles could be a promising carrier by enhancing the BBB penetration of the drug and helping in the improvement of the bioavailability and therapeutic efficacy of BCR in the management of PD.
PubMed: 38931387
DOI: 10.3390/ph17060720 -
Pharmaceuticals (Basel, Switzerland) May 2024Neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, Huntington's disease, and others) and cancer, seemingly disparate in their etiology and... (Review)
Review
Neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, Huntington's disease, and others) and cancer, seemingly disparate in their etiology and manifestation, exhibit intriguing associations in certain cellular and molecular processes. Both cancer and neurodegenerative diseases involve the deregulation of cellular processes such as apoptosis, proliferation, and DNA repair and pose a significant global health challenge. Afzelin (kaempferol 3-O-rhamnoside) is a flavonoid compound abundant in various plant sources. Afzelin exhibits a diverse range of biological activities, offering promising prospects for the treatment of diseases hallmarked by oxidative stress and deregulation of cell death pathways. Its protective potential against oxidative stress is also promising for alleviating the side effects of chemotherapy. This review explores the potential therapeutic implications of afzelin, including its capacity to mitigate oxidative stress, modulate inflammation, and promote cellular regeneration in neurodegenerative and cancer diseases.
PubMed: 38931368
DOI: 10.3390/ph17060701 -
Pharmaceuticals (Basel, Switzerland) May 2024Chronic inflammation is driven by proinflammatory cytokines such as interleukin 6 (IL-6), tumor necrosis factor-α (TNF-α), and chemokines, such as c-c motif chemokine...
Chronic inflammation is driven by proinflammatory cytokines such as interleukin 6 (IL-6), tumor necrosis factor-α (TNF-α), and chemokines, such as c-c motif chemokine ligand 2 (CCL2), CCL3, C-X-C motif chemokine ligand 2 (CXCL2), and CXCL10. Inflammatory processes of the central nervous system (CNS) play an important role in the pathogenesis of various neurological and psychiatric disorders like Alzheimer's disease, Parkinson's disease, and depression. Therefore, identifying novel anti-inflammatory drugs may be beneficial for treating disorders with a neuroinflammatory background. The G-protein-coupled receptor 55 (GPR55) gained interest due to its role in inflammatory processes and possible involvement in different disorders. This study aims to identify the anti-inflammatory effects of the coumarin-based compound KIT C, acting as an antagonist with inverse agonistic activity at GPR55, in lipopolysaccharide (LPS)-stimulated BV2 microglial cells in comparison to the commercial GPR55 agonist O-1602 and antagonist ML-193. All compounds significantly suppressed IL-6, TNF-α, CCL2, CCL3, CXCL2, and CXCL10 expression and release in LPS-treated BV2 microglial cells. The anti-inflammatory effects of the compounds are partially explained by modulation of the phosphorylation of p38 mitogen-activated protein kinase (MAPK), p42/44 MAPK (ERK 1/2), protein kinase C (PKC) pathways, and the transcription factor nuclear factor (NF)-κB, respectively. Due to its potent anti-inflammatory properties, KIT C is a promising compound for further research and potential use in inflammatory-related disorders.
PubMed: 38931342
DOI: 10.3390/ph17060674 -
Molecules (Basel, Switzerland) Jun 2024The abnormal deposition of protein in the brain is the central factor in neurodegenerative disorders (NDs). These detrimental aggregates, stemming from the misfolding...
The abnormal deposition of protein in the brain is the central factor in neurodegenerative disorders (NDs). These detrimental aggregates, stemming from the misfolding and subsequent irregular aggregation of α-synuclein protein, are primarily accountable for conditions such as Parkinson's disease, Alzheimer's disease, and dementia. Two-photon-excited (TPE) probes are a promising tool for the early-stage diagnosis of these pathologies as they provide accurate spatial resolution, minimal intrusion, and the ability for prolonged observation. To identify compounds with the potential to function as diagnostic probes using two-photon techniques, we explore three distinct categories of compounds: Hydroxyl azobenzene (AZO-OH); Dicyano-vinyl bithiophene (DCVBT); and Tetra-amino phthalocyanine (PcZnNH). The molecules were structurally and optically characterized using a multi-technique approach via UV-vis absorption, Raman spectroscopy, three-dimensional fluorescence mapping (PLE), time-resolved photoluminescence (TRPL), and pump and probe measurements. Furthermore, quantum chemical and molecular docking calculations were performed to provide insights into the photophysical properties of the compounds as well as to assess their affinity with the α-synuclein protein. This innovative approach seeks to enhance the accuracy of in vivo probing, contributing to early Parkinson's disease (PD) detection and ultimately allowing for targeted intervention strategies.
Topics: alpha-Synuclein; Humans; Photons; Molecular Docking Simulation; Protein Aggregates; Azo Compounds; Fluorescent Dyes; Spectrum Analysis, Raman; Parkinson Disease; Thiophenes; Indoles; Molecular Structure
PubMed: 38930882
DOI: 10.3390/molecules29122817 -
Journal of Clinical Medicine Jun 2024: Microbial dysbiosis may contribute to alpha-synuclein (α-Syn) homeostasis disruption, yet the burden of inflammatory periodontal infection and its treatment have...
: Microbial dysbiosis may contribute to alpha-synuclein (α-Syn) homeostasis disruption, yet the burden of inflammatory periodontal infection and its treatment have never been studied in this regard. We aimed to compare the cytokine and α-Syn levels in the saliva and blood of patients with periodontitis who underwent non-surgical periodontal therapy (NSPT) and those of their healthy counterparts. : Periodontal examination and saliva and blood sample collection were carried out in incoming patients at a university clinic. The periodontitis group (PG) received NSPT. The sample collection and periodontal observation were repeated 30 days after. IL-6, IL1-β and total α-Syn were quantified using immunoassay methods. The periodontal inflamed surface area (PISA) was calculated as a proxy for periodontal inflammation. : Eleven participants formed the PG, and there were fifteen healthy controls (HC). At baseline, no correlation between salivary and plasma α-Syn was found. The salivary α-Syn levels revealed a tendency to decrease 30 days after, particularly in the PD cases. The variation in PISA and α-Syn showed significant correlation. Salivary α-Syn correlated negatively with salivary IL-6 levels at both timepoints in the total sample (rho = -0.394 and rho = -0.451) and in the HC (rho = -0.632 and rho = -0.561). Variations in plasma IL-6 and α-Syn were negatively correlated (rho = -0.518) in the healthy participants. Baseline plasma IL1-β negatively correlated with plasmatic α-Syn at 30 days in the HC (rho = -0.581). : Salivary and plasma α-Syn bioavailability operate independently, and periodontal diagnosis was not a confounding factor. Salivary α-Syn levels were significantly affected by NSPT, contrary to plasma levels. These results should be confirmed in future larger and prospective studies.
PubMed: 38930115
DOI: 10.3390/jcm13123586 -
Journal of Clinical Medicine Jun 2024Early dislocation following primary total hip arthroplasty (THA) is a rare but devastating complication and represents a source of patient morbidity and financial...
Early dislocation following primary total hip arthroplasty (THA) is a rare but devastating complication and represents a source of patient morbidity and financial burden to the healthcare system. The objective of this study was to identify patient characteristics and comorbidities that are associated with increased early in-hospital dislocation rates following primary THA. A retrospective cohort study was conducted using patient data from the Nationwide Inpatient Sample (NIS) database; we identified patients who had undergone THA from 2016 to 2019 and compared those with an early periprosthetic dislocation prior to discharge to those without. The patient characteristics and comorbidities were compared using univariate analysis with a subsequent investigation of statistically significant variables using multivariate analysis. The variables were compared using chi square, Fisher's exact test, and independent sample t-tests with data assessed using odds ratio with 95% confidence intervals. A total of 5151 patients sustained an early dislocation compared to 362,743 who did not. Those who sustained an in-hospital dislocation were more likely to share the following characteristics: female sex (OR 1.21, < 0.01), age > 70 (OR 1.45, < 0.01), Caucasian ethnicity (OR 1.22, < 0.01), SLE (OR 1.87, < 0.01), and Parkinson's disease (OR 1.93, < 0.01). Certain characteristics were also associated with decreased odds of having an in-hospital dislocation including elective surgery (OR 0.14, < 0.01), tobacco use (OR 0.8, < 0.01), diabetes without complications (OR 0.87, < 0.01), and a history of heart valve replacement (OR 0.81, < 0.01). The length of stay was significantly longer (4.7 days vs. 2.3 days) as was the total hospital charges (USD $101,517 vs. USD $66,388) for the early in-hospital dislocation group. Several patient characteristics and comorbidities are associated with early in-hospital dislocation episodes following total hip arthroplasty including female sex, age > 70, non-elective surgery, SLE, and Parkinson's. This information may be useful to help guide intraoperative implant selection and/or postoperative protocol in select patient populations to limit early instability as well as decrease the financial burden associated with this postoperative complication.
PubMed: 38929981
DOI: 10.3390/jcm13123456