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Journal of Parkinson's Disease 2021The hallmark of Parkinson's disease is depletion of dopamine in the basal ganglia. Models of Parkinson's disease include dopamine as a contributor to disease... (Meta-Analysis)
Meta-Analysis
BACKGROUND
The hallmark of Parkinson's disease is depletion of dopamine in the basal ganglia. Models of Parkinson's disease include dopamine as a contributor to disease progression. However, intraneuronal levels of dopamine have not been reported.
OBJECTIVE
Meta-analytic methods were utilized to determine intracellular dopamine levels in Parkinson's disease.
METHODS
A systematic review of the literature and frequentist meta-analyses were performed. Dopamine levels were scaled for cell and axon numbers as well as VMAT2 protein levels.
RESULTS
Reduced tissue dopamine, dopaminergic cell bodies and VMAT2 protein were confirmed. The ratio of Parkinson's to normal brain intracellular dopamine scaled for either cell or axon number, each with VMAT2 level in the caudate ranged from 1.49 to 1.87 (p = 0.51 and p = 0.12, respectively) and in the putamen from 0.75 to 4.61 (p = 0.40 and 0.001, respectively).
CONCLUSION
Free, intracellular dopamine levels are not reduced in Parkinson's disease compared to normals to a similar degree as are total tissue concentrations, supporting the relevance of modulating VMAT2, neuromelanin and/or dopamine synthesis as rational neuroprotective strategies.
Topics: Basal Ganglia; Dopamine; Dopaminergic Neurons; Humans; Parkinson Disease; Putamen
PubMed: 34024786
DOI: 10.3233/JPD-212715 -
Frontiers in Pharmacology 2021Parkinson's disease (PD) is a common neurodegenerative disease featured by progressive degeneration of nigrostriatal dopaminergic neurons (DA) accompanied with motor... (Review)
Review
Parkinson's disease (PD) is a common neurodegenerative disease featured by progressive degeneration of nigrostriatal dopaminergic neurons (DA) accompanied with motor function impairment. Accumulating evidence has demonstrated that natural compounds from herbs have potent anti-PD efficacy in PD models. Among those compounds, resveratrol, a polyphenol found in many common plants and fruits, is more effective against PD. Resveratrol has displayed a potent neuroprotective efficacy in several PD animal models. However, there is still no systematic analysis of the quality of methodological design of these studies, nor of their results. In this review, we retrieved and analyzed 18 studies describing the therapeutic effect of resveratrol on PD animal models. There are 5 main kinds of PD rodent models involved in the 18 articles, including chemical-induced (MPTP, rotenone, 6-OHDA, paraquat, and maneb) and transgenic PD models. The neuroprotective mechanisms of resveratrol were mainly concentrated on the antioxidation, anti-inflammation, ameliorating mitochondrial dysfunction, and motor function. We discussed the disadvantages of different PD animal models, and we used meta-analysis approach to evaluate the results of the selected studies and used SYRCLE's risk of bias tool to evaluate the methodological quality. Our analytical approach minimized the bias of different studies. We have also summarized the pharmacological mechanisms of resveratrol on PD models as reported by the researchers. The results of this study support the notion that resveratrol has significant neuroprotective effects on different PD models quantified using qualitative and quantitative methods. The collective information in our review can guide researchers to further plan their future experiments without any hassle regarding preclinical and clinical studies. In addition, this collective assessment of animal studies can provide a qualitative analysis of different PD animal models, either to guide further testing of these models or to avoid unnecessary duplication in their future research.
PubMed: 33967780
DOI: 10.3389/fphar.2021.644219 -
Current Neuropharmacology 2022Parkinson's disease (PD) is the second most common neurodegenerative disease and is characterized by a significant decrease in dopamine levels, caused by progressive...
Parkinson's disease (PD) is the second most common neurodegenerative disease and is characterized by a significant decrease in dopamine levels, caused by progressive degeneration of the dopaminergic neurons in the nigrostriatal pathway. Multiple mechanisms have been implicated in its pathogenesis, including oxidative stress, neuroinflammation, protein aggregation, mitochondrial dysfunction, insufficient support for neurotrophic factors and cell apoptosis. The absence of treatments capable of slowing or stopping the progression of PD has increased the interest in the natural antioxidant substances present in the diet, since they have multiple beneficial properties and it is possible that they can influence the mechanisms responsible for the dysfunction and death of dopaminergic neurons. Thus, the purpose of this systematic review is to analyze the results obtained in a set of studies carried out in the last years, which describe the neuroprotective, antioxidant and regenerative functions of some naturally occurring antioxidants in experimental models of PD. The results show that the exogenous no enzymatic antioxidants can significantly modify the biochemical and behavioral mechanisms that contribute to the pathophysiology of Parkinsonism in experimental animals. Therefore, it is possible that they may contribute to effective neuroprotection by providing a significant improvement in neuropathological markers. In conclusion, the results of this review suggest that exogenous antioxidants can be promising therapeutic candidates for the prevention and treatment of PD.
Topics: Animals; Antioxidants; Disease Models, Animal; Dopamine; Neurodegenerative Diseases; Neuroprotective Agents; Parkinson Disease
PubMed: 33882808
DOI: 10.2174/1570159X19666210421092725 -
Experimental and Therapeutic Medicine Jun 2021Previous studies have reported that ginsenoside-Rg1 (G-Rg1) was able to mitigate the loss of dopaminergic neurons in animal models of Parkinson's disease (PD). The...
Previous studies have reported that ginsenoside-Rg1 (G-Rg1) was able to mitigate the loss of dopaminergic neurons in animal models of Parkinson's disease (PD). The present study provided a systematic review and meta-analysis of preclinical studies to pool current evidence on the effect of G-Rg1 on neurogenesis in the treatment of PD. Eligible studies were identified through a search from six databases: PubMed, EMBASE, Web of Science, VIP, Chinese National Knowledge Infrastructure and the Wanfang database. Primary outcomes were tyrosine hydroxylase (TH)-positive cells in the nigra, Nissl staining-positive cells in the nigra, pole test time and dopamine (DA) levels in the striatum. A total of 18 eligible studies were identified, involving 343 animals. Of these, 13 reported a significant relationship between G-Rg1 and improved TH-positive cells in the nigra compared with the control group (P<0.00001). Furthermore, 3 studies reported a significant relationship between G-Rg1 and improved Nissl-positive cells in the nigra compared with the control group (P<0.00001). In addition, 4 studies reported a significant effect of G-Rg1 to reduce the total pole test time compared with that in the control group (P=0.001). A total of 3 studies indicated a significant association between G-Rg1 and improved DA levels in the striatum compared with the control group (P<0.00001). These results suggested that G-Rg1 has positive effects in attenuating damage in models of PD, and thus, it is a potential candidate neuroprotective drug for human PD.
PubMed: 33850524
DOI: 10.3892/etm.2021.9984 -
International Immunopharmacology Jun 2021Parkinson's disease is a progressive neurodegenerative disease associated with a loss of dopaminergic neurons in the substantia nigra of the brain. Neuroinflammation,...
Parkinson's disease is a progressive neurodegenerative disease associated with a loss of dopaminergic neurons in the substantia nigra of the brain. Neuroinflammation, another hallmark of the disease, is thought to play an important role in the neurodegenerative process. While mitigating neuroinflammation could prove beneficial for Parkinson's disease, identifying the most relevant biological processes and pharmacological targets as well as drugs to modulate them remains highly challenging. The present study aimed to better understand the protein network behind neuroinflammation in Parkinson's disease and to prioritize possible targets for its pharmacological modulation. We first used text-mining to systematically collect the proteins significantly associated to Parkinson's disease neuroinflammation over the scientific literature. The functional interaction network formed by these proteins was then analyzed by integrating functional enrichment, network topology analysis and drug-protein interaction analysis. We identified 57 proteins significantly associated to neuroinflammation in Parkinson's disease. Toll-like Receptor Cascades as well as Interleukin 4, Interleukin 10 and Interleukin 13 signaling appeared as the most significantly enriched biological processes. Protein network analysis using STRING and CentiScaPe identified 8 proteins with the highest ability to control these biological processes underlying neuroinflammation, namely caspase 1, heme oxygenase 1, interleukin 1beta, interleukin 4, interleukin 6, interleukin 10, tumor necrosis factor alpha and toll-like receptor 4. These key proteins were indexed to be targetable by a total of 38 drugs including 27 small compounds 11 protein-based therapies. In conclusion, our study highlights key proteins in Parkinson's disease neuroinflammation as well as pharmacological compounds acting on them. As such, it may facilitate the prioritization of biomarkers for the development of diagnostic, target-engagement assessment and therapeutic tools against Parkinson's disease.
Topics: Animals; Brain; Humans; Inflammation; Parkinson Disease; Protein Interaction Maps
PubMed: 33756233
DOI: 10.1016/j.intimp.2021.107526 -
Frontiers in Neural Circuits 2021The globus pallidus externa (GPe) functions as a central hub in the basal ganglia for processing motor and non-motor information through the creation of complex...
The globus pallidus externa (GPe) functions as a central hub in the basal ganglia for processing motor and non-motor information through the creation of complex connections with the other basal ganglia nuclei and brain regions. Recently, with the adoption of sophisticated genetic tools, substantial advances have been made in understanding the distinct molecular, anatomical, electrophysiological, and functional properties of GPe neurons and non-neuronal cells. Impairments in dopamine transmission in the basal ganglia contribute to Parkinson's disease (PD), the most common movement disorder that severely affects the patients' life quality. Altered GPe neuron activity and synaptic connections have also been found in both PD patients and pre-clinical models. In this review, we will summarize the main findings on the composition, connectivity and functionality of different GPe cell populations and the potential GPe-related mechanisms of PD symptoms to better understand the cell type and circuit-specific roles of GPe in both normal and PD conditions.
Topics: Basal Ganglia; Dopamine; Globus Pallidus; Humans; Neurons; Parkinson Disease
PubMed: 33737869
DOI: 10.3389/fncir.2021.645287 -
Frontiers in Aging Neuroscience 2021Parkinson's disease (PD) is one of the most common neurodegenerative maladies with unforeseen complex pathologies. While this neurodegenerative disorder's neuropathology...
Failure of Glial Cell-Line Derived Neurotrophic Factor (GDNF) in Clinical Trials Orchestrated By Reduced NR4A2 (NURR1) Transcription Factor in Parkinson's Disease. A Systematic Review.
Parkinson's disease (PD) is one of the most common neurodegenerative maladies with unforeseen complex pathologies. While this neurodegenerative disorder's neuropathology is reasonably well known, its etiology remains a mystery, making it challenging to aim therapy. Glial cell-line derived neurotrophic factor (GDNF) remains an auspicious therapeutic molecule for treating PD. Neurotrophic factor derived from glial cell lines is effective in rodents and nonhuman primates, but clinical findings have been equivocal. Laborious exertions have been made over the past few decades to improve and assess GDNF in treating PD (clinical studies). Definitive clinical trials have, however, failed to demonstrate a survival advantage. Consequently, there seemed to be a doubt as to whether GDNF has merit in the potential treatment of PD. The purpose of this cutting edge review is to speculate as to why the clinical trials have failed to meet the primary endpoint. We introduce a hypothesis, "Failure of GDNF in clinical trials succumbed by nuclear receptor-related factor 1 (Nurr1) shortfall." We demonstrate how Nurr1 binds to GDNF to induce dopaminergic neuron synthesis. Due to its undisputable neuro-protection aptitude, we display Nurr1 (also called Nr4a2) as a promising therapeutic target for PD.
PubMed: 33716718
DOI: 10.3389/fnagi.2021.645583 -
Journal of Neuromuscular Diseases 2021Parkinson's disease (PD) is a disabling neurological condition characterized by the loss of dopaminergic neurons. Currently, the treatment for PD is symptomatic and...
Parkinson's disease (PD) is a disabling neurological condition characterized by the loss of dopaminergic neurons. Currently, the treatment for PD is symptomatic and compensates for the endogenous loss of dopamine production. In cases where the pharmacological therapy is only partly beneficial or results in major wearing-off complications, surgical interventions such as deep brain stimulation may be an alternative treatment. The disease cause often remains unknown, but in some patients, a monogenic cause can be identified. Mutations in at least six genes, LRRK2, SNCA, and VPS35 (dominant forms) or Parkin/PRKN, PINK1, and DJ1/PARK7 (recessive forms) have been unequivocally linked to PD pathogenesis. We here systematically screened 8,576 publications on these monogenic PD forms. We identified 2,226 mutation carriers from 456 papers. Levodopa was the most widely applied treatment; only 34 patients were indicated to be untreated at the time of reporting. Notably, detailed treatment data was rarely mentioned including response quantification (good, moderate, minimal) in 951 and/or dose in 293 patients only. Based on available data, levodopa showed an overall good outcome, especially in LRRK2, VPS35, Parkin, and PINK1 mutation carriers ("good" response in 94.6-100%). Side effects of levodopa therapy were reported in ∼15-40%of levodopa-treated patients across genes with dyskinesias as the most frequent one. Non-levodopa medication was indicated to be administered to <200 patients with mainly good outcome. Only a few reports were available on outcomes of brain surgery. Here, most mutation carriers showed a good response. Importantly, none of the available treatments is harmful to one genetic form but effective in another one. In the light of different medication schemes, the progressive nature of PD, and side effects, an improvement of therapeutic options for PD is warranted including a treatabolome database to guide clinicians in treatment decisions. Further, novel disease-cause-modifying drugs are needed.
Topics: Antiparkinson Agents; Humans; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Levodopa; Mutation; Parkinson Disease; Protein Deglycase DJ-1; Protein Kinases; Ubiquitin-Protein Ligases; Vesicular Transport Proteins; alpha-Synuclein
PubMed: 33459660
DOI: 10.3233/JND-200598 -
Frontiers in Aging Neuroscience 2020Bone marrow stromal cells (BMSCs) has been reported to have beneficial effects in improving behavioral deficits, and rescuing dopaminergic neuron loss in rodent models...
Bone marrow stromal cells (BMSCs) has been reported to have beneficial effects in improving behavioral deficits, and rescuing dopaminergic neuron loss in rodent models of Parkinson's disease (PD). However, their pooled effects for dopaminergic neuron have yet to be described. To review the neuroprotective effect of naïve BMSCs in rodent models of PD. The PubMed, EMBASE, and Web of Science databases were searched up to September 30, 2020. Inclusion criteria according to PICOS criteria were as follows: (1) population: rodents; (2) intervention: unmodified BMSCs; (3) comparison: not specified; (4) primary outcome: tyrosine hydroxylase level in the substantia nigra pars compacta and rotational behavior; secondary outcome: rotarod test, and limb function; (5) study: experimental studies. Multiple prespecified subgroup and meta-regression analysis were conducted. Following quality assessment, random effects models were used for this meta-analysis. Twenty-seven animal studies were included. The median quality score was 4.7 (interquartile range, 2-8). Overall standardized mean difference between animals treated with naïve BMSCs and controls was 2.79 (95% confidence interval: 1.70, 3.87; < 0.001) for densitometry of tyrosine hydroxylase-positive staining; -1.54 (95% confidence interval: -2.11, -0.98; < 0.001) for rotational behavior. Significant heterogeneity among studies was observed. Results of this meta-analysis suggest that naïve BMSCs therapy increased dopaminergic neurons and ameliorated behavioral deficits in rodent models of PD.
PubMed: 33362527
DOI: 10.3389/fnagi.2020.539933 -
Acta Neuropsychiatrica Feb 2021Vitamin D deficiency may be a clinical problem in patients with addictions. The authors systematically searched for studies addressing vitamin D and addiction and...
OBJECTIVE
Vitamin D deficiency may be a clinical problem in patients with addictions. The authors systematically searched for studies addressing vitamin D and addiction and develop a hypothesis which can direct future research of the possible mechanistic role of vitamin D in the process of addiction.
METHODS
Systematic review of the literature found in PubMed and EMBASE followed by narrative review combined with clinical experiences leading to hypotheses for future research.
RESULTS
Only five articles were identified about a role of vitamin D in the pathophysiology of addiction. Their results are in line with a possible influence of vitamin D in dopaminergic transmission. The cerebral vitamin D status depends on the functionality of genetic variants of vitamin D receptor and other involved genes. Routine serum calcidiol levels may not adequately reflect cerebral vitamin D status. Uncertainty exists regarding appropriate calcidiol blood levels and proper dosages for affecting the central nervous system (CNS).
CONCLUSIONS
The putative pathophysiological role of vitamin D in substance abuse has been insufficiently studied which calls to more studies how to measure cerebral vitamin D status in clinical practice. Research is indicated whether vitamin D supplementation should use higher dosages and aim to reach higher calcidiol serum levels. Measuring dopaminergic functioning within the prefrontal cortex as reflected by neuropsychological tests selected as suitable could be a appropriate proxy for the cerebral vitamin D status when studying the pharmacogenomics of this functionality in patients.
Topics: Adult; Alcoholism; Animals; Behavior, Addictive; Calcifediol; Central Nervous System; Dopaminergic Neurons; Female; Humans; Male; Middle Aged; Models, Animal; Pharmacogenetics; Polymorphism, Single Nucleotide; Rats; Receptors, Calcitriol; Vitamin D; Vitamin D Deficiency
PubMed: 33183376
DOI: 10.1017/neu.2020.41