Search Results (1,994)

Neuroinflammation driven by microglial activation and α-synuclein (αSyn) aggregation is one of the central features driving Parkinson’s disease (PD) pathogenesis. GM1 ganglioside’s oligosaccharide moiety (OligoGM1) has shown neuroprotective potential in PD neuronal models, but its direct effects on inflammation remain poorly defined. This study investigated the ability of OligoGM1 to modulate microglial activation and αSyn handling in a human in vitro model. Human embryonic microglial (HMC3) cells were exposed to αSyn pre-formed fibrils (PFFs) in the presence or absence of OligoGM1. Microglial activation markers, intracellular αSyn accumulation, and cytokine release were assessed by immunofluorescence and ELISA. OligoGM1 had no effect on microglial morphology or cytokine release under basal conditions. Upon αSyn challenge, cells exhibited increased amounts of ionized calcium-binding adaptor molecule 1 (Iba1), triggered receptor expressed on myeloid cells 2 (TREM2), elevated αSyn accumulation, and secreted pro-inflammatory cytokines. OligoGM1 pre-treatment significantly reduced the number and area of Iba1(+) cells, the intracellular αSyn burden in TREM2(+) microglia, and the release of interleukin 6 (IL-6). OligoGM1 selectively attenuated αSyn-induced microglial activation and enhanced αSyn clearance without compromising basal immune function. These findings confirm and support the potential of OligoGM1 as a multitarget therapeutic candidate for PD that is capable of modulating glial reactivity and neuroinflammatory responses. Full article

Background: Parkinson’s disease (PD) often involves autonomic dysfunction, most notably impaired baroreflex sensitivity (BRS), which disrupts cardiovascular homeostasis and contributes to orthostatic hypotension (OH). Pharmacological and invasive treatments, including deep brain stimulation, have yielded inconsistent benefits and carry procedural risks, highlighting the need for safer, more accessible alternatives. In this systematic review, we evaluated non-invasive interventions—spanning somatosensory stimulation, exercise modalities, thermal therapies, and positional strategies—aimed at improving cardiovascular autonomic function in PD. Methods: We searched PubMed, Embase, MEDLINE (Ovid), Google Scholar, ScienceDirect, and Web of Science for studies published between January 2014 and December 2024. Eight original studies (n = 8) including 205 participants met the inclusion criteria for analyzing cardiac sympathovagal balance. Results: Five studies demonstrated significant post-intervention increases in BRS. Most reported favorable shifts in heart rate variability (HRV) and favorable changes in the low-frequency/high-frequency (LF/HF) ratio. Across modalities, systolic blood pressure (SBP) decreased by an average of 5%, and some interventions produced benefits that persisted up to 24 h. Conclusion: Although sample sizes were small and protocols heterogeneous, the collective findings support the potential of non-invasive neuromodulation to enhance BRS and overall cardiovascular regulation in PD. Future research should focus on standardized, higher-intensity or combined protocols with longer follow-up periods to establish durable, clinically meaningful improvements in autonomic function and quality of life for people living with PD. Full article

Oxidative stress is a defining and pervasive driver of neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS). As a molecular accelerant, reactive oxygen species (ROS) and reactive nitrogen species (RNS) compromise mitochondrial function, amplify lipid peroxidation, induce protein misfolding, and promote chronic neuroinflammation, creating a positive feedback loop of neuronal damage and cognitive decline. Despite its centrality in promoting disease progression, attempts to neutralize oxidative stress with monotherapeutic antioxidants have largely failed owing to the multifactorial redox imbalance affecting each patient and their corresponding variation. We are now at the threshold of precision redox medicine, driven by advances in syndromic multi-omics integration, Artificial Intelligence biomarker identification, and the precision of patient-specific therapeutic interventions. This paper will aim to reveal a mechanistically deep assessment of oxidative stress and its contribution to diseases of neurodegeneration, with an emphasis on oxidatively modified proteins (e.g., carbonylated tau, nitrated α-synuclein), lipid peroxidation biomarkers (F2-isoprostanes, 4-HNE), and DNA damage (8-OHdG) as significant biomarkers of disease progression. We will critically examine the majority of clinical trial studies investigating mitochondria-targeted antioxidants (e.g., MitoQ, SS-31), Nrf2 activators (e.g., dimethyl fumarate, sulforaphane), and epigenetic reprogramming schemes aiming to re-establish antioxidant defenses and repair redox damage at the molecular level of biology. Emerging solutions that involve nanoparticles (e.g., antioxidant delivery systems) and CRISPR (e.g., correction of mutations in SOD1 and GPx1) have the potential to transform therapeutic approaches to treatment for these diseases by cutting the time required to realize meaningful impacts and meaningful treatment. This paper will argue that with the connection between molecular biology and progress in clinical hyperbole, dynamic multi-targeted interventions will define the treatment of neurodegenerative diseases in the transition from disease amelioration to disease modification or perhaps reversal. With these innovations at our doorstep, the future offers remarkable possibilities in translating network-based biomarker discovery, AI-powered patient stratification, and adaptive combination therapies into individualized/long-lasting neuroprotection. The question is no longer if we will neutralize oxidative stress; it is how likely we will achieve success in the new frontier of neurodegenerative disease therapies. Full article

Background: The increased incidence of malignant melanoma is observed in patients with Parkinson’s disease. Methods: The anti-proliferative effects of carbidopa and rasagiline on four human malignant melanoma cell lines (A375, SK-MEL28, FM55P and FM55M2) were determined in MTT assay. The interaction profiles of rasagiline in combinations with cisplatin (CDDP) and mitoxantrone (MTX) in four human melanoma cell lines (A375, SK-MEL28, FM55P and FM55M2) were assessed by means of the isobolographic analysis in the MTT test; Results: Rasagiline, but not carbidopa, produced clear-cut anti-proliferative effects on various melanoma cell lines. The median inhibitory concentrations (IC₅₀ values) of rasagiline in the MTT were 280.69 µM for A375, 402.89 µM for SK-MEL28, 349.44 µM for FM55P, and 117.45 µM for FM55M2, respectively. The experimentally-derived selectivity index for rasagiline ranged from 8.22 to 28.18. Flow cytometry assay revealed, in two melanoma cell lines (FM55P and A375), a significant increase in the number of cells in the G0/G1 (up to 76.48% and 75.46% for cell lines, respectively), accompanied by a decrease in the percentage of cells in the S phase (decrease to 9.91% and 10.83% for cell lines, respectively), which may indicate potential cytostatic properties of rasagiline. The combinations of rasagiline with CDDP (at the fixed-ratio of 1:1) exerted either antagonistic interactions (p < 0.05) in the A375 and SK-MEL28, or additive interactions, with a tendency toward antagonism in the FM55P and FM55M2 cell lines in the MTT test. In contrast, the combinations of rasagiline with MTX (ratio of 1:1) produced either synergistic interaction (p < 0.05) in the FM55P cell line or additive interactions with a tendency toward synergy in the FM55M2, SK-MEL28, and A375 cell lines in the MTT test. Conclusions: Rasagiline combined with MTX exerted the most desirable synergistic interactions in relation to the anti-proliferative effects in four malignant melanoma cell lines, as assessed isobolographically. In contrast, rasagiline should not be combined with CDDP during the treatment of malignant melanoma due to the antagonistic interactions in the MTT assay. Full article

DNA connects the domains of genetic regulation and environmental interactions and plays a crucial role in neural development and cognitive function. The complex roles of genetic and epigenetic processes in brain development, synaptic plasticity, and higher-order cognitive abilities were reviewed in this study. Neural progenitors are formed and differentiated according to genetic instructions, whereas epigenetic changes, such as DNA methylation, dynamically control gene expression in response to external stimuli. These processes shape behavior and cognitive resilience by influencing neural identity, synaptic efficiency, and adaptation. This review also examines how DNA damage and repair mechanisms affect the integrity of neurons, which are essential for memory and learning. It also emphasizes how genetic predispositions and environmental factors interact to determine a person’s susceptibility to neurodegenerative disorders, such as Parkinson’s and Alzheimer’s diseases. Developments in gene-editing technologies, such as CRISPR, and non-viral delivery techniques provide encouraging treatment avenues for neurodegenerative disorders. This review highlights the fundamental role of DNA in coordinating the intricate interactions between molecular and environmental factors that underlie brain function and diseases. Full article

It is well established that combining exercise with medication may benefit functionality in individuals with PD (Parkinson’s disease). However, the long-term evolution of gait biomechanics under this combination remains poorly understood. Objectives: This study aims to analyze the evolution of spatiotemporal gait parameters, kinetics, and kinematics throughout a long-term exercise program conducted in water and on dry land. Methods: We have compared the trajectories of biomechanical variables across the treatment phases using statistical parametric mapping (SPM). A cohort of fourteen individuals with PD (mean age: 65.6 ± 12.1 years) participated in 24 sessions of aquatic exercises over three months, followed by a three-month retention phase, and then 24 additional sessions of land-based exercises. Three-dimensional gait data and spatiotemporal parameters were collected before and after each phase. Two-way ANOVA with repeated measures was used to compare spatiotemporal parameters. Results: The walking speed increased while the duration of the double support phase decreased. Additionally, the knee extensor moment consistently increased in the entire interval from midstance to midswing (20% to 70% of the stride period), approaching normal gait patterns. Regarding kinematics, significant increases were observed in both hip and knee flexion angles. Furthermore, the abnormal ankle dorsiflexion observed at the foot strike disappeared. Conclusions: These findings collectively suggest positive adaptations in gait biomechanics during the observation period. Full article

Background/Objectives: Neurodegenerative proteinopathies, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and dementia with Lewy bodies (DLB), are increasingly prevalent worldwide mainly due to population aging. These conditions are marked by complex etiologies, overlapping pathologies, and progressive clinical decline, with significant consequences for patients, caregivers, and healthcare systems. This review aims to synthesize evidence on the healthcare complexities of major neurodegenerative proteinopathies to highlight current knowledge gaps, and to inform future care models, policies, and research directions. Methods: We conducted a comprehensive literature search in PubMed/MEDLINE using combinations of MeSH terms and keywords related to neurodegenerative diseases, proteinopathies, diagnosis, sex, management, treatment, caregiver burden, and healthcare delivery. Studies were included if they addressed the clinical, pathophysiological, economic, or care-related complexities of aging-related neurodegenerative proteinopathies. Results: Key themes identified include the following: (1) multifactorial and unclear etiologies with frequent co-pathologies; (2) long prodromal phases with emerging biomarkers; (3) lack of effective disease-modifying therapies; (4) progressive nature requiring ongoing and individualized care; (5) high caregiver burden; (6) escalating healthcare and societal costs; and (7) the critical role of multidisciplinary and multi-domain care models involving specialists, primary care, and allied health professionals. Conclusions: The complexity and cost of neurodegenerative proteinopathies highlight the urgent need for prevention-focused strategies, innovative care models, early interventions, and integrated policies that support patients and caregivers. Prevention through the early identification of risk factors and prodromal signs is critical. Investing in research to develop effective disease-modifying therapies and improve early detection will be essential to reducing the long-term burden of these disorders. Full article

Glucose is the main source of energy and the source of carbon for the biosynthesis of several molecules, such as neurotransmitters, for most mammalian cells. Therefore, the transport of glucose into cells is very important. There are described three distinct families of glucose transporters: facilitative glucose transporters (GLUTs), sodium-dependent glucose cotransporters (SGLTs), and a uniporter, the SWEET protein. Impaired function and/or expression of these transporters due to, for example, mutations in their genes, may cause severe diseases. Associations with the impaired function of glucose transporters have been described in the case of neurodegenerative diseases (NDs) such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, GLUT1-deficiency syndrome, stroke, and traumatic brain injury. Changes in the presence of glucose transporters may be a cause of NDs, and they may be the effect of NDs. On the other hand, in many cases of neurodegenerative diseases, changes in the expression of glucose transporters may be a targeted therapy in the treatment of patients with these diseases. Full article

Background: Cerebrotendinous Xanthomatosis (CTX) is a rare, inherited metabolic disease caused by pathogenic variants in CYP27A1. The clinical presentation of this progressive disease includes cognitive deficits, ataxia, peripheral neuropathy, and pyramidal signs, as well as bilateral cataracts and tendon xanthomas. In some cases, CTX also includes parkinsonism. The goals of this study are to develop a data source that provides improved characterization and awareness of parkinsonism in CTX. Methods: We conducted a systematic review of the literature according to PRISMA guidelines to identify all published individuals diagnosed with CTX and parkinsonism. Clinical signs, imaging findings and treatment response to both chenodeoxycholic acid and dopaminergic medications were examined for 72 subjects. Results: The average age of onset of parkinsonism in these CTX patients was 42 years, illustrating the early onset nature of parkinsonism in CTX. Functional dopaminergic imaging revealed the loss of presynaptic dopaminergic neurons in the substantia nigra which points to neurodegeneration of the dopaminergic system as the underlying pathophysiology for parkinsonism in CTX. Brain MRI showed abnormalities in the basal ganglia in 38% of subjects. MRI also showed abnormalities in the cerebellum in 88% of subjects which is typical for CTX and can be utilized to distinguish subjects with CTX and parkinsonism from individuals with other forms of atypical parkinsonism. Dopaminergic medication mitigated parkinsonism signs in most individuals with CTX. Conclusion: CTX is a neurometabolic disease that can result in levodopa-responsive parkinsonism that should be included in the differential for atypical parkinsonism. Full article

The popularity of bioactive compounds extracted from sea cucumbers is growing due to their wide application in the pharmaceutical industry, particularly in the development of drugs for neurological disorders. Different types of compounds, such as saponins, phenolic compounds, cerebrosides, and glucocerebrosides, are being studied intensively for their efficacy in assessing the treatment of neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, and brain tumors, among others. Positive results have been observed in the upregulation in the content of p-CREB, p-PL3K, BDNF, SOD, and MDA. Furthermore, the neuroprotective mechanism of the compounds against Alzheimer’s disease revealed that suppressing the phosphorylation of tau protein by the PI3K/Akt/GSK3β pathway leads to improved synaptic plasticity and reduced nerve fiber tangles. This comprehensive review explores recent findings on the therapeutic potential of sea cucumber bioactives in the treatment of brain-related disorders. Full article

The genera Allium (Liliaceae) and Anchusa (Boraginaceae) are flowering plant genera with a rich diversity, also including the Allium kharputense Freyn & Sint. and Anchusa azurea Mill. var. azurea species. The antioxidant, anti-Alzheimer’s disease (AD), antidiabetic, and antiglaucoma effects of the Allium kharputense Freyn & Sint. and Anchusa azurea Mill. var. azurea species, which are commonly eaten foods in the Southeast of Türkiye in the treatment of several diseases, were studied. To interpret the antioxidant capacities of ethanol extract of two plant species, aerial parts were analyzed by ABTS and DPPH assays. The IC₅₀ values of A. kharputense and A. azurea ethanol and water extracts for ABTS^•+ activities were recorded in the range of 30.93 to 33.94 µg/mL and 33.45 to 33.78 µg/mL, respectively. Also, DPPH^• activities were measured at 30.78 to 36.87 µg/mL and 31.67 to 32.45 µg/mL, respectively. The best of the IC₅₀ values was measured in the ethanol extract of A. kharputense as 30.78 µg/mL for DPPH scavenging activity. The total phenolic and flavonoid quantities in A. kharputense and A. azurea plants were measured. The highest phenolic and flavonoid contents of A. kharputense and A. azurea species were recorded in amounts of 445.52 and 327.35 mg GAE/g in ethanol extracts, respectively, and 332.88 and 234.03 mg QE/g in ethanol extracts, respectively. The effects of A. kharputense and A. azurea on diabetes, AD, and glaucoma were studied on the target enzymes of diseases. The most efficient IC₅₀ values were recorded at 10.72 μg/mL against α-glycosidase, 35.01 μg/mL against AChE, 38.05 μg/mL against BChE, 9.21 μg/mL towards hCA I, and 81.02 μg/mL towards hCA II isoenzymes. The kinds and amounts of phenolic compounds in A. kharputense and A. azurea were determined using LC-MS/MS against 53 standards. A. kharputense and A. azurea plants have prospective use in enhancing glaucoma, diabetes, AD, Parkinson’s disease, epilepsy, and cancerous disorders. Full article

Parkinson’s disease (PD) is a common neurodegenerative disorder with substantial global impact. Although current therapies can provide symptomatic relief, they are often associated with high costs and adverse effects. Natural compounds with a history of traditional medicinal use have emerged as promising alternatives. In this study, we investigated the therapeutic potential and underlying mechanisms of berberine in both cellular and animal models of PD. In vitro, SH-SY5Y cells exposed to 6-hydroxydopamine (6-OHDA) exhibited decreased viability and increased oxidative stress, both of which were significantly alleviated by berberine treatment based on cell viability assays and DCFH-DA staining. Western blot analysis revealed that berberine modulated the AMPK–PGC-1α–SIRT1 signaling pathway and restored the expression of autophagy-related proteins LC3B and P62, suggesting that berberine could improve mitochondrial function and autophagy balance. In vivo studies using a 6-OHDA-induced PD mouse model further confirmed these effects, showing that berberine could improve motor function and lead to molecular changes consistent with in vitro studies. Additionally, safety evaluations indicated no significant hepatotoxicity based on AST and ALT levels. Body weight also remained stable throughout treatment. Collectively, our findings suggest that berberine can not only alleviate PD-related symptoms but also target key pathological mechanisms, supporting its potential as a therapeutic candidate for PD and other neurodegenerative diseases. Full article

Background: Despite growing interest in the literature on Parkinson’s disease (PD) on cognitive functioning, financial incompetence—a crucial aspect of daily living—and its modulation susceptibility by PD treatment regimens remains relatively understudied. Objective: This systematic review and meta-analysis aimed to synthesize existing evidence on how PD treatments affect financial capacity, assessing both direct financial competence and cognitive or behavioral proxies of financial decision-making. Methods: A comprehensive literature search according to PRISMA protocol was conducted across major biomedical databases, supplemented by gray literature and manual reference list checks. Eligible studies assessed financial capacity directly or indirectly through cognitive proxies (e.g., executive function, decision-making) or financial risk behaviors (e.g., impulse control disorders). Two separate meta-analyses were performed. Heterogeneity (I²), publication bias (Egger’s test), and sensitivity analyses were conducted to assess robustness. Results: Twenty-three studies met inclusion criteria. One study directly measured financial capacity and was analyzed narratively, reporting diminished competence in patients on levodopa therapy. A meta-analysis of cognitive proxies (10 studies) showed a moderate effect size (Hedges’ g = 0.70, 95% CI [0.45, 0.92], p < 0.001), indicating that PD treatments negatively affect executive function and financial decision-making. A second meta-analysis of impulse control and financial risk behaviors (12 studies) revealed a larger effect size (Hedges’ g = 0.98, 95% CI [0.75, 1.22], p < 0.001), strongly linking dopamine agonists to increased financial risk-taking. Moderate heterogeneity (I² = 45.8–60.5%) and potential publication bias (Egger’s test p = 0.027) were noted. Conclusions: These findings suggest that PD treatments negatively impact financial decision-making both directly and indirectly through cognitive and behavioral pathways. Integrating financial decision-making assessments into PD care, particularly for patients on dopamine agonists, is recommended. Future research should prioritize longitudinal studies and standardized neuropsychological measures to guide clinical practice and optimize patient outcomes. Full article

Mitochondrial dysfunction is a key contributor to neurodegeneration, particularly in Parkinson’s disease (PD), where dopaminergic neurons being highly metabolically active are vulnerable to oxidative stress and bioenergetic failure. In this study, we investigate the effects of rotenone, a Complex I inhibitor, and antimycin A, a Complex III inhibitor, on mitochondrial function in MN9D dopaminergic neuronal cells. Cells were treated with rotenone (1.5 µM) or antimycin A (10 µM) for one hour, and key biochemical parameters were assessed, including ATP levels, reactive oxygen species (ROS) production, dopamine metabolism, and neuromelanin formation. Our results indicate significant ATP depletion and ROS accumulation following treatment with both inhibitors, with antimycin A inducing a more pronounced oxidative stress response. Dysregulation of dopamine biosynthesis differed mechanistically from vesicular monoamine transporter (VMAT2) inhibition by tetrabenazine, suggesting alternative pathways of catecholamine disruption. Additionally, oxidative stress led to increased neuromelanin accumulation, indicating a possible adaptive response to mitochondrial dysfunction. These findings provide insights into the cellular mechanisms underlying dopaminergic neurotoxicity and highlight mitochondrial electron transport chain inhibition as a key driver of PD pathogenesis. Future research should explore therapeutic strategies aimed at enhancing mitochondrial function to mitigate neurodegenerative progression. Full article

Neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis remain incurable. Current therapeutic strategies primarily focus on slowing disease progression, alleviating symptoms, and improving patients’ quality of life, including the management of comorbid conditions. Over the past few decades, the incidence of diagnosed neurodegenerative disorders has risen significantly. As the number of affected individuals continues to grow, so does the urgent need for effective treatments that can halt or mitigate the progression of these diseases. Among the most promising therapeutic resources are bioactive compounds derived from fungi. The high quality of proteins, polysaccharides, unsaturated fatty acids, triterpenoids, sterols, and secondary metabolites found in fungi have attracted growing interest from researchers across multiple disciplines. One intensively studied direction involves the use of naturally occurring fungi-derived nutraceuticals in the treatment of various diseases, including neurodegenerative conditions. This article provides an overview of recent findings on fungal compounds—such as phenolic compounds, carbohydrates, peptides and proteins, and lipids—that may have potential applications in the treatment of neurodegenerative diseases and the alleviation of their symptoms. Full article