scholarly journals Deciduous DPSCs Ameliorate MPTP-Mediated Neurotoxicity, Sensorimotor Coordination and Olfactory Function in Parkinsonian Mice

2019 ◽  
Vol 20 (3) ◽  
pp. 568 ◽  
Author(s):  
Christopher Simon ◽  
Quan Gan ◽  
Premasangery Kathivaloo ◽  
Nur Mohamad ◽  
Jagadeesh Dhamodharan ◽  
...  
Keyword(s):  
Dopaminergic Neurons ◽  
Neurodegenerative Disorder ◽  
Therapeutic Potential ◽  
Olfactory Function ◽  
Substantia Nigra Pars Compacta ◽  
Sensorimotor Coordination ◽  
Cell Based Therapy ◽  
Effective Delivery ◽  
Mptp Treatment ◽  
The Many

Parkinson’s disease (PD) is a neurodegenerative disorder defined by progressive deterioration of dopaminergic neurons in the substantia nigra pars compacta (SNpc). Dental pulp stem cells (DPSCs) have been proposed to replace the degenerated dopaminergic neurons due to its inherent neurogenic and regenerative potential. However, the effective delivery and homing of DPSCs within the lesioned brain has been one of the many obstacles faced in cell-based therapy of neurodegenerative disorders. We hypothesized that DPSCs, delivered intranasally, could circumvent these challenges. In the present study, we investigated the therapeutic efficacy of intranasally administered DPSCs in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of PD. Human deciduous DPSCs were cultured, pre-labelled with PKH 26, and intranasally delivered into PD mice following MPTP treatment. Behavioural analyses were performed to measure olfactory function and sensorimotor coordination, while tyrosine hydroxylase (TH) immunofluorescence was used to evaluate MPTP neurotoxicity in SNpc neurons. Upon intranasal delivery, degenerated TH-positive neurons were ameliorated, while deterioration in behavioural performances was significantly enhanced. Thus, the intranasal approach enriched cell delivery to the brain, optimizing its therapeutic potential through its efficacious delivery and protection against dopaminergic neuron degeneration.

Effect of Cabergoline on Cognitive Impairments in Transgenic Drosophila Model of Parkinson’s Disease

2020 ◽  
Vol 17 (10) ◽  
pp. 1261-1269
Author(s):  
Yasir Hasan Siddique ◽  
Rahul ◽  
Mantasha Idrisi ◽  
Mohd. Shahid
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Dopaminergic Neurons ◽  
Neurodegenerative Disorder ◽  
Cognitive Impairments ◽  
Alpha Synuclein ◽  
Substantia Nigra Pars Compacta ◽  
Positive Interaction ◽  
Drosophila Model ◽  
Transgenic Drosophila

Background: Parkinson’s disease is a common neurodegenerative disorder characterized by selective loss of dopaminergic neurons in the substantia nigra pars compacta. Introduction: The effects of alpha synuclein, parkin mutation and pharmacological agents have been studied in the Drosophila model. Methods: The effect of cabergoline was studied on the cognitive impairments exhibited by the transgenic Drosophila expressing human alpha-synuclein in the neurons. The PD flies were allowed to feed on the diet having 0.5, 1 and 1.5 μM of cabergoline. Results and Discussion: The exposure of cabergoline not only showed a dose-dependent significant delay in the cognitive impairments but also prevented the loss of dopaminergic neurons. Molecular docking studies showed the positive interaction between cabergoline and alpha-synuclein. Conclusion: The results suggest a protective effect of cabergoline against the cognitive impairments.

Levodopa Therapy for Parkinson's Disease: History, Current Status and Perspectives

2020 ◽  
Vol 19 (8) ◽  
pp. 572-583
Author(s):  
Helle Bogetofte ◽  
Arezo Alamyar ◽  
Morten Blaabjerg ◽  
Morten Meyer
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Side Effects ◽  
Dopaminergic Neurons ◽  
Neurodegenerative Disorder ◽  
Neuroprotective Effect ◽  
Substantia Nigra Pars Compacta ◽  
Current Status ◽  
Current Evidence ◽  
Muscle Rigidity

Parkinson’s Disease (PD) is a neurodegenerative disorder characterized by a preferential degeneration of dopaminergic neurons in the substantia nigra pars compacta. This results in a profound decrease of striatal dopamine (DA) levels, which in turn leads to the cardinal motor symptoms of PD; muscle rigidity, hypo- and bradykinesia and resting tremor. Even 50 years after its initial use, the DA precursor levodopa (L-dopa), is still the most effective medical therapy for the symptomatic treatment of PD. Long-term L-dopa treatment is however, unfortunately associated with undesirable side effects such as motor fluctuations and dyskinesias. Furthermore, despite the disease alleviating effects of L-dopa, it is still discussed whether L-dopa has a neurotoxic or neuroprotective effect on dopaminergic neurons. Here we review the history of L-dopa, including its discovery, development and current use in the treatment of PD. We furthermore review current evidence of the L-dopa-induced side effects and perspectives of L-dopa treatment in PD compared to other established treatments such as DA-agonists and the inhibitors of catechol-o-methyltransferase and monoamine oxidase B.

scholarly journals Genes critical for development and differentiation of dopaminergic neurons are downregulated in Parkinson’s disease

2020 ◽  
Author(s):  
Aditi Verma ◽  
Priya Suresh ◽  
Barathan Gnanabharathi ◽  
Etienne C. Hirsch ◽  
Vijayalakshmi Ravindranath
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Dopaminergic Neurons ◽  
Substantia Nigra Pars Compacta ◽  
Vesicle Recycling ◽  
Expression Of Genes ◽  
Dopamine Biosynthesis ◽  
Mptp Treatment ◽  
Development And Differentiation ◽  
Acute And Chronic Exposure

AbstractWe performed transcriptome analysis using RNA sequencing on substantia nigra pars compacta (SNpc) from mice after acute and chronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment and Parkinson’s disease (PD) patients. Acute and chronic exposure to MPTP resulted in decreased expression of genes involved in sodium channel regulation. However, upregulation of pro-inflammatory pathways was seen after single dose but not after chronic MPTP treatment. Dopamine biosynthesis and synaptic vesicle recycling pathways were downregulated in PD patients and after chronic MPTP treatment in mice. Genes essential for midbrain development and determination of dopaminergic phenotype such as, LMX1B, FOXA1, RSPO2, KLHL1, EBF3, PITX3, RGS4, ALDH1A1, RET, FOXA2, EN1, DLK1, GFRA1, LMX1A, NR4A2, GAP43, SNCA, PBX1, and GRB10 were downregulated in human PD and overexpression of LMX1B rescued MPP+ induced death in SH-SY5Y neurons. Downregulation of gene ensemble involved in development and differentiation of dopaminergic neurons indicate their critical involvement in pathogenesis and progression of human PD.

scholarly journals Exosomes in Parkinson: Revisiting Their Pathologic Role and Potential Applications

2022 ◽  
Vol 15 (1) ◽  
pp. 76
Author(s):  
Yassamine Ouerdane ◽  
Mohamed Y. Hassaballah ◽  
Abdalrazeq Nagah ◽  
Tarek M. Ibrahim ◽  
Hosny A. H. Mohamed ◽  
...  
Keyword(s):  
Dopaminergic Neurons ◽  
Neurodegenerative Disorder ◽  
Cell Communication ◽  
Lewy Bodies ◽  
Substantia Nigra Pars Compacta ◽  
Intracellular Membrane ◽  
Pyrin Domain ◽  
Potential Applications ◽  
Pathological Determinant ◽  
And Oxidative Stress

Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by bradykinesia, rigidity, and tremor. Considerable progress has been made to understand the exact mechanism leading to this disease. Most of what is known comes from the evidence of PD brains’ autopsies showing a deposition of Lewy bodies—containing a protein called α-synuclein (α-syn)—as the pathological determinant of PD. α-syn predisposes neurons to neurotoxicity and cell death, while the other associated mechanisms are mitochondrial dysfunction and oxidative stress, which are underlying precursors to the death of dopaminergic neurons at the substantia nigra pars compacta leading to disease progression. Several mechanisms have been proposed to unravel the pathological cascade of these diseases; most of them share a particular similarity: cell-to-cell communication through exosomes (EXOs). EXOs are intracellular membrane-based vesicles with diverse compositions involved in biological and pathological processes, which their secretion is driven by the NLR family pyrin domain-containing three proteins (NLRP3) inflammasome. Toxic biological fibrils are transferred to recipient cells, and the disposal of damaged organelles through generating mitochondrial-derived vesicles are suggested mechanisms for developing PD. EXOs carry various biomarkers; thus, they are promising to diagnose different neurological disorders, including neurodegenerative diseases (NDDs). As nanovesicles, the applications of EXOs are not only restricted as diagnostics but also expanded to treat NDDs as therapeutic carriers and nano-scavengers. Herein, the aim is to highlight the potential incrimination of EXOs in the pathological cascade and progression of PD and their role as biomarkers and therapeutic carriers for diagnosing and treating this neuro-debilitating disorder.

scholarly journals Transcriptome responses to reduced dopamine in the Substantia Nigra Pars Compacta reveals a potential protective role for dopamine

2018 ◽  
Author(s):  
M. Koltun ◽  
K. Cichewicz ◽  
J.T. Gibbs ◽  
M. Darvas ◽  
J. Hirsh
Keyword(s):  
Substantia Nigra ◽  
Dopaminergic Neurons ◽  
Neurodegenerative Disorder ◽  
Brain Regions ◽  
Protective Role ◽  
Differentially Expressed ◽  
Substantia Nigra Pars Compacta ◽  
Selective Depletion ◽  
Transcriptional Changes ◽  
Dopaminergic Genes

AbstractParkinson’s Disease (PD), is a neurodegenerative disorder affecting both cognitive and motor functions. It is characterized by decreased brain dopamine (DA) and a selective and progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNc), whereas dopaminergic neurons in the ventral tegmental area (VTA) show reduced vulnerability. The majority of animal models of PD are genetic lesion or neurotoxin exposure models that lead to death of dopaminergic neurons. Here we use a DAT:TH KO mouse model that by inactivation of the tyrosine hydroxylase (Th) gene in dopamine transporter-expressing neurons, causes selective depletion of striatal dopamine without affecting DA neuron survival. We analyzed transcriptome responses to decreased DA in both pre- and post-synaptic dopaminergic brain regions of DAT:TH KO animals. We detected only few differentially expressed genes in the post-synaptic regions as a function of DA deficiency. This suggests that the broad striatal transcriptional changes in neurodegeneration-based PD models are not direct effects of DA depletion, but are rather a result of DA neuronal death. However, we find a number of dopaminergic genes differentially expressed in SNc, and to a lesser extent in VTA, as a function of DA deficiency, providing evidence for a DA-dependent feedback loop. Of particular interest, expression ofNr4a2, a crucial transcription factor maintaining DA neuron identity, is significantly decreased in SNc, but not VTA, of DAT:TH KO mice, implying a potential protective role for DA in the SNc.

The Therapeutic Potential of Quercetin in Parkinson’s Disease: Insights into its Molecular and Cellular Regulation

2020 ◽  
Vol 21 (5) ◽  
pp. 509-518 ◽  
Author(s):  
Omid Reza Tamtaji ◽  
Tooba Hadinezhad ◽  
Maryam Fallah ◽  
Arash Rezaei Shahmirzadi ◽  
Mohsen Taghizadeh ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neurodegenerative Disorder ◽  
Therapeutic Potential ◽  
Substantia Nigra Pars Compacta ◽  
Cellular Regulation ◽  
Pathophysiological Role ◽  
Underlying Mechanisms ◽  
Treatment Procedures

Parkinson’s disease (PD) is a chronic and progressive neurodegenerative disorder characterized by the progressive death of dopaminergic neurons in the substantia nigra pars compacta (SNc). PD is a multifactorial disorder, with several different factors being suggested to play a synergistic pathophysiological role, including oxidative stress, autophagy, underlying pro-inflammatory events and neurotransmitters abnormalities. Overall, PD can be viewed as the product of a complex interaction of environmental factors acting on a given genetic background. The importance of this subject has gained more attention to discover novel therapies to prevent as well as treat PD. According to previous research, drugs used to treat PD have indicated significant limitations. Therefore, the role of flavonoids has been extensively studied in PD treatment. Quercetin, a plant flavonol from the flavonoid group, has been considered as a supplemental therapy for PD. Quercetin has pharmacological functions in PD by controlling different molecular pathways. Although few studies intended to evaluate the basis for the use of quercetin in the context of PD have been conducted so far, at present, there is very little evidence available addressing the underlying mechanisms of action. Various principal aspects of these treatment procedures remain unknown. Here, currently existing knowledge supporting the use of quercetin for the clinical management of PD has been reviewed.

scholarly journals Toxicity of Necrostatin-1 in Parkinson’s Disease Models

Antioxidants ◽  
2020 ◽  
Vol 9 (6) ◽  
pp. 524
Author(s):  
Eva Alegre-Cortés ◽  
Alicia Muriel-González ◽  
Saray Canales-Cortés ◽  
Elisabet Uribe-Carretero ◽  
Guadalupe Martínez-Chacón ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Cell Death ◽  
Dopaminergic Neurons ◽  
Neurodegenerative Disorder ◽  
Neuronal Loss ◽  
Environmental Toxins ◽  
Substantia Nigra Pars Compacta ◽  
Mitochondrial Morphology ◽  
Primary Fibroblasts

Parkinson’s disease (PD) is a neurodegenerative disorder that is characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta. This neuronal loss, inherent to age, is related to exposure to environmental toxins and/or a genetic predisposition. PD-induced cell death has been studied thoroughly, but its characterization remains elusive. To date, several types of cell death, including apoptosis, autophagy-induced cell death, and necrosis, have been implicated in PD progression. In this study, we evaluated necroptosis, which is a programmed type of necrosis, in primary fibroblasts from PD patients with and without the G2019S leucine-rich repeat kinase 2 (LRRK2) mutation and in rotenone-treated cells (SH-SY5Y and fibroblasts). The results showed that programmed necrosis was not activated in the cells of PD patients, but it was activated in cells exposed to rotenone. Necrostatin-1 (Nec-1), an inhibitor of the necroptosis pathway, prevented rotenone-induced necroptosis in PD models. However, Nec-1 affected mitochondrial morphology and failed to protect mitochondria against rotenone toxicity. Therefore, despite the inhibition of rotenone-mediated necroptosis, PD models were susceptible to the effects of both Nec-1 and rotenone.

scholarly journals Inflammation in Parkinson’s Disease: Mechanisms and Therapeutic Implications

Cells ◽  
2020 ◽  
Vol 9 (7) ◽  
pp. 1687 ◽  
Author(s):  
Marta Pajares ◽  
Ana I. Rojo ◽  
Gina Manda ◽  
Lisardo Boscá ◽  
Antonio Cuadrado
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Dopaminergic Neurons ◽  
Transcriptional Control ◽  
Neurodegenerative Disorder ◽  
Substantia Nigra Pars Compacta ◽  
Therapeutic Implications ◽  
Cellular Mediators ◽  
Molecular Bases

Parkinson’s disease (PD) is a common neurodegenerative disorder primarily characterized by the death of dopaminergic neurons that project from the substantia nigra pars compacta. Although the molecular bases for PD development are still little defined, extensive evidence from human samples and animal models support the involvement of inflammation in onset or progression. However, the exact trigger for this response remains unclear. Here, we provide a systematic review of the cellular mediators, i.e., microglia, astroglia and endothelial cells. We also discuss the genetic and transcriptional control of inflammation in PD and the immunomodulatory role of dopamine and reactive oxygen species. Finally, we summarize the preclinical and clinical approaches targeting neuroinflammation in PD.

Frontal Cognitive Impairments and Saccadic Deficits in Low-Dose MPTP-Treated Monkeys

1999 ◽  
Vol 81 (2) ◽  
pp. 858-874 ◽  
Author(s):  
Hamutal Slovin ◽  
Moshe Abeles ◽  
Eilon Vaadia ◽  
Iris Haalman ◽  
Yifat Prut ◽  
...  
Keyword(s):  
Dopaminergic Neurons ◽  
Low Dose ◽  
Movement Time ◽  
Cognitive Impairments ◽  
Substantia Nigra Pars Compacta ◽  
Delayed Response ◽  
Primate Model ◽  
Mptp Treatment ◽  
Perseverative Errors ◽  
Response Task

Frontal cognitive impairments and saccadic deficits in low-dose MPTP-treated monkeys. There is considerable overlap between the cognitive deficits observed in humans with frontal lobe damage and those described in patients with Parkinson’s disease. Similar frontal impairments have been found in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) primate model of Parkinsonism. Here we provide quantitative documentation of the cognitive, oculomotor, and skeletomotor dysfunctions of monkeys trained on a frontal task and treated with low-doses (LD) of MPTP. Two rhesus monkeys were trained to perform a spatial delayed-response task with frequent alternations between two behavioral modes (go andno-go). After control recordings, the monkeys were treated with one placebo and successive LD MPTP courses. Monkey Cdeveloped motor Parkinsonian signs after a fourth course of medium-dose (MD) MPTP and later was treated with combined dopaminergic therapy (CDoT). There were no gross motor changes after the LD MPTP courses, and the average movement time (MT) did not increase. However, reaction time (RT) increased significantly. Both RT and MT were further increased in the symptomatic state, under CDoT. Self-initiated saccades became hypometric after LD MPTP treatments and their frequency decreased. Visually triggered saccades were affected to a lesser extent by the LD MPTP treatments. All saccadic parameters declined further in the symptomatic state and improved partially during CDoT. The number ofgo mode (no-response, location, and early release) errors increased after MPTP treatment. The monkeys made more perseverative errors while switching from the go to the no-gomode. Saccadic eye movement patterns suggest that frontal deficits were involved in most observed errors. CDoT had a differential effect on the behavioral errors. It decreased omission errors but did not improve location errors or perseverative errors. Tyrosine hydroxylase immunohistochemistry showed moderate (∼70–80%) reduction in the number of dopaminergic neurons in the substantia nigra pars compacta after MPTP treatment. These results show that cognitive and motor disorders can be dissociated in the LD MPTP model and that cognitive and oculomotor impairments develop before the onset of skeletal motor symptoms. The behavioral and saccadic deficits probably result from the marked reduction of dopaminergic neurons in the midbrain. We suggest that these behavioral changes result from modified neuronal activity in the frontal cortex.

scholarly journals Alpha-Synuclein Aggregation in Parkinson's Disease

2021 ◽  
Vol 8 ◽  
Author(s):  
E. Srinivasan ◽  
G. Chandrasekhar ◽  
P. Chandrasekar ◽  
K. Anbarasu ◽  
A. S. Vickram ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Dopaminergic Neurons ◽  
Genetic Factors ◽  
Neurodegenerative Disorder ◽  
Neuronal Loss ◽  
Alpha Synuclein ◽  
Substantia Nigra Pars Compacta ◽  
Vulnerability Factors ◽  
Alpha Synuclein Aggregation

Parkinson's disease (PD), a neurodegenerative disorder characterized by distinct aging-independent loss of dopaminergic neurons in substantia nigra pars compacta (SNpc) region urging toward neuronal loss. Over the decade, various key findings from clinical perspective to molecular pathogenesis have aided in understanding the genetics with assorted genes related with PD. Subsequently, several pathways have been incriminated in the pathogenesis of PD, involving mitochondrial dysfunction, protein aggregation, and misfolding. On the other hand, the sporadic form of PD cases is found with no genetic linkage, which still remain an unanswered question? The exertion in ascertaining vulnerability factors in PD considering the genetic factors are to be further dissevered in the forthcoming decades with advancement in research studies. One of the major proponents behind the prognosis of PD is the pathogenic transmutation of aberrant alpha-synuclein protein into amyloid fibrillar structures, which actuates neurodegeneration. Alpha-synuclein, transcribed by SNCA gene is a neuroprotein found predominantly in brain. It is implicated in the modulation of synaptic vesicle transport and eventual release of neurotransmitters. Due to genetic mutations and other elusive factors, the alpha-synuclein misfolds into its amyloid form. Therefore, this review aims in briefing the molecular understanding of the alpha-synuclein associated with PD.

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