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Schematic diagram showing pallidotomy (a), and thalamotomy (c) and the basal ganglia circuitory during pallidotomy (b) and thallatomy (d). In case of pallidotomy, the globus pallidus (GP) is surgically destroyed. In the case of a thalamotomy, both thalami are destroyed surgically, which causes a loos of thalamic excitation to the motor cortex, which can decrease Parkinson-like symptoms. Scematic diagram of basal ganglia circuitory in normal brain is shown in "e"
Source publication
Gradual degeneration and loss of dopaminergic neurons in the substantia nigra, pars compacta and subsequent reduction of dopamine levels in striatum are associated with motor deficits that characterize Parkinson’s disease (PD). In addition, half of the PD patients also exhibit frontostriatal-mediated executive dysfunction, including deficits in att...
Citations
... Cys-HCl administration has been reported to impair dopamine synthesis in the GI tract, resulting in gastric ulceration leading to affective and neurodegenerative disorders [7]. The degeneration of dopamine-producing neurons in the SN and OB is a prominent neuropathogenic hallmark of PD [40,41]. As a consequence, reduced levels of dopamine in the brain have been directly linked to motor deficits, olfactory dysfunction, and memory loss in PD [42]. ...
Cysteamine hydrochloride (Cys-HCl) has been established as a potent ulcerogenic agent of the gastrointestinal (GI) system. GI dysfunction and olfactory deficits are the most common clinical symptoms of many movement disorders, including Parkinson’s disease (PD). Cys-HCl has been shown to interfere with dopamine, a neurotransmitter crucial for motor, olfactory, and cognitive functions. However, the reports on the effect of Cys-HCl treatment on the behavioral aspects and functions of the dopamine system appear to be inconsistent. Therefore, we revisited the impact of Cys-HCl on the motor function in experimental mice using a battery of behavioral tests, such as the pole test (PT), beam-walking test (BWT), and rotarod test (RDT), while the olfactory ability and cognitive functions were examined through the buried-food test (BFT) and Y-maze test. Furthermore, we investigated the effect of Cys-HCl on the number of dopaminergic tyrosine hydroxylase (TH)-positive cells in the substantia nigra (SN) and olfactory bulb (OB) of the experimental mice using immunohistochemistry. The results revealed that Cys-HCl administration in the mice induced significant impairments in their motor balance and coordination, as their movement-related performances were markedly reduced in terms of the behavioral tasks. Mice exposed to Cys-HCl showed pronounced reductions in their odor discrimination abilities as well as cognitive impairments. Strikingly, the number of TH-positive neurons was found to be reduced in the SN and OB of the Cys-HCl-treated group, which is a bonafide neuropathogenic hallmark of PD. This study highlights the potential neurotoxic effects of Cys-HCl in experimental brains and suggests further investigation into its role in the pathogenesis of Parkinsonism.
... However, they are not capable of treating all the motor symptoms that are common in people with PD. Non-motor symptoms such as neuropsychiatric difficulties and postural instability may be aggravated by treatments in certain cases [26]. Though these drugs can help with the motor symptoms of PD, particularly in the early stages, long-term usage of L-DOPA, in particular, has major side effects that are an important part of the clinical features in advanced-stage PD. ...
Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by motor and non-motor symptoms due to the loss of dopamine-producing neurons and the presence of Lewy bodies in the brain. While current treatments such as dopamine replacement with levodopa and deep brain stimulation mainly manage symptoms and do not stop disease progression, recent advancements in nanomedicine provide promising new therapy options. These include drug-loaded nanocarriers that improve drug delivery to the brain, enhancing effectiveness and reducing side effects. This review explores novel nanomedical approaches like solid lipid nanocarriers (SLNs), which could improve drug profiles and decrease the adverse effects seen with traditional PD treatments. Additionally, it discusses the challenge of crossing the blood–brain barrier, which is crucial for treating central nervous system disorders, and how nanocarriers facilitate targeted brain delivery. Despite these advancements, the review emphasizes more research into the safety and long-term impacts of nanomedicine in PD, highlighting the challenge of moving these treatments from lab to clinical use.
... Consequently, therapeutic strategies targeting the reduction of oxidative stress and augmentation of the antioxidant defense system have been proposed as potentially effective interventions for PD. Furthermore, a comprehensive investigation of alterations in gut microbiota composition, which instigate an imbalance of commensal gut microbes, increased intestinal permeability, and intestinal inflammation, has shed light on the connection between these factors and the accumulation of α-synuclein in the intestinal and enteric nervous systems, contributing to the pathophysiology of PD (Kalia & Lang, 2015;Maiti et al., 2017;Poewe et al., 2017). ...
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.
... Cysteamine HCl administration has been reported to impair dopamine synthesis in the GI tract resulting in gastric ulceration in association with affective and neurodegenerative disorders [7]. Degeneration of dopamine-producing neurons in SN and OB is a prominent neuropathogenic hallmark of PD [34,35]. As a consequence, reduced levels of dopamine in the brain have been directly linked to motor deficits, olfactory dysfunction, and memory loss in PD [36]. ...
Cysteamine HCl has been established as a potent ulcerogenic agent of the gastrointestinal (GI) system. GI dysfunction and olfactory deficits are the most common clinical symptoms of many movement disorders including Parkinson's disease (PD). Cysteamine HCl has been shown to interfere with dopamine, a neurotransmitter crucial for motor, olfactory, and cognitive functions. However, the reports on the effect of cysteamine HCl treatment on the behavior and dopamine system appear to be inconsistent. Therefore, we revisited the impact of cysteamine HCl on motor function in experimental mice using a battery of behavioral tests such as pole test (PT), beam walking test (BWT), and rotarod test (RDT), while the olfactory ability and cognitive functions were examined through food buried test (FBT) and Y maze. Furthermore, we investigated the effect of cysteamine HCl on the density of dopaminergic tyrosine hydroxylase (TH)-positive cells in the substantia nigra (SN) and olfactory bulb (OB) of experimental mice using immunohistochemistry. Results revealed that cysteamine HCl administration in mice induced significant impairments in motor balance and coordination, as their movement-related performance was markedly reduced in behavioral tasks. Mice exposed to cysteamine HCl showed a pronounced reduction in odor discrimination ability and cognitive impairments. Strikingly, the number of TH-positive neurons was found to be reduced in the SN and OB of the cysteamine HCl-treated group which is a bonafide neuropathogenic hallmark of PD. This study highlights the potential neurotoxic effects of cysteamine HCl in experimental brains and suggests further investigation into its role in pathogenesis of Parkinsonism.
... A second CMR that replicated in DIGPD was annotated to the DLGAP1 gene, which encodes an adaptor protein found at glutamatergic synapses and may also be of interest for follow-up experiments. Aside from the replicated CMR genes, the full list of PD-associated CMRs in females from TERRE included additional genes which could have relevance for PD: CRTC1, which has been reported as differentially methylated in prefrontal cortex (PFC) neurons from PD patients and whose protein product is involved in mitochondrial biogenesis; SLC1A7, encoding a glutamate transporter; FXR2, whose protein product is involved in DNA damage response; and ST5, SNPs of which are associated with PD progression, and whose protein product is involved in endosomal trafficking [56][57][58][59] . We note these potential links to PD will require further experimental work to validate, as our study was not designed to causally assess disease mechanisms. ...
Although sex, genetics, and exposures can individually influence risk for sporadic Parkinson’s disease (PD), the joint contributions of these factors to the epigenetic etiology of PD have not been comprehensively assessed. Here, we profiled sex-stratified genome-wide blood DNAm patterns, SNP genotype, and pesticide exposure in agricultural workers (71 early-stage PD cases, 147 controls) and explored replication in three independent samples of varying demographics ( n = 218, 222, and 872). Using a region-based approach, we found more associations of blood DNAm with PD in females (69 regions) than in males (2 regions, Δβ adj | ≥0.03, p adj ≤ 0.05). For 48 regions in females, models including genotype or genotype and pesticide exposure substantially improved in explaining interindividual variation in DNAm ( p adj ≤ 0.05), and accounting for these variables decreased the estimated effect of PD on DNAm. The results suggested that genotype, and to a lesser degree, genotype-exposure interactions contributed to variation in PD-associated DNAm. Our findings should be further explored in larger study populations and in experimental systems, preferably with precise measures of exposure.
... Parkinson's disease (PD) is a chronic progressive neurodegenerative disorder characterized by degeneration of dopaminergic neurons in the substantia nigra pars compacta and the presence of intercellular protein alpha-synuclein. [1,2] The diagnosis and management of PD are very challenging due to the similarity of the idiopathic PD with other neurodegenerative disorders such as dementia with Lewy bodies, corticobasal degeneration, multiple system atrophy, and progressive supranuclear palsy. [3,4] The imaging plays a decisive role in the diagnosis of PD, though routine diagnostic modalities such as computed tomography (CT) and magnetic resonance imaging are less helpful in the earlier stages. ...
Background
Parkinson’s disease (PD) is characterized by the degeneration of dopaminergic neurons in the substantia nigra. SPECT imaging using technetium-99m [ 99m Tc] labeled trodat is the choice of imaging to differentiate PD from its other forms like drug-induced PD. Aims and Objectives: The main objective of our study was to prepare in-house sterile formulation of [ 99m Tc]Tc-trodat and use in clinics.
Materials and Methods
The labeling of trodat was standardized using glucoheptonate sodium salt (GHA), stannous chloride dihydrate (in 0.05 N HCl), and ethylenediaminetetraacetic acid (Na-EDTA). The preparation was mixed and autoclaved at 15 psi for 15 min. The standardised formulation was stored at 4°C, -20°C and -80°C and labeling with 99m Tc was tested for up to 6 days. The radiochemical purity, chemical impurities, and endotoxin levels were tested. The frozen formulation was tested in swiss mice (n = 3) for biodistribution studies at 4 h. Around 18 ± 2 mCi was injected intravenously in each patient (n = 5) and the image was acquired at 4 h post-injection.
Results
The radiochemical purity of the preparation was 98.3 ± 1.4% with a retention time of 16.8 ± 1.5 min as compared to 4.0 ± 0.5 min for free 99m Tc. Animal distribution showed highest uptake in liver and dual excretion via hepatobiliary and renal system. [ 99m Tc]Tc-trodat imaging was able to differentiate both caudate and putamen. Conclusions: In-house frozen preparation was advantageous, as it has decreased the chance of manual error as compared to daily make up formulations and economical as compared to commercially available kits.
... Dopamine is a neurotransmitter that plays essential role in regulating movement and coordination [6]. When dopamine levels decrease in SN, the brain cells communication deteriorates which leads to the development of motor symptoms such as tremors, slowness of movement (bradykinesia), stiffness, and difficulties with balance and coordination [7]. The other pathological feature is the presence of Lewy bodies (LBs), in surviving cells. ...
Codon usage bias (CUB) is the phenomenon of non-uniform usage of synonymous codons in which some codons are more used than others and it helps in understanding the molecular organization of genome. Bioinformatic approach was used to analyze the protein-coding sequences of genes associated with Parkinson’s disease (PD) to explore compositional features and codon usage pattern as no details work was reported yet. The average improved effective number of codons (Nc) and Nc prime were 42.74 and 44.26 respectively, indicated that CUB was low in these genes. In most of the genes, the overall GC content was almost 50% and GC content at the 1st codon position was the highest while GC content at the 2nd codon position was lowest. Relative synonymous codon usage (RSCU) analysis elucidated over-represented (p > 1.6) and under-represented codons (p < 0.6). The GTG (Val) is the only codon over-represented in all genes. Over-represented codons except (GTG) were A or T ending while under-represented codons (except ACT) were G or C ending. The codons namely TTA (Leu), CTA (Leu), ATC (Ile), ATA (Ile), AGT (Ser), AAC (Asn), TGT (Cys), TGC (Cys), CGC (Arg), AGA (Arg), and AGG (Arg) were absent in SNCA1 to SNCA8 genes. The codon TCG (Ser) was absent in all genes except UCHL1 and PINK1. Correspondence analysis (COA) revealed that the pattern of codon usage differs among genes associated with PD. Neutrality plot analysis indicated some of the points are diagonal distribution suggested that mutation pressure influenced the CUB in genes associated with PD.
... Parkinson's disease (PD) stands as one of the most prevalent neurodegenerative disorders globally, characterized by the progressive degeneration of dopaminergic neurons in the substantia nigra region of the brain (Maiti et al. 2017). This debilitating condition manifests clinically with motor symptoms such as tremors, bradykinesia, rigidity, and postural instability, alongside a spectrum of non-motor symptoms, signi cantly impacting patients' quality of life (DeMaagd et al., 2015).Despite signi cant advancements in understanding the pathophysiology of PD, available therapeutic interventions primarily aim at alleviating symptoms and fail to address the underlying mechanisms driving neurodegeneration. ...
Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons in the brain, leading to motor and non-motor symptoms. The development of novel pharmacotherapies targeting specific molecular pathways implicated in PD pathogenesis is crucial for disease management. Leucine-rich repeat kinase 2 (LRRK2) has emerged as a promising therapeutic target due to its involvement in both familial and sporadic forms of PD. In this study, we employed computational drug discovery techniques to identify potential small molecule inhibitors targeting LRRK2 for PD treatment. The binding affinities of virtual test compounds with the LRRK2 drug target were assessed, revealing a range of affinities from − 6.8 to -10.2 kcal/mol. Lead compounds, including Compound 7, 14, and 15, exhibited the highest binding affinities (-10.2, -10.1, and − 10.1 kcal/mol, respectively), surpassing those of standard ligands. Molecular docking analysis elucidated the inhibitory properties of selected lead compounds, with C7, C14, and C15 identified as the most potent LRRK2 inhibitors. These compounds demonstrated favorable interactions with specific amino acid residues within the LRRK2 receptor, indicating their potential therapeutic efficacy. The validation of the docking protocol confirmed the accuracy of the computational methodology employed, ensuring reliable predictions of ligand-receptor interactions. Furthermore, the ADMET profile analysis provided insights into the drug-like characteristics and pharmacokinetic properties of selected lead compounds. Despite variations in lipophilicity, water solubility, and bioavailability scores, most test compounds exhibited moderate to high GI absorption potential and skin permeation values, suggesting their suitability for oral administration and blood-brain barrier penetration. Toxicity profile predictions highlighted potential hepatotoxicity and mutagenicity risks associated with selected lead compounds, emphasizing the importance of further experimental validation and optimization. Overall, this study contributes to the identification and characterization of novel small molecule inhibitors targeting LRRK2 for PD treatment, offering valuable insights into the rational design of potential disease-modifying therapies.
... PD is a prevalent neurodegenerative disease characterized by the degeneration of dopaminergic neurons in the substantia nigra (SN) and the presence of Lewy bodies. 23 Several studies have implicated the gradual accumulation of misfolded α-synuclein (α-syn) in the pathogenesis of PD. 24,25 Thus, identifying the potential pathways responsible for α-syn clearance is vital for PD treatment. Previous studies have reported that intracellular α-syn is degraded through the ubiquitin-proteasome system and autophagy-lysosomal pathway. ...
Introduction
Neonatal stress disrupts brain development and increases the risk of neurological disorders later in life. However, the impact of neonatal stress on the development of the glymphatic system and susceptibility to Parkinson's disease (PD) remains largely unknown.
Methods
Neonatal maternal deprivation (NMD) was performed on mice for 14 consecutive days to model chronic neonatal stress. Adeno‐associated virus expressing A53T‐α‐synuclein (α‐syn) was injected into the substantia nigra to establish PD model mice. Glymphatic activity was determined using in vivo magnetic resonance imaging, ex vivo fluorescence imaging and microplate assay. The transcription and expression of aquaporin‐4 (AQP4) and other molecules were evaluated by qPCR, western blotting, and immunofluorescence. Animal's responses to NMD and α‐syn overexpression were observed using behavioral tests.
Results
Glymphatic activity was impaired in adult NMD mice. AQP4 polarization and platelet‐derived growth factor B (PDGF‐B) signaling were reduced in the frontal cortex and hippocampus of both young and adult NMD mice. Furthermore, exogenous α‐syn accumulation was increased and PD‐like symptoms were aggravated in adult NMD mice.
Conclusion
The results demonstrated that NMD could disrupt the development of the glymphatic system through PDGF‐B signaling and increase the risk of PD later in life, indicating that alleviating neonatal stress could be beneficial in protecting the glymphatic system and reducing susceptibility to neurodegeneration.
... The effectiveness of pharmacological treatment gradually decreases as the disease progresses due to the progressive degeneration and disruption of dopamine production in the brain [6]. For many patients, Parkinson's disease medications remain effective for only around ten years [7]. ...
Background
In the daily life of individuals living with Parkinson's disease, their loved ones are crucial. Adapting family members to the patient's condition, support in providing care, and psychosocial adaptations is essential.
Aim
To explore family members' perception of everyday caregiving for a family member living with Parkinson's disease and to describe their role in the care and everyday life.
Methods
In a descriptive, qualitative thematic analysis study, semi-structured interviews were conducted with ten people between the ages of 20 and 70, the closest family members of people living with Parkinson's disease. The analysis of the collected data was carried out using thematic analysis.
Results
We generated the main theme: "Living with a family member with Parkinson’s disease", with associated secondary-level sub-themes: “Response”, “Change”, “Care”, and “Support”. Family members of individuals living with Parkinson's disease frequently encounter similar life situations. The most notable transformation in their daily lives primarily revolves around adapting to various activities.
Conclusions
Family members are the ones who most often take on the role of caregiver and provide help to their loved ones. Many of them accept the disease as a part of everyday life and learn to live with it. It is of fundamental importance that we offer family members the necessary support, knowledge, and involvement in holistic treatment and care.
