Parkinson's disease (PD) is chronic and progressive, manifested by both motor and non-motor symptoms, such as anxiety. Anxiety occurs in more than 50% of patients. Rehabilitation in PD is more focused on controlling motor symptoms. However, non-motor symptoms affect independence, functionality, and motivation.

The present study aimed to compare the effects of immersive virtual reality (IVR) and non-immersive virtual reality (NIVR) training on anxiety and cognition in PD patients.

Two VR devices were used: Nintendo Wii (NIVR) and Samsung Gear VR (IVR). A convenience sample of 60 participants was distributed into 3 groups: a no intervention control group (CG) and two training groups (IVR and NIVR). All were evaluated at the baseline (T1), 7 days after (T7), and 30 days after training (T30). The Beck Anxiety Inventory (BAI), Semantic Verbal Fluency test (VF), and Digits subtest in reverse order (DR) were evaluated. The intervention protocol consisted of 10 sessions, each lasting 1 h, twice a week, for 5 weeks. According to the motor and cognitive requirements of games, 4 games were selected for each VR system. The Friedman test was used for comparing groups at different times (P ≤ 0.05).

The findings revealed a significant decrease in the BAI score in the IVR group (F = 15 217; p < 0.001) between T1 and T7 (and between T1 and T30. No significant differences were found between T7 and T30. No significant differences were found for the cognition variables.

IVR is a useful and feasible tool for managing anxiety symptoms in patients with PD.

Parkinson's disease (PD) is the fastest-growing neurodegenerative disorder worldwide, and no effective cure is currently available. Neuropathologically, PD is characterized by the selective degeneration of dopaminergic neurons in the substantia nigra and by the accumulation of alpha-synuclein (aSyn)-rich proteinaceous inclusions within surviving neurons. As a multifactorial disorder, approximately 85 % of PD cases are sporadic with unknown etiology. Among the many risk factors implicated in PD, exposure to neurotoxic pesticides stands out as a significant contributor. While the effects of many are still uncharacterized, it has already been shown that rotenone, paraquat, maneb, and dieldrin affect critical cellular pathways, including mitochondrial and proteasomal dysfunction, aSyn aggregation, autophagy dysregulation, and disruption of dopamine metabolism. With the constant rise in pesticide usage to meet the demands of a growing human population, the risk of environmental contamination and subsequent PD development is also increasing. This review explores the molecular mechanisms by which pesticide exposure influences PD development, shedding light on their role in the pathogenesis of PD and highlighting the need for preventative measures and regulatory oversight to mitigate these risks.

Caveolae are small flask-shaped invaginations of the plasma membrane enriched in cholesterol and sphingolipids. They play a critical role in various cellular processes, including signal transduction, endocytosis, and mechanotransduction. Caveolin proteins, specifically Cav-1, Cav-2, and Cav-3, in addition to their role as structural components of caveolae, have been found to regulate the activity of signaling molecules. A growing body of research has highlighted the pivotal role of caveolae and caveolins in maintaining cellular metabolic homeostasis. Indeed, studies have demonstrated that caveolins interact with the key components of insulin signaling, glucose uptake, and lipid metabolism, thereby influencing energy production and storage. The dysfunction of caveolae or the altered expression of caveolins has been associated with metabolic disorders, including obesity, type 2 diabetes, and ocular diseases. Remarkably, mutations in caveolin genes can disrupt cellular energy balance, promote oxidative stress, and exacerbate metabolic dysregulation. This review examines current research on the molecular mechanisms through which caveolae and caveolins regulate cellular metabolism, explores their involvement in the pathogenesis of metabolic disorders, and discusses potential therapeutic strategies targeting caveolin function and the stabilization of caveolae to restore metabolic homeostasis.

Parkinson's disease (PD) is the second most common neurodegenerative disorder, after Alzheimer's disease. Many individuals with PD experience cognitive impairment, significantly threatening both their physical and mental well-being. Research has shown that abnormal DNA methylation is closely linked to neurodegenerative conditions such as Alzheimer's and Parkinson's disease. The RIN3 gene, which encodes a guanine nucleotide exchange factor, plays a role in inhibiting amyloid-beta formation and affects protein endocytosis, both of which are linked to cognitive impairment. However, the potential connection between RIN3 gene methylation and cognitive impairment in Parkinson's disease has not yet been explored. This study aims to explore whether the methylation status of the RIN3 gene is connected to cognitive decline in Parkinson's patients, thereby shedding light on the gene's crucial role in the disease's development and identifying potential targets for diagnosing and treating cognitive impairment in this context.

This study aims to explore whether the methylation status of the RIN3 gene is associated with cognitive impairment in Parkinson's disease and to further clarify the gene's significant role in the disease's pathogenesis.

This study involved 50 control subjects and 51 Parkinson's disease (PD) patients, who were assessed using a cognitive scale. Additionally, DNA methylation in whole blood was analyzed. The research compared RIN3 methylation levels between the PD group and the normal control group (NC), as well as between the subgroups of PD-Mild Cognitive Impairment (PD-MCI), PD-Normal Cognition (PD-NC), and the control group.

The DNA methylation level of the RIN3 gene in the whole blood of patients with PD was lower than that in healthy controls (22.3%vs.23.6%, P=0.009). Moreover, individuals with PD-MCI had significantly lower RIN3 methylation levels than both the control group (21.3%vs.23.6%, P<0.001) and those in the PD-NC group (21.3%vs.23.3%, P=0.001).

RIN3 methylation is associated with PD-MCI. With appropriate lifestyle changes and clinical interventions, methylation may influence disease progression, suggesting that RIN3 gene methylation could serve as a predictor for the development of PD-MCI.

At the turn of the century a fundamental resolution barrier in fluorescence microscopy known as the diffraction limit was broken, giving rise to the field of super-resolution microscopy. Subsequent nanoscopic investigation with visible light revolutionised our understanding of how previously unknown molecular features give rise to the emergent behaviour of cells. It transpires that the devil is in these fine molecular details, and essential nanoscale processes were found everywhere researchers chose to look. Now, after nearly two decades, super-resolution microscopy has begun to address previously unmet challenges in the study of human disease and is poised to become a pivotal tool in drug discovery.

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Aspirin is a potent lysine acetylation inducer, but its impact on lysine ubiquitination and ubiquitination-directed protein degradation is unclear. Herein, we develop the reversed-pulsed-SILAC strategy to systematically profile protein degradome in response to aspirin. By integrating degradome, acetylome, and ubiquitinome analyses, we show that aspirin impairs proteasome activity to inhibit proteasomal degradation, rather than directly suppressing lysine ubiquitination. Interestingly, aspirin increases lysosomal degradation-implicated K63-linked ubiquitination. Accordingly, using the major pathological protein of Parkinson's disease (PD), α-synuclein (α-syn), as an example of protein aggregates, we find that aspirin is able to reduce α-syn in cultured cells, neurons, and PD model mice with rescued locomotor ability. We further reveal that the α-syn aggregate clearance induced by aspirin is K63-ubiquitination dependent in both cells and PD mice. These findings suggest two complementary mechanisms by which aspirin regulates the degradation of soluble and insoluble proteins, providing insights into its diverse pharmacological effects that can aid in future drug development efforts.

Parkinson's disease (PD) is a progressive neurodegenerative disorder that primarily affects movement. It occurs due to a gradual deficit of dopamine-producing brain cells, particularly in the substantia nigra. The precise etiology of PD is not fully understood, but it likely involves a combination of genetic and environmental factors. The therapies available at present alleviate symptoms but do not stop the disease's advancement. Research endeavors are currently directed at inventing disease-controlling therapies that aim at the inherent mechanisms of PD. PD biomarker breakthroughs hold enormous potential: earlier diagnosis, better monitoring, and targeted treatment based on individual response could significantly improve patient outcomes and ease the burden of this disease. PD research is an active and evolving field, focusing on understanding disease mechanisms, identifying biomarkers, developing new treatments, and improving care. In this report, we explore data from the CAS Content Collection to outline the research progress in PD. We analyze the publication landscape to offer perspective into the latest expertise advancements. Key emerging concepts are reviewed and strategies to fight disease evaluated. Pharmacological targets, genetic risk factors, as well as comorbid diseases are explored, and clinical usage of products against PD with their production pipelines and trials for drug repurposing are examined. This review aims to offer a comprehensive overview of the advancing landscape of the current understanding about PD, to define challenges, and to assess growth prospects to stimulate efforts in battling the disease.

Parkinson's disease (PD) is characterized by a slow, short-stepping, shuffling gait pattern caused by a combination of motor control limitations due to a reduction in dopaminergic neurons. Gait disorders are indicators of global health, cognitive status, and risk of falls and increase with disease progression. Therefore, the use of quantitative information on the gait mechanisms of PD patients is a promising approach, particularly for monitoring gait disorders and potentially informing therapeutic interventions, though it is not yet a well-established tool for early diagnosis or direct assessment of disease progression. Over the years, many studies have investigated the spatiotemporal parameters that are altered in the PD gait pattern, while kinematic and kinetic gait parameters are more limited. A scoping review was performed according to the PRISMA guidelines. The Scopus and PubMed databases were searched between 1999 and 2023. A total of 29 articles were included that reported gait changes in PD patients under different gait conditions: single free walking, sequential motor task, and dual task. The main findings of our review highlighted the use of optoelectronic systems for recording kinematic parameters and force plates for measuring kinetic parameters, due to their high accuracy. Most gait analyses in PD patients have been conducted at self-selected walking speeds to capture natural movement, although studies have also examined gait under various conditions. The results of our review indicated that PD patients experience alterations in the range of motion of the hip, knee, and ankle joints, as well as a reduction in the power generated/absorbed and the extensor/flexor moments. These findings suggest that the PD gait pattern may be more effectively understood using kinematic and kinetic parameters.

Neurodegenerative diseases (NDDs), characterized by the progressive deterioration of the structure and function of the nervous system, represent a significant global health challenge. Emerging research suggests that the gut microbiota plays a critical role in regulating neurodegeneration via modulation of the gut-brain axis. Probiotics, defined as live microorganisms that confer health benefits to the host, have garnered significant attention owing to their therapeutic potential in NDDs. This review examines the current research trends related to the microbiome-gut-brain axis across various NDDs, highlighting key findings and their implications. Additionally, the effects of specific probiotic strains, including Lactobacillus plantarum, Bifidobacterium breve, and Lactobacillus rhamnosus, on neurodegenerative processes were assessed, focusing on their potential therapeutic benefits. Overall, this review emphasizes the potential of probiotics as promising therapeutic agents for NDDs, underscoring the importance of further investigation into this emerging field.

Parkinson's disease (PD) is the second most prevalent neurodegenerative disease, characterized by pathogenesis involving mitochondrial dysfunction, oxidative stress, and ferroptosis. Unfortunately, there are currently no effective interventions to slow down the progression of PD. The mitochondrial protein coiled-coil-helix-coiled-coil-helix domain containing 2 (CHCHD2), which is implicated in neurodegeneration and serves as a biomarker for PD, has been reported to have neuroprotective effects against oxidative stress, but the potential molecular mechanisms involved remain elusive. In this study, we uncovered a critical mechanism by which CHCHD2 protected neuronal cells against oxidative stress with the ferroptosis pathway playing a pivotal role, as determined through tandem mass tags (TMT)-based proteomic analysis. The overexpression of CHCHD2 was observed to enhance cell viability, reduce levels of lipid peroxidation and reactive oxygen species (ROS), and upregulate the expression of the ferroptosis negative regulatory protein Glutathione peroxidase 4 (GPX4) in PD cells. Conversely, CHCHD2 knockdown led to reduced cell viability, elevated lipid peroxidation, and a decreased expression of GPX4. Additionally, CHCHD2 overexpression ameliorated motor function impairment, reduced α-synuclein levels, and mitigated dopaminergic (DA) neuron loss in the substantia nigra and striatum of PD mice. Importantly, we show that the inhibitory effect of CHCHD2 on ferroptosis in PD is related to the GPX4 signaling pathway. In summary, our study elucidates the neuroprotective role of CHCHD2 in regulating the GPX4-related ferroptosis pathway in PD, providing new targets and ideas for future PD drug development and therapy.

The present study investigates the neuroprotective effects of the sea urchin Paracentrotus lividus gonadal extract on rotenone-induced neurotoxicity in a Parkinson's disease (PD) rat model. Parkinson's disease, characterized by the progressive loss of dopaminergic neurons in the substantia nigra (SN), is exacerbated by oxidative stress and neuroinflammation. The study involved fifty Wistar rats divided into five groups: control, dimethyl sulfoxide (DMSO) control, Paracentrotus lividus gonadal extract-treated, rotenone-treated, and combined rotenone with Paracentrotus lividus gonadal extract-treated. Behavioral assessments included the rotarod and open field tests, while biochemical analyses measured oxidative stress markers (malondialdehyde (MDA), nitric oxide (NO), glutathione (GSH)), antioxidants (superoxide dismutase (SOD), catalase (CAT)), pro-inflammatory cytokines (interleukin-1 beta (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α)), and neurotransmitters (dopamine (DA), levodopa (L-Dopa)). Histological and immunohistochemical analyses evaluated the neuronal integrity and tyrosine hydroxylase (TH) and alpha-synuclein expression. The results showed that Paracentrotus lividus gonadal extract significantly mitigated rotenone-induced motor deficits and improved locomotor activity. Biochemically, the extract reduced oxidative stress and inflammation markers while enhancing antioxidant levels. Histologically, it restored neuronal integrity and reduced alpha-synuclein accumulation. Molecularly, it increased tyrosine hydroxylase and dopa decarboxylase gene expression, essential for dopamine synthesis. These findings suggest that Paracentrotus lividus gonadal extract exerts neuroprotective effects by modulating oxidative stress, neuroinflammation, and dopaminergic neuron integrity, highlighting its potential as a therapeutic agent for Parkinson's disease.

Parkinson's disease (PD) presents a complex etiology involving genetics and environmental factors. Non-motor symptoms often precede motor manifestations. Dopaminergic neuron degeneration, oxidative stress, and vascular changes characterize PD. Retinal changes are studied as potential biomarkers, yet choroidal involvement remains unclear. This review aims to clarify choroidal thickness's role in PD progression for diagnostic advancements.

We examined PubMed, Scopus, and Embase databases. Depending on the heterogeneity, an appropriate model was used for the meta-analysis. Additionally, meta-regression, publication bias, subgroup analyses, and quality evaluation were carried out.

We evaluated twelve studies involving 442 PD patients and 608 healthy controls. This study found insignificant differences in choroidal thickness between PD patients and healthy controls.

Choroidal thickness is influenced by age, axial length, and intraocular pressure, with PD potentially impacting thickness through neurodegenerative mechanisms. However, inconsistencies exist in the findings, warranting further investigation. Future studies should explore the impact of disease severity, medication effects, and other confounding variables on choroidal thickness in PD patients. Additionally, advanced imaging modalities like optical coherence tomography angiography (OCTA) may provide more comprehensive evaluations of choroidal vascular changes in PD.

Parkinson's disease (PD) is a common neurodegenerative disorder marked by the degeneration of dopaminergic neurons and the buildup of α-synuclein aggregates. The current treatments focus on symptom relief, with no drugs available to halt disease progression. This has prompted interest in plant-based extracts as alternative therapies. This study examines the neuroprotective and antioxidant effects of walnut oil (WO), extracted from Juglans regia L., in an in vitro PD model using the neurotoxin rotenone (ROT). WO, rich in polyunsaturated fatty acids (PUFAs), including linoleic acid (LA) and α-linolenic acid (ALA), together with minor bioactive components, is known for its neuroprotective properties. Using human HMC3 microglial and SH-SY5Y neuroblastoma cells, we tested WO's effects on ROT-induced toxicity. The experiments were performed at different time points. The results showed that the co-administration of WO with ROT significantly improved cell viability and reduced reactive oxygen species (ROS) levels. Additionally, conditioned media from WO-treated HMC3 cells enhanced SH-SY5Y cell survival, indicating positive microglia-neuron interactions. Cell viability appeared to be concentration- and time-dependent. These findings highlight WO's potential, mainly due to its PUFA content, as a promising candidate for preventing neurodegenerative diseases like PD; they underscore the potential of WO content in food for the prevention of neurodegenerative diseases such as PD.

Parkinson's disease (PD) is primarily characterized by three histological hallmarks: dopaminergic neuronal degeneration, α-synuclein accumulation and iron deposition. Over the last years, neuroimaging, particularly magnetic resonance imaging (MRI) has provided invaluable insights into the mechanisms underlying the disease. However, no imaging method has yet been able to translate α-synuclein protein accumulation and spreading. Amongst the animal models mimicking the disease, the α-synuclein rat, generated through the injection of human α-synuclein, has been characterized in terms of behavioural and histological aspects but not thoroughly explored in MRI. The aim of this study is, therefore, to identify the radiological signature from several MRI sequences, while controlling for histological and behavioural characteristics. Rats were assessed for motor and cognitive functions over a 4-month period. During this time, three MRI sessions, including both morphological and functional sequences, were conducted. Histological studies evaluated the three main hallmarks of PD. The progressive dopaminergic neurodegeneration and the spread of human α-synuclein corresponded to the level of sensorimotor, attentional and learning deficits observed in this PD model. MRI analyses showed progressive structural abnormalities in the midbrain, diencephalon and several cortical structures, as well as a pattern of hyperconnectivity in the basal ganglia and cortical networks. The regions affected in imaging demonstrated the highest load of human α-synuclein. This model's structural and functional MRI changes could serve as indirect indicators of α-synuclein accumulation and its association with impaired non-motor functions.

Alpha-synuclein (α-syn) is a 140-amino-acid, intrinsically disordered, soluble protein that is abundantly present in the brain. It plays a crucial role in maintaining cellular structures and organelle functions, particularly in supporting synaptic plasticity and regulating neurotransmitter turnover. However, for reasons not yet fully understood, α-syn can lose its physiological role and begin to aggregate. This altered α-syn disrupts dopaminergic transmission and causes both presynaptic and postsynaptic dysfunction, ultimately leading to cell death. A group of neurodegenerative diseases known as α-synucleinopathies is characterized by the intracellular accumulation of α-syn deposits in specific neuronal and glial cells within certain brain regions. In addition to Parkinson's disease (PD), these conditions include dementia with Lewy bodies (DLBs), multiple system atrophy (MSA), pure autonomic failure (PAF), and REM sleep behavior disorder (RBD). Given that these disorders are associated with α-syn-related neuroinflammation-and considering that SARS-CoV-2 infection has been shown to affect the nervous system, with COVID-19 patients experiencing neurological symptoms-it has been proposed that COVID-19 may contribute to neurodegeneration in PD and other α-synucleinopathies by promoting α-syn misfolding and aggregation. In this review, we focus on whether SARS-CoV-2 could act as an environmental trigger that facilitates the onset or progression of α-synucleinopathies. Specifically, we present new evidence on the potential role of SARS-CoV-2 in modulating α-syn function and discuss the causal relationship between SARS-CoV-2 infection and the development of parkinsonism-like symptoms.

Previous observational research has indicated a correlation between Parkinson's disease (PD) and multiple cancers; but the causality remains unclear. Thus, we utilized Mendelian randomization (MR) analysis to explore the potential causal link between PD and various cancers.

We conducted a bidirectional two-sample Mendelian randomization (TSMR) of genetic variants associated with PD and 14 types of cancers. Summary statistics on PD and 14 types of cancers were obtained from the International Parkinson's Disease Genomics Consortium and the study by Sakaue et al. The primary method employed was inverse variance weighted (IVW), complemented by multiple sensitivity analyses to evaluate heterogeneity and pleiotropy. The false discovery rate (FDR) was employed to control the false positive rate of multiple hypothesis testing.

Following rigorous sensitivity analyses and corrections, our findings revealed suggestive associations between PD and certain cancers. We observed that PD decreases the risk of gastric cancer and colorectal cancer (OR = 0.936, 95% CI = 0.881-0.995, p = 0.034, P FDR = 0.239; OR = 0.955, 95% CI = 0.912-0.999, p = 0.046, P FDR = 0.215), while increasing the risk of breast cancer (OR = 1.043, 95% CI = 1.004-1.084, p = 0.029, P FDR = 0.402). Notably, we found no evidence supporting a reverse causal relationship. Additionally, in the reverse pathway, skin cancer demonstrated a suggestive causal relationship with PD (OR = 0.913, 95% CI = 0.857-0.973, p = 0.005, P FDR = 0.066).

Our MR analysis provides evidence supporting unidirectional suggestive causal relationships between PD and certain cancers. These findings enrich our comprehension of the intricate interplay between PD and cancer, warranting further investigation into the underlying biological mechanisms.

By disturbing the prooxidant-antioxidant balance in the cell, a condition called oxidative stress is created, causing severe damage to the nucleic acid, protein, and lipid of the host cell, and as a result, endangers the viability of the host cell. A relationship between oxidative stress and several different diseases such as cardiovascular diseases, cancer, and obesity has been reported. Therefore, maintaining this prooxidant-antioxidant balance is vital for the cell. Probiotics as one of the potent antioxidants have recently received attention. Many health-promoting and beneficial effects of probiotics are known, and it has been found that the consumption of certain strains of probiotics alone or in combination with food exerts antioxidant efficacy and reduces oxidative damage. Studies have reported that certain probiotic strains implement their antioxidant effects by producing metabolites and antioxidant enzymes, increasing the antioxidant capacity, and reducing host oxidant metabolites. Therefore, we aimed to review and summarize the latest anti-oxidative activity of probiotics and its efficacy in aging, cardiovascular diseases, cancer, and obesity.

Parkinson's disease (PD) patients are prone to fall and fall-related injuries (FI). Vascular disease is common in PD and is positively associated with falls in elderly. We aimed to evaluate the association of vascular disease with FI risk in PD.

A nationwide cohort study of patients with primary PD diagnosis in Sweden was performed using Swedish national registers. Patients with and without vascular disease were followed from PD diagnosis until subsequent FI or 2013-12-31. The association of vascular disease with FI risk was estimated as hazard ratio (HR) and 95 % confidence interval (CI) by Cox regression using attained age as underlying timescale.

We identified 2734 and 6979 incident FI from 8025 PD patients with and 20,543 without vascular disease, respectively. Overall, vascular disease associated positively with subsequent FI, which was mainly driven by the significant risk elevation within the first 6 months following vascular disease (HR < 0.5year [95 % CI] for PD diagnosed ≤75 years is 1.61 [1.39-1.87] and for PD diagnosed >75 years is 1.48 [1.32-1.65]). Thereafter, the association attenuated to null before it rebounded five years after exposure in PD diagnosed ≤75 years (HR > 5year = 1.26, 95 % CI: 1.10-1.45); whereas for PD diagnosed >75 years, it dropped remarkably and remained non-significant 6 months after exposure. When vascular disease was restricted to stroke, we saw a similar temporal pattern except that the short-term HRs among younger patients were stronger, lasted longer, and declined continuously without rebound.

Fall prevention is crucial to PD patients immediately after a vascular event.

The gut microbiota (GM) produces various molecules that regulate the physiological functionality of the brain through the gut-brain axis (GBA). Studies suggest that alteration in GBA may lead to the onset and progression of various neurological dysfunctions. Moreover, aging is one of the prominent causes that contribute to the alteration of GBA. With age, GM undergoes a shift in population size and species of microflora leading to changes in their secreted metabolites. These changes also hamper communications among the HPA (hypothalamic-pituitary-adrenal), ENS (enteric nervous system), and ANS (autonomic nervous system). A therapeutic intervention that has recently gained attention in improving health and maintaining communication between the gut and the brain is calorie restriction (CR), which also plays a critical role in autophagy and neurogenesis processes. However, its strict regime and lifelong commitment pose challenges. The need is to produce similar beneficial effects of CR without having its rigorous compliance. This led to an exploration of calorie restriction mimetics (CRMs) which could mimic CR's functions without limiting diet, providing long-term health benefits. CRMs ensure the efficient functioning of the GBA through gut bacteria and their metabolites i.e., short-chain fatty acids, bile acids, and neurotransmitters. This is particularly beneficial for elderly individuals, as the GM deteriorates with age and the body's ability to digest the toxic accumulates declines. In this review, we have explored the beneficial effect of CRMs in extending lifespan by enhancing the beneficial bacteria and their effects on metabolite production, physiological conditions, and neurological dysfunctions including neurodegenerative disorders.

Parkinson disease (PD) is a neurodegenerative condition affecting multiple sensorimotor and cognitive systems. The Pink1-/- rat model exhibits vocal, cognitive, and limb use deficits seen in idiopathic PD. We sought to measure glucose metabolism in brain regions in Pink1-/- and wild type (WT) rats, and to associate these to measures of ultrasonic vocalization, cognition, and limb use behavior.

Pink1-/- (n = 12) and WT (n = 14) rats were imaged by [18F]fluorodeoxyglucose (FDG) positron emission tomography (PET) in a repeated measures design at approximately 10 months of age and 6 weeks later. Relative regional glucose metabolism was indexed by whole brain normalized FDG uptake, which was calculated for 18 regions identified a priori for comparison. Behavioral measures included tests of communication via ultrasonic vocalization, cognition with 5-Choice Serial Reaction Time Test (5-CSRTT), and limb use with Cylinder Test and Challenge Beam.

Relative glucose metabolism was significantly different in Pink1-/- rats in prelimbic area, striatum, nucleus ambiguus, globus pallidus, and posterior parietal association cortex compared to WT controls. For behavioral measures, Pink1-/- rats demonstrated quieter vocalizations with a restricted frequency range, and they showed increased number of foot-faults and hindlimb steps (shuffling) in limb motor tests. Significant behavior vs. brain correlations included associations of ultrasonic vocalization parameters with glucose metabolism indices in locus coeruleus and substantia nigra.

FDG PET reveals abnormalities in relative regional brain glucose metabolism in Pink1-/- rats in brain regions that are important to cognition, vocalization, and limb motor control that are also impacted by Parkinson disease. This method may be useful for mechanistic studies of behavioral deficits and therapeutic interventions in translational studies in the Pink1-/- PD model.

The pathophysiology of Parkinson's disease (PD) is marked by degeneration of dopaminergic neurons in the substantia nigra. With advent of COVID-19, which is closely associated with generalized inflammation and multiple organ dysfunctions, the PD patients may develop severe conditions of disease leading to exacerbated degeneration. This condition is caused by the excessive release of pro-inflammatory markers, called cytokine storm, that is capable of triggering neurodegenerative conditions by affecting the blood-brain barrier (BBB). A possible SARS-CoV-2 infection, in serious cases, may compromise the immune system by triggering a hyperstimulation of the neuroimmune response, similar to the pathological processes found in PD. From this perspective, the inflammatory scenario triggers oxidative stress and, consequently, cellular dysfunction in the nervous tissue. The P2X7R seems to be the key mediator of the neuroinflammatory process, as it acts by increasing the concentration of ATP, allowing the influx of Ca2+ and the occurrence of mutations in the α-synuclein protein, causing activation of this receptor. Thus, modulation of the purinergic system may have therapeutic potential on the effects of PD, as well as on the damage caused by inflammation of the BBB, which may be able to mitigate the neurodegeneration caused by diseases. Considering all the processes of neuroinflammation, oxidative stress, and mitochondrial dysfunction that PD propose, we can conclude that the P2X7 antagonist acts in the prevention of viral diseases, and it also controls purinergic receptors formed by multi-target compounds directed to self-amplification circuits and, therefore, may be a viable strategy to obtain the desired disease-modifying effect. Thus, purinergic system receptor modulations have a high therapeutic potential for neurodegenerative diseases such as PD.

Experimental models play a pivotal role in biomedical research, facilitating the understanding of disease mechanisms and the development of novel therapeutics. This is particularly true for neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and motor neuron disease, which present complex challenges for research and therapy development. In this work, we review the recent literature about experimental models and motor neuron disease. We identified three main categories of models that are highly studied by scientists. In fact, experimental models for investigating these diseases encompass a variety of approaches, including modeling the patient's cell culture, patient-derived induced pluripotent stem cells, and organoids. Each model offers unique advantages and limitations, providing researchers with a range of tools to address complex biological questions. Here, we discuss the characteristics, applications, and recent advancements in terms of each model system, highlighting their contributions to advancing biomedical knowledge and translational research.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the loss of dopaminergic neurons and the presence of Lewy bodies, which predominantly consist of aggregated forms of the protein alpha-synuclein (aSyn). While these aggregates are a pathological hallmark of PD, the etiology of most cases remains elusive. Although environmental risk factors have been identified, such as the pesticides dieldrin and MTPT, many others remain to be assessed and their molecular impacts are underexplored. This study aimed to identify pesticides that could enhance aSyn aggregation using a humanized yeast model expressing aSyn fused to GFP as a primary screening platform, which we validated using dieldrin. We found that the pesticides cymoxanil and metalaxyl induce aggregation of aSyn in yeast, which we confirmed also occurs in a model of aSyn inclusion formation using human H4 cells. In conclusion, our approach generated invaluable molecular data on the effect of pesticides, therefore providing insights into mechanisms associated with the onset and progression of PD and other synucleinopathies.

Neurodegenerative diseases (NDDs) are identified by the progressive deterioration of neurons and a subsequent decline in cognitive function, creating an enormous burden on the healthcare system globally. Neuroinflammation is an intricate procedure that initiates the immune response in the central nervous system (CNS) and significantly impacts the expansion of NDDs. This study scrutinizes the complicated interaction between neuronal degeneration and neuroinflammation, with an appropriate emphasis on their reciprocal impacts. It also describes how neuroinflammatory reactions in NDDs are controlled by activating certain pro-inflammatory transcription factors, including p38 MAPK, FAF1, Toll-like receptors (TLRs), and STAT3. Alternatively, it evaluates the impact of pro-survival transcription factors, such as the SOCS pathway, YY1, SIRT1, and MEF2, which provide neuroprotective protection against damage triggered by neuroinflammation. Moreover, we study the feasibility of accommodating drug repositioning as a therapeutic approach for treating neuroinflammatory disorders. This suggests the use of existing medications for novel utilization in the treatment of NDDs. Furthermore, the study intends to reveal novel biomarkers of neuroinflammation that contribute fundamental observation for the initial detection and diagnosis of these disorders. This study aims to strengthen therapy interference and augment patient outcomes by combining ongoing data and evaluating novel therapeutic and diagnostic approaches. The goal is to devote the growth of an effective strategy to reducing the impact of neuroinflammation on neuronal protection in NDDs.

Perilla seed oil, derived from a regional plant native to northern Thailand, undergoes cold-pressing to analyze its bioactive components, notably alpha-linolenic acid (ALA). ALA, constituting approximately 61% of the oil, serves as a precursor for therapeutic omega-3 fatty acids, EPA and DHA, with neurodegenerative disease benefits and anti-inflammatory responses. This study administered different concentrations of perilla seed oil to male C57BL/6 mice, categorized as low dose (LP 5% w/w), middle dose (MP 10% w/w), and high dose (HP 20% w/w), along with a fish oil (FP 10% w/w) diet. An experimental group received soybean oil (5% w/w). Over 42 days, these diets were administered while inducing Parkinson's disease (PD) with rotenone injections. Mice on a high perilla seed oil dose exhibited decreased Cox-2 expression in the colon, suppressed Iba-1 microglia activation, reduced alpha-synuclein accumulation in the colon and hippocampus, prevented dopaminergic cell death in the substantia nigra, and improved motor and non-motor symptoms. Mice on a middle dose showed maintenance of diverse gut microbiota, with an increased abundance of short-chain fatty acid (SCFA)-producing bacteria (Bifidobacteria, Lactobacillus, and Faecalibacteria). A reduction in bacteria correlated with PD (Turicibacter, Ruminococcus, and Akkermansia) was observed. Results suggest the potential therapeutic efficacy of high perilla seed oil doses in mitigating both intestinal and neurological aspects linked to the gut-brain axis in PD.

Vocal and swallowing deficits are common in Parkinson disease (PD). Because these impairments are resistant to dopamine replacement therapies, vocal and lingual exercise are the primary treatment, but not all individuals respond to exercise and neural mechanisms of treatment response are unclear. To explore putative mechanisms, we used the progressive Pink1-/- rat model of early to mid-stage PD and employed vocal and lingual exercises at 6- and 10-months of age in male Pink1-/- and wild type (WT) rats. We hypothesized that vocal and lingual exercise would improve vocal and tongue use dynamics and increase serotonin (5HT) immunoreactivity in related brainstem nuclei. Rats were tested at baseline and after 8 weeks of exercise or sham exercise. At early-stage PD (6 months), vocal exercise resulted in increased call complexity, but did not change intensity, while at mid-stage (10 months), vocal exercise no longer influenced vocalization complexity. Lingual exercise increased tongue force generation and reduced relative optical density of 5HT in the hypoglossal nucleus at both time points. The effects of vocal and lingual exercise at these time points are less robust than in prodromal stages observed in previous work, suggesting that early exercise interventions may yield greater benefit. Future work targeting optimization of exercise at later time points may facilitate clinical translation.

The incidence of neurological disorders, particularly age-related neurodegenerative pathologies, exhibits an alarming upward trend, while current pharmacological interventions seldom achieve curative outcomes. Despite their diverse clinical presentations, neurological diseases often share a common pathological thread: the aberrant accumulation of misfolded proteins within the endoplasmic reticulum (ER). This phenomenon, known as ER stress, arises when the cell's intrinsic quality control mechanisms fail to cope with the protein-folding burden. Consequently, misfolded proteins accumulate in the ER lumen, triggering a cascade of cellular stress responses. Recognizing this challenge, researchers have intensified their efforts over the past two decades to explore natural compounds that could potentially slow or even reverse these devastating pathologies. Flavonoids constitute a vast and heterogeneous class of plant polyphenols, with over 10,000 identified from diverse natural sources such as wines, vegetables, medicinal plants, and organic products. Flavonoids are generally divided into six different subclasses: anthocyanidins, flavanones, flavones, flavonols, isoflavones, and flavonols. The diverse family of flavonoids, featuring a common phenolic ring backbone adorned with varying hydroxyl groups and additional modifications, exerts its antioxidant activity by inhibiting the formation of ROS, as evidenced by research. Also, studies suggest that polyphenols such as flavonoids can regulate ER stress through apoptosis and autophagy. By understanding these mechanisms, we can unlock the potential of flavonoids as novel therapeutic agents for neurodegenerative disorders. Therefore, this review critically examines the literature exploring the modulatory effects of flavonoids on various steps of the ER stress in neurological disorders.

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.

Neurodegeneration is a gradual decay process leading to the depletion of neurons in both the central and peripheral nervous systems, ultimately resulting in cognitive dysfunctions and the deterioration of brain functions, alongside a decline in motor skills and behavioral capabilities. Neurodegenerative disorders (NDs) impose a substantial socio-economic strain on society, aggravated by the advancing age of the world population and the absence of effective remedies, predicting a negative future. In this context, the urgency of discovering viable therapies is critical and, despite significant efforts by medicinal chemists in developing potential drug candidates and exploring various small molecules as therapeutics, regrettably, a truly effective treatment is yet to be found. Nitrogen heterocyclic compounds, and particularly those containing the indole nucleus, which has emerged as privileged scaffold, have attracted particular attention for a variety of pharmacological applications. This review analyzes the rational design strategy adopted by different research groups for the development of anti-neurodegenerative indole-based compounds which have the potential to modulate various molecular targets involved in NDs, with reference to the most recent advances between 2018 and 2023.

Parkinson's disease (PD) is a common neurodegenerative disease characterized by progressive loss of dopaminergic neurons in the substantia nigra and the aggregation of alpha-synuclein (α-syn). The central nervous system (CNS) has previously been considered as an immune-privileged area. However, studies have shown that the immune responses are involved in PD. The major histocompatibility complex (MHC) presents antigens from antigen-presenting cells (APCs) to T lymphocytes, immune responses will be induced. MHCs are expressed in microglia, astrocytes, and dopaminergic neurons. Single nucleotide polymorphisms in MHC are related to the risk of PD. The aggregated α-syn triggers the expression of MHCs by activating glia cells. CD4+ and CD8+ T lymphocytes responses and microglia activation are detected in brains of PD patients. In addiction immune responses further increase blood-brain barrier (BBB) permeability and T cell infiltration in PD. Thus, MHCs are involved in PD through participating in immune and inflammatory responses.

Parkinson's disease (PD) is a neurodegenerative disease featured by progressive loss of nigrostriatal dopaminergic neurons, the etiology of which is associated with the existence of neuroinflammatory response and oxidative stress. Vincamine is an indole alkaloid that was reported to exhibit potent anti-inflammatory and antioxidant properties in many central and/or peripheral diseases. Nevertheless, the specific role of vincamine in PD development remains unknown. In our study, dopaminergic neuron loss was determined through immunohistochemistry staining and western blot analysis of tyrosine hydroxylase (TH) expression in the substantia nigra (SN) of PD mice. Reactive oxygen species (ROS) production and malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione (GSH) levels were detected through DHE staining and commercially available kits to assess oxidative stress. Pro-inflammatory cytokine (TNF-α, IL-1β, and IL-6) levels in the SN were measured via RT-qPCR and western blot analysis. Microglial and astrocyte activation was examined through immunofluorescence staining of Iba-1 (microglia marker) and GFAP (astrocyte marker) in the SN. The regulation of vincamine on the NF-κB and Nrf2/HO-1 pathway was estimated through western blot analysis. Our results showed that vincamine treatment decreased TNF-α, IL-1β, and IL-6 mRNA and protein levels, reduced GFAP and Iba-1 expression, decreased ROS production and MDA level, and increased SOD activity and GSH level in the SN of PD mice. Mechanically, vincamine repressed the phosphorylation levels of p65, IKKβ, and IκBα but enhanced the protein levels of Nrf2 and HO-1 in PD mice. Collectively, vincamine plays a neuroprotective role in PD mouse models by alleviating neuroinflammation and oxidative damage via suppressing the NF-κB pathway and activating the Nrf2/HO-1 pathway.

Parkinson's disease is a neurodegenerative condition characterized by the degeneration of dopaminergic neurons, resulting in motor disabilities such as rigidity, bradykinesia, postural instability, and resting tremors. While the exact cause of Parkinson's remains uncertain, both familial and sporadic forms are often associated with the G2019S mutation found in the kinase domain of LRRK2. Roco4 is an analogue of LRRK2 protein in Dictyostelium discoideum which is an established model organism to investigate LRRK2 inhibitors. In this study, the potential treatment of Parkinson's was explored by inhibiting the activity of the mutated LRRK2 protein using Roco4 as the base protein structure. Mongolicain-A and Bacoside-A exhibited significant selectivity towards the G2019S mutation, displaying a binding affinity of - 12.3 Kcal/mol and - 11.4 Kcal/mol respectively. Mongolicain-A demonstrated increased specificity towards Roco4, while Bacoside-A demonstrated significant binding affinity to all 34 kinases proteins alike. The Molecular Dynamics Studies (MDS) results strongly suggests that Mongolicain-A is a significant inhibitor of Roco4 kinase. ADMET and drugability analysis also suggests that among the two best ligands, Mongolicain-A demonstrates significant physicochemical properties to be suitable for best drug like molecule. Based on the in-silico molecular docking, molecular dynamic simulation, ADMET and drugability analyses, it is strongly suggested that, Mongolicain-A could be a potential candidate for treatment and management of Parkinson's disease via inhibition of LRRK2 protein. Further in-vitro and in-vivo investigations are in demand to validate these findings.

To identify potential inhibitors, 3069 phytochemicals were screened using molecular docking via AutoDock Vina. Molecular Dynamics Simulation was carried out using GROMACS 2022.2 for a duration of 100ns per complex to study the stability and inhibition potential of the protein ligand complexes. ADMET analysis was carriedout using Molinspiration and preADMET web tool.

The etiology underlying most sporadic Parkinson's' disease (PD) cases is unknown. Environmental exposures have been suggested as putative causes of the disease. In cell models and in animal studies, certain chemicals can destroy dopaminergic neurons. However, the mechanisms of how these chemicals cause the death of neurons is not understood. Several of these agents are mitochondrial toxins that inhibit the mitochondrial complex I of the electron transport chain. Familial PD genes also encode proteins with important functions in mitochondria. Mitochondrial dysfunction of the respiratory chain, in combination with the presence of redox active dopamine molecules in these cells, will lead to the accumulation of reactive oxygen species (ROS) in dopaminergic neurons. Here, I propose a mechanism regarding how ROS may lead to cell killing with a specificity for neurons. One rarely considered hypothesis is that ROS produced by defective mitochondria will lead to the formation of oxidative DNA damage in nuclear DNA. Many genes that encode proteins with neuron-specific functions are extraordinary long, ranging in size from several hundred kilobases to well over a megabase. It is predictable that such long genes will contain large numbers of damaged DNA bases, for example in the form of 8-oxoguanine (8-oxoG), which is a major DNA damage type produced by ROS. These DNA lesions will slow down or stall the progression of RNA polymerase II, which is a term referred to as transcription stress. Furthermore, ROS-induced DNA damage may cause mutations, even in postmitotic cells such as neurons. I propose that the impaired transcription and mutagenesis of long, neuron-specific genes will lead to a loss of neuronal integrity, eventually leading to the death of these cells during a human lifetime.

Several genetic pathogenic variants increase the risk of Parkinson's disease (PD) with pathogenic variants in the leucine-rich repeat kinase 2 (LRRK2) gene being among the most common. A joint pattern analysis based on multi-set canonical correlation analysis (MCCA) was utilized to extract PD and LRRK2 pathogenic variant-specific spatial patterns in relation to healthy controls (HCs) from multi-tracer Positron Emission Tomography (PET) data. Spatial patterns were extracted for individual subject cohorts, as well as for pooled subject cohorts, to explore whether complementary spatial patterns of dopaminergic denervation are different in the asymptomatic and symptomatic stages of PD. The MCCA results are also compared to the traditional univariate analysis, which serves as a reference. We identified PD-induced spatial distribution alterations common to DAT and VMAT2 in both asymptomatic LRRK2 pathogenic variant carriers and PD subjects. The inclusion of HCs in the analysis demonstrated that the dominant common PD-induced pattern is related to an overall dopaminergic terminal density denervation, followed by asymmetry and rostro-caudal gradient with deficits in the less affected side still being the best marker of disease progression. The analysis was able to capture a trend towards PD-related patterns in the LRRK2 pathogenic variant carrier cohort with increasing age in line with the known increased risk of this patient cohort to develop PD as they age. The advantage of this method thus resides in its ability to identify not only regional differences in tracer binding between groups, but also common disease-related alterations in the spatial distribution patterns of tracer binding, thus potentially capturing more complex aspects of disease induced alterations.

Parkinson's disease (PD) is a progressive neurodegenerative disease that affects approximately 1% of people over the age of 60 and 5% of those over the age of 85. Current drugs for Parkinson's disease mainly affect the symptoms and cannot stop its progression. Nanotechnology provides a solution to address some challenges in therapy, such as overcoming the blood-brain barrier (BBB), adverse pharmacokinetics, and the limited bioavailability of therapeutics. The reformulation of drugs into nanoparticles (NPs) can improve their biodistribution, protect them from degradation, reduce the required dose, and ensure target accumulation. Furthermore, appropriately designed nanoparticles enable the combination of diagnosis and therapy with a single nanoagent. In recent years, gold nanoparticles (AuNPs) have been studied with increasing interest due to their intrinsic nanozyme activity. They can mimic the action of superoxide dismutase, catalase, and peroxidase. The use of 13-nm gold nanoparticles (CNM-Au8®) in bicarbonate solution is being studied as a potential treatment for Parkinson's disease and other neurological illnesses. CNM-Au8® improves remyelination and motor functions in experimental animals. Among the many techniques for nanoparticle synthesis, green synthesis is increasingly used due to its simplicity and therapeutic potential. Green synthesis relies on natural and environmentally friendly materials, such as plant extracts, to reduce metal ions and form nanoparticles. Moreover, the presence of bioactive plant compounds on their surface increases the therapeutic potential of these nanoparticles. The present article reviews the possibilities of nanoparticles obtained by green synthesis to combine the therapeutic effects of plant components with gold.

This study focuses on the discovery of new potential drugs for treating PD by targeting the aggregation of α-Syn. A series of hybrids combining Coumarin and phenolic acid were designed and synthesized. Four particularly promising compounds were identified, showing strong inhibitory effects with IC50 values ranging from low micromolar to submicromolar concentrations, as low as 0.63 μM. These compounds exhibited a higher binding affinity to α-Syn residues and effectively hindered the entire aggregation process, maintaining the proteostasis conformation of α-Syn and preventing the formation of β-sheet aggregates. This approach holds significant promise for PD prevention. Additionally, these candidate compounds demonstrated the ability to break down preformed α-Syn oligomers and fibrils, resulting in the formation of smaller aggregates and monomers. Moreover, the candidate compounds showed impressive effectiveness in inhibiting α-Syn aggregation within nerve cells, thereby reducing the likelihood of α-Syn inclusion formation resembling Lewy bodies, which highlights their potential for treating PD.

The aetiology of a progressive neuronal Parkinson's disease has been discussed in several studies. However, due to the multiple risk factors involved in its development, such as environmental toxicity, parental inheritance, misfolding of protein, ageing, generation of reactive oxygen species, degradation of dopaminergic neurons, formation of neurotoxins, mitochondria dysfunction, and genetic mutations, its mechanism of involvement is still discernible. Therefore, this study aimed to review the processes or systems that are crucially implicated in the conversion of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) into its lethal form, which directly blockades the performance of mitochondria, leading to the formation of oxidative stress in the dopaminergic neurons of substantia nigra pars compacta (SNpc) and resulting in the progression of an incurable Parkinson's disease. This review also comprises an overview of the mutated genes that are frequently associated with mitochondrial dysfunction and the progression of Parkinson's disease. Altogether, this review would help future researchers to develop an efficient therapeutic approach for the management of Parkinson's disease via identifying potent prognostic and diagnostic biomarkers.

Parkinson's disease (PD) is a common, progressive neurodegenerative disorder characterized by substantia nigra dopamine cell death and a varied clinical picture that affects older people. Although more than two centuries have passed since the earliest attempts to find a cure for PD, it remains an unresolved problem. With this in mind, cell replacement therapy is a new strategy for treating PD. This novel approach aims to replace degenerated dopaminergic (DAergic) neurons with new ones or provide a new source of cells that can differentiate into DAergic neurons. Induced pluripotent stem cells (iPSCs), mesenchymal stem cells (MSCs), neural stem cells (NSCs), and embryonic stem cells (ESCs) are among the cells considered for transplantation therapies. Recently disease-modifying strategies like cell replacement therapies combined with other therapeutic approaches, such as utilizing natural compounds or biomaterials, are proposed to modify the underlying neurodegeneration. In the present review, we discuss the current advances in cell replacement therapy for PD and summarize the existing experimental and clinical evidence supporting this approach.

Insulin alters several brain functions, and perturbations in insulin levels could be a precipitating factor for Parkinson's disease, a disease associated with the degeneration of dopaminergic neurons. It is unclear whether insulin alters the dopamine signaling pathway and modulates learning and memory. In Caenorhabditis elegans, daf-2 insulin receptor mutants have extended memory when trained for olfactory adaptation. In this study, we show that the absence of daf-2 receptors in dopamine neurons results in this unusual learning behavior. Our results show that insulin function in memory is dopamine-dependent. In the absence of the daf-2 receptor, the calcium influx in dopamine neurons shows an altered pattern resulting in memory recall for an extended period. These results indicate that learning and memory involve insulin-dopamine crosstalk. Imbalances in this pathway result in changes in memory recall.

A library of 3-aryl-3-azetidinyl acetic acid methyl ester derivatives was prepared from N-Boc-3-azetidinone employing the Horner-Wadsworth-Emmons reaction, rhodium(I)-catalyzed conjugate addition of arylboronic acids, and subsequent elaborations to obtain N-unprotected hydrochlorides, N-alkylated and N-acylated azetidine derivatives. The compounds were evaluated for acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activity, revealing several derivatives to possess AChE inhibition comparable to that of the AChE inhibitor rivastigmine. The binding mode of the AChE inhibitor donepezil and selected active compounds 26 and 27 within the active site of AChE was studied using molecular docking. Furthermore, the neuroprotective activity of the prepared compounds was evaluated in models associated with Parkinson's disease (salsolinol-induced) and aspects of Alzheimer's disease (glutamate-induced oxidative damage). Compound 28 showed the highest neuroprotective effect in both salsolinol- and glutamate-induced neurodegeneration models, and its protective effect in the glutamate model was revealed to be driven by a reduction in oxidative stress and caspase-3/7 activity.