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Frontiers in Aging Neuroscience 2024Parkinson's disease resultant in the degeneration of Dopaminergic neurons and accumulation of α-synuclein in the substantia nigra pars compacta. The synthetic...
Parkinson's disease resultant in the degeneration of Dopaminergic neurons and accumulation of α-synuclein in the substantia nigra pars compacta. The synthetic therapeutics for Parkinson's disease have moderate symptomatic benefits but cannot prevent or delay disease progression. In this study, nicotine was employed by using transgenic Parkinson's disease models to minimize the Parkinson's disease symptoms. The results showed that the nicotine at 100, 150, and 200 μM doses reduced degeneration of Dopaminergic neurons caused by 6-hydroxydopamine (14, 33, and 40%), lowered the aggregative toxicity of α-synuclein by 53, 56, and 78%, respectively. The reduction in food-sensing behavioral disabilities of BZ555 was observed to be 18, 49, and 86%, respectively, with nicotine concentrations of 100 μM, 150 μM, and 200 μM. Additionally, nicotine was found to enhance Daf-16 nuclear translocation by 14, 31, and 49%, and dose-dependently increased SOD-3 expression by 10, 19, and 23%. In summary, the nicotine might a promising therapy option for Parkinson's disease.
PubMed: 38813528
DOI: 10.3389/fnagi.2024.1358141 -
Chinese Medical Journal May 2024Iron deposition plays a crucial role in the pathophysiology of Parkinson's disease (PD), yet the distribution pattern of iron deposition in the subcortical nuclei has...
BACKGROUND
Iron deposition plays a crucial role in the pathophysiology of Parkinson's disease (PD), yet the distribution pattern of iron deposition in the subcortical nuclei has been inconsistent across previous studies. We aimed to assess the difference patterns of iron deposition detected by quantitative iron-sensitive magnetic resonance imaging (MRI) between patients with PD and patients with atypical parkinsonian syndromes (APSs), and between patients with PD and healthy controls (HCs).
METHODS
A systematic literature search was conducted on PubMed, Embase, and Web of Science databases to identify studies investigating the iron content in PD patients using the iron-sensitive MRI techniques (R2* and quantitative susceptibility mapping [QSM]), up until May 1, 2023. The quality assessment of case-control and cohort studies was performed using the Newcastle-Ottawa Scale, whereas diagnostic studies were assessed using the Quality Assessment of Diagnostic Accuracy Studies-2. Standardized mean differences and summary estimates of sensitivity, specificity, and area under the curve (AUC) were calculated for iron content, using a random effects model. We also conducted the subgroup-analysis based on the MRI sequence and meta-regression.
RESULTS
Seventy-seven studies with 3192 PD, 209 multiple system atrophy (MSA), 174 progressive supranuclear palsy (PSP), and 2447 HCs were included. Elevated iron content in substantia nigra (SN) pars reticulata (P <0.001) and compacta (P <0.001), SN (P <0.001), red nucleus (RN, P <0.001), globus pallidus (P <0.001), putamen (PUT, P = 0.009), and thalamus (P = 0.046) were found in PD patients compared with HCs. PD patients showed lower iron content in PUT (P <0.001), RN (P = 0.003), SN (P = 0.017), and caudate nucleus (P = 0.027) than MSA patients, and lower iron content in RN (P = 0.001), PUT (P <0.001), globus pallidus (P = 0.004), SN (P = 0.015), and caudate nucleus (P = 0.001) than PSP patients. The highest diagnostic accuracy distinguishing PD from HCs was observed in SN (AUC: 0.85), and that distinguishing PD from MSA was found in PUT (AUC: 0.90). In addition, the best diagnostic performance was achieved in the RN for distinguishing PD from PSP (AUC: 0.84).
CONCLUSION
Quantitative iron-sensitive MRI could quantitatively detect the iron content of subcortical nuclei in PD and APSs, while it may be insufficient to accurately diagnose PD. Future studies are needed to explore the role of multimodal MRI in the diagnosis of PD.
REGISTRISION
PROSPERO; CRD42022344413.
PubMed: 38809051
DOI: 10.1097/CM9.0000000000003167 -
Acta Pharmaceutica Sinica. B May 2024Parkinson's disease (PD) is a neurodegeneration disease with -synuclein accumulated in the substantia nigra pars compacta (SNpc) and most of the dopaminergic neurons are...
Parkinson's disease (PD) is a neurodegeneration disease with -synuclein accumulated in the substantia nigra pars compacta (SNpc) and most of the dopaminergic neurons are lost in SNpc while patients are diagnosed with PD. Exploring the pathology at an early stage contributes to the development of the disease-modifying strategy. Although the "gut-brain" hypothesis is proposed to explain the underlying mechanism, where the earlier lesioned site in the brain of gastric -synuclein and how -synuclein further spreads are not fully understood. Here we report that caudal raphe nuclei (CRN) are the early lesion site of gastric -synuclein propagating through the spinal cord, while locus coeruleus (LC) and substantia nigra pars compacta (SNpc) were further affected over a time frame of 7 months. Pathological -synuclein propagation CRN leads to neuron loss and disordered neuron activity, accompanied by abnormal motor and non-motor behavior. Potential neuron circuits are observed among CRN, LC, and SNpc, which contribute to the venerability of dopaminergic neurons in SNpc. These results show that CRN is the key region for the gastric -synuclein spread to the midbrain. Our study provides valuable details for the "gut-brain" hypothesis and proposes a valuable PD model for future research on early PD intervention.
PubMed: 38799632
DOI: 10.1016/j.apsb.2024.01.015 -
Research Square May 2024Parkinson's disease (PD) is marked by degeneration in the nigrostriatal dopaminergic pathway, affecting motor control via complex changes in the cortico-basal...
Parkinson's disease (PD) is marked by degeneration in the nigrostriatal dopaminergic pathway, affecting motor control via complex changes in the cortico-basal ganglia-thalamic motor network, including the primary motor cortex (M1). The modulation of M1 neuronal activity by dopaminergic inputs, particularly from the ventral tegmental area (VTA) and substantia nigra pars compacta (SNc), plays a crucial role in PD pathophysiology. This study investigates how nigrostriatal dopaminergic degeneration influences M1 neuronal activity in rats using in vivo calcium imaging. Histological analysis confirmed dopaminergic lesion severity, with high lesion level rats showing significant motor deficits. Levodopa treatment improved fine motor abilities, particularly in high lesion level rats. Analysis of M1 calcium signals based on dopaminergic lesion severity revealed distinct M1 activity patterns. Animals with low dopaminergic lesion showed increased calcium events, while high lesion level rats exhibited decreased activity, partially restored by levodopa. These findings suggest that M1 activity is more sensitive to transient fluctuations in dopaminergic transmission, rather than to chronic high or low dopaminergic signaling. This study underscores the complex interplay between dopaminergic signaling and M1 neuronal activity in PD symptoms development. Further research integrating behavioral and calcium imaging data can elucidate mechanisms underlying motor deficits and therapeutic responses in PD.
PubMed: 38798359
DOI: 10.21203/rs.3.rs-4365911/v1 -
The European Journal of Neuroscience May 2024As opposed to those requiring a single action for reward acquisition, tasks necessitating action sequences demand that animals learn action elements and their sequential...
As opposed to those requiring a single action for reward acquisition, tasks necessitating action sequences demand that animals learn action elements and their sequential order and sustain the behaviour until the sequence is completed. With repeated learning, animals not only exhibit precise execution of these sequences but also demonstrate enhanced smoothness and efficiency. Previous research has demonstrated that midbrain dopamine and its major projection target, the striatum, play crucial roles in these processes. Recent studies have shown that dopamine from the substantia nigra pars compacta (SNc) and the ventral tegmental area (VTA) serve distinct functions in action sequence learning. The distinct contributions of dopamine also depend on the striatal subregions, namely the ventral, dorsomedial and dorsolateral striatum. Here, we have reviewed recent findings on the role of striatal dopamine in action sequence learning, with a focus on recent rodent studies.
PubMed: 38798086
DOI: 10.1111/ejn.16426 -
CNS Neuroscience & Therapeutics May 2024Parkinson's disease (PD) is a degenerative neurological condition marked by the gradual loss of dopaminergic neurons in the substantia nigra pars compacta. The precise... (Review)
Review
BACKGROUND
Parkinson's disease (PD) is a degenerative neurological condition marked by the gradual loss of dopaminergic neurons in the substantia nigra pars compacta. The precise etiology of PD remains unclear, but emerging evidence suggests a significant role for disrupted autophagy-a crucial cellular process for maintaining protein and organelle integrity.
METHODS
This review focuses on the role of non-coding RNAs (ncRNAs) in modulating autophagy in PD. We conducted a comprehensive review of recent studies to explore how ncRNAs influence autophagy and contribute to PD pathophysiology. Special attention was given to the examination of ncRNAs' regulatory impacts in various PD models and patient samples.
RESULTS
Findings reveal that ncRNAs are pivotal in regulating key processes associated with PD progression, including autophagy, α-synuclein aggregation, mitochondrial dysfunction, and neuroinflammation. Dysregulation of specific ncRNAs appears to be closely linked to these pathogenic processes.
CONCLUSION
ncRNAs hold significant therapeutic potential for addressing autophagy-related mechanisms in PD. The review highlights innovative therapeutic strategies targeting autophagy-related ncRNAs and discusses the challenges and prospective directions for developing ncRNA-based therapies in clinical practice. The insights from this study underline the importance of ncRNAs in the molecular landscape of PD and their potential in novel treatment approaches.
Topics: Humans; Parkinson Disease; Autophagy; RNA, Untranslated; Animals
PubMed: 38790149
DOI: 10.1111/cns.14763 -
Molecular Biology Reports May 2024The loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc) is a major pathological hallmark of Parkinson's disease (PD). Orexin B (OXB) has been...
Orexin B protects dopaminergic neurons from 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neurotoxicity associated with reduced extracellular signal-regulated kinase phosphorylation.
BACKGROUND
The loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc) is a major pathological hallmark of Parkinson's disease (PD). Orexin B (OXB) has been reported to promote the growth of DA neurons. However, the roles of OXB in the degeneration of DA neurons still remained not fully clear.
METHODS
An in vivo PD model was constructed by administrating 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in mice. Pole test was performed to investigate the motor function of mice and the number of DA neurons was detected by immunofluorescence (IF). A PD cell model was established by treating SH-SY5Y cells with 1-methyl-4-phenylpyridinium (MPP+). OXB was added to the culture medium 2 h after MPP + treatment. Microscopic analysis was carried out to investigate the function of OXB in the cell model of PD 24 h after MPP + challenge. RNA-Seq analysis of the PD cell model was performed to explore the possible mechanisms. Western blot was used to detect the phosphorylation levels of extracellular signal-regulated kinase (ERK).
RESULTS
OXB significantly decreased the DA neurons death caused by MPTP, alleviated MPP+-induced neurotoxicity in SH-SY5Y cells, and robustly enhanced the weight and motor ability of PD mice. Besides, RNA-Seq analysis demonstrated that the mitogen-activated protein kinase (MAPK) pathway was involved in the pathology of PD. Furthermore, MPP + led to increased levels of phosphorylation of ERK (p-ERK), OXB treatment significantly decreased the levels of p-ERK in MPP+-treated SH-SY5Y cells.
CONCLUSIONS
This study demonstrated that OXB exerts a neuroprotective role associated with reduced ERK phosphorylation in the PD model. This suggests that OXB may have therapeutic potential for treatment of PD.
Topics: Dopaminergic Neurons; Animals; Mice; Phosphorylation; 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Extracellular Signal-Regulated MAP Kinases; Orexins; Humans; Male; Cell Line, Tumor; Disease Models, Animal; Neuroprotective Agents; Mice, Inbred C57BL; Parkinson Disease; 1-Methyl-4-phenylpyridinium; MAP Kinase Signaling System
PubMed: 38787465
DOI: 10.1007/s11033-024-09587-2 -
Cells May 2024Parkinson's disease (PD) is the second-most common neurodegenerative disorder worldwide and is diagnosed based on motor impairments. Non-motor symptoms are also...
Parkinson's disease (PD) is the second-most common neurodegenerative disorder worldwide and is diagnosed based on motor impairments. Non-motor symptoms are also well-recognised in this disorder, and peripheral neuropathy is a frequent but poorly appreciated non-motor sign. Studying how central and peripheral sensory systems are affected can contribute to the development of targeted therapies and deepen our understanding of the pathophysiology of PD. Although the cause of sporadic PD is unknown, chronic exposure to the pesticide rotenone in humans increases the risk of developing the disease. Here, we aimed to investigate whether peripheral neuropathy is present in a traditional model of PD. Mice receiving intrastriatal rotenone showed greatly reduced dopamine terminals in the striatum and a reduction in tyrosine hydroxylase-positive neurons in the and developed progressive motor impairments in hindlimb stepping and rotarod but no change in spontaneous activity. Interestingly, repeated testing using gold-standard protocols showed no change in gut motility, a well-known non-motor symptom of PD. Importantly, we did not observe any change in heat, cold, or touch sensitivity, again based upon repeated testing with well-validated protocols that were statistically well powered. Therefore, this traditional model fails to replicate PD, and our data again reiterate the importance of the periphery to the disorder.
Topics: Animals; Disease Models, Animal; Mice; Parkinson Disease; Rotenone; Mice, Inbred C57BL; Male; Peripheral Nervous System Diseases; Corpus Striatum; Dopamine
PubMed: 38786023
DOI: 10.3390/cells13100799 -
Magnetic Resonance Imaging Sep 2024This study aimed to examine the structural alterations of the deep gray matter (DGM) in the basal ganglia circuitry of Parkinson's disease (PD) patients with freezing of...
OBJECTIVE
This study aimed to examine the structural alterations of the deep gray matter (DGM) in the basal ganglia circuitry of Parkinson's disease (PD) patients with freezing of gait (FOG) using quantitative susceptibility mapping (QSM) and neuromelanin-sensitive magnetic resonance imaging (NM-MRI).
METHODS
Twenty-five (25) PD patients with FOG (PD-FOG), 22 PD patients without FOG (PD-nFOG), and 30 age- and sex-matched healthy controls (HCs) underwent 3-dimensional multi-echo gradient recalled echo and NM-MRI scanning. The mean volume and susceptibility of the DGM on QSM data and the relative contrast (NM) and volume (NM) of the substantia nigra pars compacta on NM-MRI were analyzed among groups. A multiple linear regression analysis was performed to explore the associations of FOG severity with MRI measurements and disease stage.
RESULTS
The PD-FOG group showed higher susceptibility in the bilateral caudal substantia nigra (SN) compared to the HC group. Both the PD-FOG and PD-nFOG groups showed lower volumes than the HC group in the bilateral caudate and putamen as determined from the QSM data. The NM on NM-MRI in the PD-FOG group was significantly lower than in the HC and PD-nFOG groups. Both the PD-FOG and PD-nFOG groups showed significantly decreased NM.
CONCLUSIONS
The PD-FOG patients showed abnormal neostriatum atrophy, increases in iron deposition in the SN, and lower NM. The structural alterations of the DGM in the basal ganglia circuits could lead to the abnormal output of the basal ganglia circuit to trigger the FOG in PD patients.
Topics: Humans; Parkinson Disease; Female; Male; Magnetic Resonance Imaging; Basal Ganglia; Melanins; Aged; Iron; Middle Aged; Gait Disorders, Neurologic; Substantia Nigra; Gray Matter
PubMed: 38777243
DOI: 10.1016/j.mri.2024.05.011 -
Parkinsonism & Related Disorders May 2024Identifying biomarkers reflecting cellular dysfunctions in early Parkinson's disease patients (ePD) is needed to develop targeted therapeutic strategies. We aimed to...
INTRODUCTION
Identifying biomarkers reflecting cellular dysfunctions in early Parkinson's disease patients (ePD) is needed to develop targeted therapeutic strategies. We aimed to determine if cellular energetic dysfunction related to increased brain sodium concentration would be co-located to microstructural alterations and iron deposition in ePD.
METHODS
We prospectively included 12 ePD (mean disease duration 20.0 ± 10.2 months) and 13 healthy controls (HC), scanned with a 7 T H and Na MRI. Complementary voxel-based and region-based assessments were performed, the latter utilizing a high-resolution multimodal template we created (combining quantitative T maps (qT1), transverse relaxation rate (R2*), quantitative magnetic susceptibility mapping (QSM) images) from 200 subjects. This template allowed a precise multiparametric assessment of sodium concentration, QSM, R*, qT, mean diffusivity, and fractional anisotropy values. A two-sided p-value<0.05 was considered statistically significant after the Bonferroni correction.
RESULTS
Relative to HC, ePD showed significantly higher sodium concentration in left Substantia nigra (SN) pars reticulata (46.13 mM ± 3.52 vs 38.60 mM ± 6.10, p = 0.038), a subpart of the SN pars compacta (SNc) and ventral tegmental area, Putamen, Globus Pallidum external, accumbens nucleus and claustrum. Significantly increased QSM and R2* values, and decreased T values, were limited to the Nigrosomes 1 (Nig) and right SNc (all p < 0.05). QSM values in the Nig were significantly correlated to UPDRS-III scores (r = 0.91,p < 0.001).
CONCLUSION
In ePD, brain sodium accumulation was broad and dissociated from iron accumulation. As with iron accumulation, a sodium-related pathophysiological approach could lead to identifying potential new therapeutic agents and deserves further investigation.
PubMed: 38776725
DOI: 10.1016/j.parkreldis.2024.106996