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Biomedicines Jun 2024Synaptic zinc ions (Zn) play an important role in the development of vascular dementia (VD) and Parkinson's disease (PD). In this article, we reviewed the current... (Review)
Review
Synaptic zinc ions (Zn) play an important role in the development of vascular dementia (VD) and Parkinson's disease (PD). In this article, we reviewed the current comprehension of the Zn-induced neurotoxicity that leads to the pathogenesis of these neuronal diseases. Zn-induced neurotoxicity was investigated by using immortalised hypothalamic neurons (GT1-7 cells). This cell line is useful for the development of a rapid and convenient screening system for investigating Zn-induced neurotoxicity. GT1-7 cells were also used to search for substances that prevent Zn-induced neurotoxicity. Among the tested substances was a protective substance in the extract of Japanese eel (), and we determined its structure to be like carnosine (β-alanylhistidine). Carnosine may be a therapeutic drug for VD and PD. Furthermore, we reviewed the molecular mechanisms that involve the role of carnosine as an endogenous protector and its protective effect against Zn-induced cytotoxicity and discussed the prospects for the future therapeutic applications of this dipeptide for neurodegenerative diseases and dementia.
PubMed: 38927502
DOI: 10.3390/biomedicines12061296 -
Biomedicines Jun 2024Playing a key role in the organization of striatal motor output, the dopamine (DA)-ergic system regulates both innate and complex learned behaviors. Growing evidence...
Playing a key role in the organization of striatal motor output, the dopamine (DA)-ergic system regulates both innate and complex learned behaviors. Growing evidence clearly indicates the involvement of the DA-ergic system in different forms of repetitive (perseverative) behavior. Some of these behaviors accompany such disorders as obsessive-compulsive disorder (OCD), Tourette's syndrome, schizophrenia, and addiction. In this study, we have traced how the inflexibility of repetitive reactions in the recently developed animal model of hyper-DA-ergia, dopamine transporter knockout rats (DAT-KO rats), affects the realization of innate behavior (grooming) and the learning of spatial (learning and reversal learning in T-maze) and non-spatial (extinction of operant reaction) tasks. We found that the microstructure of grooming in DAT-KO rats significantly differed in comparison to control rats. DAT-KO rats more often demonstrated a fixed syntactic chain, making fewer errors and very rarely missing the chain steps in comparison to control rats. DAT-KO rats' behavior during inter-grooming intervals was completely different to the control animals. During learning and reversal learning in the T-maze, DAT-KO rats displayed pronounced patterns of hyperactivity and perseverative (stereotypical) activity, which led to worse learning and a worse performance of the task. Most of the DAT-KO rats could not properly learn the behavioral task in question. During re-learning, DAT-KO rats demonstrated rigid perseverative activity even in the absence of any reinforcement. In operant tasks, the mutant rats demonstrated poor extinction of operant lever pressing: they continued to perform lever presses despite no there being reinforcement. Our results suggest that abnormally elevated DA levels may be responsible for behavioral rigidity. It is conceivable that this phenomenon in DAT-KO rats reflects some of the behavioral traits observed in clinical conditions associated with endogenous or exogenous hyper-DA-ergia, such as schizophrenia, substance abuse, OCD, patients with Parkinson disease treated with DA mimetics, etc. Thus, DAT-KO rats may be a valuable behavioral model in the search for new pharmacological approaches to treat such illnesses.
PubMed: 38927477
DOI: 10.3390/biomedicines12061270 -
Biomedicines Jun 2024Neurodegenerative disorders, including Alzheimer's disease (AD) and Parkinson's disease (PD), represent debilitating conditions with complex, poorly understood...
Neurodegenerative disorders, including Alzheimer's disease (AD) and Parkinson's disease (PD), represent debilitating conditions with complex, poorly understood pathologies. Epichaperomes, pathologic protein assemblies nucleated on key chaperones, have emerged as critical players in the molecular dysfunction underlying these disorders. In this study, we introduce the synthesis and characterization of clickable epichaperome probes, PU-TCO, positive control, and PU-NTCO, negative control. Through comprehensive in vitro assays and cell-based investigations, we establish the specificity of the PU-TCO probe for epichaperomes. Furthermore, we demonstrate the efficacy of PU-TCO in detecting epichaperomes in brain tissue with a cellular resolution, underscoring its potential as a valuable tool for dissecting single-cell responses in neurodegenerative diseases. This clickable probe is therefore poised to address a critical need in the field, offering unprecedented precision and versatility in studying epichaperomes and opening avenues for novel insights into their role in disease pathology.
PubMed: 38927459
DOI: 10.3390/biomedicines12061252 -
Biomolecules Jun 2024New furan, thiophene, and triazole oximes were synthesized through several-step reaction paths to investigate their potential for the development of central nervous...
New furan, thiophene, and triazole oximes were synthesized through several-step reaction paths to investigate their potential for the development of central nervous systems (CNS)-active and cholinesterase-targeted therapeutics in organophosphorus compound (OP) poisonings. Treating patients with acute OP poisoning is still a challenge despite the development of a large number of oxime compounds that should have the capacity to reactivate acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). The activity of these two enzymes, crucial for neurotransmission, is blocked by OP, which has the consequence of disturbing normal cholinergic nerve signal transduction in the peripheral and CNS, leading to a cholinergic crisis. The oximes in use have one or two pyridinium rings and cross the brain-blood barrier poorly due to the quaternary nitrogen. Following our recent study on 2-thienostilbene oximes, in this paper, we described the synthesis of 63 heterostilbene derivatives, of which 26 oximes were tested as inhibitors and reactivators of AChE and BChE inhibited by OP nerve agents-sarin and cyclosarin. While the majority of oximes were potent inhibitors of both enzymes in the micromolar range, we identified several oximes as BChE or AChE selective inhibitors with the potential for drug development. Furthermore, the oximes were poor reactivators of AChE; four heterocyclic derivatives reactivated cyclosarin-inhibited BChE up to 70%, and - [2-(()-2-(5-(()-(hydroxyimino)methyl)thiophen-2-yl)vinyl)benzonitrile] had a reactivation efficacy comparable to the standard oxime HI-6. analysis and molecular docking studies, including molecular dynamics simulation, connected kinetic data to the structural features of these oximes and confirmed their productive interactions with the active site of cyclosarin-inhibited BChE. Based on inhibition and reactivation and their ADMET properties regarding lipophilicity, CNS activity, and hepatotoxicity, these compounds could be considered for further development of CNS-active reactivators in OP poisoning as well as cholinesterase-targeted therapeutics in neurodegenerative diseases such as Alzheimer's and Parkinson's.
Topics: Oximes; Cholinesterase Inhibitors; Butyrylcholinesterase; Acetylcholinesterase; Humans; Triazoles; Molecular Docking Simulation; Stilbenes; Cholinesterase Reactivators; Organophosphorus Compounds; Central Nervous System
PubMed: 38927082
DOI: 10.3390/biom14060679 -
Biomolecules Jun 2024One of the biggest problems in the treatment of idiopathic Parkinson's disease is the lack of new drugs that slow its progression. L-Dopa remains the star drug in the... (Review)
Review
One of the biggest problems in the treatment of idiopathic Parkinson's disease is the lack of new drugs that slow its progression. L-Dopa remains the star drug in the treatment of this disease, although it induces severe side effects. The failure of clinical studies with new drugs depends on the use of preclinical models based on neurotoxins that do not represent what happens in the disease since they induce rapid and expansive neurodegeneration. We have recently proposed a single-neuron degeneration model for idiopathic Parkinson's disease that requires years to accumulate enough lost neurons for the onset of motor symptoms. This single-neuron degeneration model is based on the excessive formation of aminochrome during neuromelanin synthesis that surpass the neuroprotective action of the enzymes DT-diaphorase and glutathione transferase M2-2, which prevent the neurotoxic effects of aminochrome. Although the neurotoxic effects of aminochrome do not have an expansive effect, a stereotaxic injection of this endogenous neurotoxin cannot be used to generate a preclinical model in an animal. Therefore, the aim of this review is to evaluate the strategies for pharmacologically increasing the expression of DT diaphorase and GSTM2-2 and molecules that induce the expression of vesicular monoamine transporter 2, such as pramipexole.
Topics: Humans; Parkinson Disease; Animals; Neurons; Nerve Degeneration; Glutathione Transferase; Neuroprotective Agents; Disease Models, Animal; Antiparkinson Agents
PubMed: 38927076
DOI: 10.3390/biom14060673 -
Biomolecules May 2024Manganese (Mn) is an essential heavy metal in the human body, while excess leads to neurotoxicity, as observed in this study, where 100 µM of was administered to the...
Manganese (Mn) is an essential heavy metal in the human body, while excess leads to neurotoxicity, as observed in this study, where 100 µM of was administered to the human neuroblastoma (SH-SY5Y) cell model of dopaminergic neurons in neurodegenerative diseases. We quantitated pathway and gene changes in homeostatic cell-based adaptations to exposure. Utilizing the Gene Expression Omnibus, we accessed the GSE70845 dataset as a microarray of SH-SY5Y cells published by Gandhi et al. (2018) and applied statistical significance cutoffs at < 0.05. We report 74 pathway and 10 gene changes with statistical significance. ReactomeGSA analyses demonstrated upregulation of histones (5 out of 10 induced genes) and histone deacetylases as a neuroprotective response to remodel/mitigate -induced DNA/chromatin damage. Neurodegenerative-associated pathway changes occurred. NF-κB signaled protective responses via Sirtuin-1 to reduce neuroinflammation. Critically, activated three pathways implicating deficits in purine metabolism. Therefore, we validated that urate, a purine and antioxidant, mitigated -losses of viability in SH-SY5Y cells. We discuss as a hypoxia mimetic and trans-activator of HIF-1α, the central trans-activator of vascular hypoxic mitochondrial dysfunction. induced a 3-fold increase in mRNA levels for antioxidant metallothionein-III, which was induced 100-fold by hypoxia mimetics deferoxamine and zinc.
Topics: Humans; Manganese; Neuroblastoma; Cell Line, Tumor; Cell Survival; Neuroprotective Agents; Biomarkers
PubMed: 38927051
DOI: 10.3390/biom14060647 -
Biomolecules May 2024The primary nucleation process of α-synuclein (AS) that forms toxic oligomeric species is the early stage of the pathological cause of Parkinson's disease. It is...
The primary nucleation process of α-synuclein (AS) that forms toxic oligomeric species is the early stage of the pathological cause of Parkinson's disease. It is well-known that copper influences this primary nucleation process. While significant efforts have been made to solve the structures of polymorphic AS fibrils, the structures of AS oligomers and the copper-bound AS oligomers at the molecular level and the effect of copper concentrations on the primary nucleation are elusive. Here, we propose and demonstrate new molecular mechanism pathways of primary nucleation of AS that are tuned by distinct copper concentrations and by a specific copper-binding site. We present the polymorphic AS dimers bound to different copper-binding sites at the atomic resolution in high- and low-copper concentrations, using extensive molecular dynamics simulations. Our results show the complexity of the primary nucleation pathways that rely on the copper concentrations and the copper binding site. From a broader perspective, our study proposes a new strategy to control the primary nucleation of other toxic amyloid oligomers in other neurodegenerative diseases.
Topics: alpha-Synuclein; Copper; Binding Sites; Molecular Dynamics Simulation; Humans; Protein Multimerization; Protein Binding; Parkinson Disease
PubMed: 38927031
DOI: 10.3390/biom14060627 -
Journal of Neuroengineering and... Jun 2024People with Parkinson's Disease (PD) show abnormal gait patterns compromising their independence and quality of life. Among all gait alterations due to PD, reduced step...
INTRODUCTION
People with Parkinson's Disease (PD) show abnormal gait patterns compromising their independence and quality of life. Among all gait alterations due to PD, reduced step length, increased cadence, and decreased ground-reaction force during the loading response and push-off phases are the most common. Wearable biofeedback technologies offer the possibility to provide correlated single or multi-modal stimuli associated with specific gait events or gait performance, hence promoting subjects' awareness of their gait disturbances. Moreover, the portability and applicability in clinical and home settings for gait rehabilitation increase the efficiency in the management of PD. The Wearable Vibrotactile Bidirectional Interface (BI) is a biofeedback device designed to extract gait features in real-time and deliver a customized vibrotactile stimulus at the waist of PD subjects synchronously with specific gait phases. The aims of this study were to measure the effect of the BI on gait parameters usually compromised by the typical bradykinetic gait and to assess its usability and safety in clinical practice.
METHODS
In this case series, seven subjects (age: 70.4 ± 8.1 years; H&Y: 2.7 ± 0.3) used the BI and performed a test on a 10-meter walkway (10mWT) and a two-minute walk test (2MWT) as pre-training (Pre-trn) and post-training (Post-trn) assessments. Gait tests were executed in random order with (Bf) and without (No-Bf) the activation of the biofeedback stimulus. All subjects performed three training sessions of 40 min to familiarize themselves with the BI during walking activities. A descriptive analysis of gait parameters (i.e., gait speed, step length, cadence, walking distance, double-support phase) was carried out. The 2-sided Wilcoxon sign-test was used to assess differences between Bf and No-Bf assessments (p < 0.05).
RESULTS
After training subjects improved gait speed (Pre-trn_No-Bf: 0.72(0.59,0.72) m/sec; Post-trn_Bf: 0.95(0.69,0.98) m/sec; p = 0.043) and step length (Pre-trn_No-Bf: 0.87(0.81,0.96) meters; Post-trn_Bf: 1.05(0.96,1.14) meters; p = 0.023) using the biofeedback during the 10mWT. Similarly, subjects' walking distance improved (Pre-trn_No-Bf: 97.5 (80.3,110.8) meters; Post-trn_Bf: 118.5(99.3,129.3) meters; p = 0.028) and the duration of the double-support phase decreased (Pre-trn_No-Bf: 29.7(26.8,31.7) %; Post-trn_Bf: 27.2(24.6,28.7) %; p = 0.018) during the 2MWT. An immediate effect of the BI was detected in cadence (Pre-trn_No-Bf: 108(103.8,116.7) step/min; Pre-trn_Bf: 101.4(96.3,111.4) step/min; p = 0.028) at Pre-trn, and in walking distance at Post-trn (Post-trn_No-Bf: 112.5(97.5,124.5) meters; Post-trn_Bf: 118.5(99.3,129.3) meters; p = 0.043). SUS scores were 77.5 in five subjects and 80.3 in two subjects. In terms of safety, all subjects completed the protocol without any adverse events.
CONCLUSION
The BI seems to be usable and safe for PD users. Temporal gait parameters have been measured during clinical walking tests providing detailed outcomes. A short period of training with the BI suggests improvements in the gait patterns of people with PD. This research serves as preliminary support for future integration of the BI as an instrument for clinical assessment and rehabilitation in people with PD, both in hospital and remote environments.
TRIAL REGISTRATION
The study protocol was registered (DGDMF.VI/P/I.5.i.m.2/2019/1297) and approved by the General Directorate of Medical Devices and Pharmaceutical Service of the Italian Ministry of Health and by the ethics committee of the Lombardy region (Milan, Italy).
Topics: Humans; Parkinson Disease; Aged; Male; Wearable Electronic Devices; Biofeedback, Psychology; Female; Gait Disorders, Neurologic; Middle Aged; Gait
PubMed: 38926876
DOI: 10.1186/s12984-024-01403-z -
Scientific Reports Jun 2024Visual hallucinations in Lewy body disease (LBD) can be differentiated based on phenomenology into minor phenomena (MVH) and complex hallucinations (CVH). MVH include a...
Visual hallucinations in Lewy body disease (LBD) can be differentiated based on phenomenology into minor phenomena (MVH) and complex hallucinations (CVH). MVH include a variety of phenomena, such as illusions, presence and passage hallucinations occurring at early stages of LBD. The neural mechanisms of visual hallucinations are largely unknown. The hodotopic model posits that the hallucination state is due to abnormal activity in specialized visual areas, that occurs in the context of wider network connectivity alterations and that phenomenology of VH, including content and temporal characteristics, may help identify brain regions underpinning these phenomena. Here we investigated both the topological and hodological neural basis of visual hallucinations integrating grey and white matter imaging analyses. We studied LBD patients with VH and age matched healthy controls (HC). VH were assessed using a North-East-Visual-Hallucinations-Interview that captures phenomenological detail. Then we applied voxel-based morphometry and tract based spatial statistics approaches to identify grey and white matter changes. First, we compared LBD patients and HC. We found a reduced grey matter volume and a widespread damage of white tracts in LBD compared to HC. Then we tested the association between CVH and MVH and grey and white matter indices. We found that CVH duration was associated with decreased grey matter volume in the fusiform gyrus suggesting that LBD neurodegeneration-related abnormal activity in this area is responsible for CVH. An unexpected finding was that MVH severity was associated with a greater integrity of white matter tracts, specifically those connecting dorsal, ventral attention networks and visual areas. Our results suggest that networks underlying MVH need to be partly intact and functional for MVH experiences to occur, while CVH occur when cortical areas are damaged. The findings support the hodotopic view and the hypothesis that MVH and CVH relate to different neural mechanisms, with wider implications for the treatment of these symptoms in a clinical context.
Topics: Humans; Hallucinations; Lewy Body Disease; Gray Matter; Female; White Matter; Male; Aged; Magnetic Resonance Imaging; Aged, 80 and over; Case-Control Studies; Middle Aged
PubMed: 38926597
DOI: 10.1038/s41598-024-65536-w -
NPJ Digital Medicine Jun 2024Gait impairments are among the most common and disabling symptoms of Parkinson's disease and worsen as the disease progresses. Early detection and diagnosis of...
Gait impairments are among the most common and disabling symptoms of Parkinson's disease and worsen as the disease progresses. Early detection and diagnosis of subtype-specific gait deficits, as well as progression monitoring, can help to implement effective and preventive personalized treatment for PD patients. Yet, the gait features have not been fully studied in PD and its motor subtypes. To characterize comprehensive and objective gait alterations and to identify the potential gait biomarkers for early diagnosis, subtype differentiation, and disease severity monitoring. We analyzed gait parameters related to upper/lower limbs, trunk and lumbar, and postural transitions from 24 tremor-dominant (TD) and 20 postural instability gait difficulty (PIGD) dominant PD patients who were in early stage and 39 matched healthy controls (HC) during the Timed Up and Go test using wearable sensors. Results show: (1) Both TD and PIGD groups showed restricted backswing range in bilateral lower extremities and more affected side (MAS) arm, reduced trunk and lumbar rotation range in the coronal plane, and low turning efficiency. The receiver operating characteristic (ROC) analysis revealed these objective gait features had high discriminative value in distinguishing both PD subtypes from the HC with the area under the curve (AUC) values of 0.7~0.9 (p < 0.01). (2) Subtle but measurable gait differences existed between TD and PIGD patients before the onset of clinically apparent gait impairment. (3) Specific gait parameters were significantly associated with disease severity in TD and PIGD subtypes. Objective gait biomarkers based on wearable sensors may facilitate timely and personalized gait treatments in PD subtypes through early diagnosis, subtype differentiation, and disease severity monitoring.
PubMed: 38926552
DOI: 10.1038/s41746-024-01163-z