scholarly journals Time-Course of Alterations in the Endocannabinoid System after Viral-Mediated Overexpression of α-Synuclein in the Rat Brain

Molecules ◽  
2022 ◽  
Vol 27 (2) ◽  
pp. 507
Author(s):  
Rachel Kelly ◽  
Alexis-Pierre Bemelmans ◽  
Charlène Joséphine ◽  
Emmanuel Brouillet ◽  
Declan P. McKernan ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Rat Brain ◽  
Time Course ◽  
Mrna Level ◽  
Endocannabinoid System ◽  
Receptor Expression ◽  
Nigrostriatal Pathway ◽  
Cannabinoid System ◽  
Post Surgery

Since the discovery of α-synuclein as the major component in Lewy bodies, research into this protein in the context of Parkinson’s disease pathology has been exponential. Cannabinoids are being investigated as potential therapies for Parkinson’s disease from numerous aspects, but still little is known about the links between the cannabinoid system and the pathogenic α-synuclein protein; understanding these links will be necessary if cannabinoid therapies are to reach the clinic in the future. Therefore, the aim of this study was to investigate the time-course of alterations in components of the endocannabinoid system after viral-mediated α-synuclein overexpression in the rat brain. Rats were given unilateral intranigral injections of AAV-GFP or AAV-α-synuclein and sacrificed 4, 8 and 12 weeks later for qRT-PCR and liquid chromatography–mass spectrometry analyses of the endocannabinoid system, in addition to histological visualization of α-synuclein expression along the nigrostriatal pathway. As anticipated, intranigral delivery of AAV-α-synuclein induced widespread overexpression of human α-synuclein in the nigrostriatal pathway, both at the mRNA level and the protein level. However, despite this profound α-synuclein overexpression, we detected no differences in CB1 or CB2 receptor expression in the nigrostriatal pathway; however, interestingly, there was a reduction in the expression of neuroinflammatory markers. Furthermore, there was a reduction in the levels of the endocannabinoid 2-AG and the related lipid immune mediator OEA at week 12 post-surgery, indicating that α-synuclein overexpression triggers dysregulation of the endocannabinoid system. Although this research does show that the endocannabinoid system is impacted by α-synuclein, further research is necessary to more comprehensively understand the link between the cannabinoid system and the α-synuclein aspect of Parkinson’s disease pathology in order for cannabinoid-based therapies to be feasible for the treatment of this disease in the coming years.

Sensitive and accurate determination of neurotransmitters from in vivo rat brain microdialysate of Parkinson's disease using in situ ultrasound-assisted derivatization dispersive liquid–liquid microextraction by UHPLC-MS/MS

RSC Advances ◽  
2016 ◽  
Vol 6 (110) ◽  
pp. 108635-108644 ◽  
Author(s):  
Xian-En Zhao ◽  
Yongrui He ◽  
Ping Yan ◽  
Na Wei ◽  
Renjun Wang ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Rat Brain ◽  
Accurate Determination ◽  
Ultrasound Assisted ◽  
Dispersive Liquid Liquid Microextraction ◽  
Liquid Microextraction

In situ UA-DDLLME coupled with UHPLC-MS/MS has been developed for simultaneous determination of neurotransmitters and baicalein from Parkinson's disease rats.

Time course of changes in striatal dopamine transporters and D2 receptors with specific iodinated markers in a rat model of Parkinson's disease

Synapse ◽  
1999 ◽  
Vol 31 (2) ◽  
pp. 134-139 ◽  
Author(s):  
Sylvie Chalon ◽  
Patrick Emond ◽  
Sylvie Bodard ◽  
Marie-Paule Vilar ◽  
Cynthia Thiercelin ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Rat Model ◽  
Time Course ◽  
D2 Receptors ◽  
Striatal Dopamine ◽  
Dopamine Transporters

scholarly journals Axial Impairment Following Deep Brain Stimulation in Parkinson’s Disease: A Surgicogenomic Approach

2021 ◽  
pp. 1-12
Author(s):  
Naomi P. Visanji ◽  
Mahdi Ghani ◽  
Eric Yu ◽  
Erfan Ghani Kakhki ◽  
Christine Sato ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Deep Brain Stimulation ◽  
Brain Stimulation ◽  
Surgical Outcome ◽  
Polygenic Risk Score ◽  
Post Surgery ◽  
Daily Dose ◽  
Levodopa Equivalent Daily Dose ◽  
Deep Brain

Background: Postoperative outcome following deep brain stimulation (DBS) of the subthalamic nucleus is variable, particularly with respect to axial motor improvement. We hypothesized a genetic underpinning to the response to surgical intervention, termed “surgicogenomics”. Objective: We aimed to identify genetic variants associated with clinical heterogeneity in DBS outcome of Parkinson’s disease (PD) patients that could then be applied clinically to target selection leading to improved surgical outcome. Methods: Retrospective clinical data was extracted from 150 patient’s charts. Each individual was genotyped using the genome-wide NeuroX array tailored to study neurologic diseases. Genetic data were clustered based on surgical outcome assessed by comparing pre- and post-operative scores of levodopa equivalent daily dose and axial impairment at one and five years post-surgery. Allele frequencies were compared between patients with excellent vs. moderate/poor outcomes grouped using a priori defined cut-offs. We analyzed common variants, burden of rare coding variants, and PD polygenic risk score. Results: NeuroX identified 2,917 polymorphic markers at 113 genes mapped to known PD loci. The gene-burden analyses of 202 rare nonsynonymous variants suggested a nominal association of axial impairment with 14 genes (most consistent with CRHR1, IP6K2, and PRSS3). The strongest association with surgical outcome was detected between a reduction in levodopa equivalent daily dose and common variations tagging two linkage disequilibrium blocks with SH3GL2. Conclusion: Once validated in independent populations, our findings may be implemented to improve patient selection for DBS in PD.

scholarly journals Alterations of the nigrostriatal pathway in a 6-OHDA rat model of Parkinson’s disease evaluated with multimodal MRI

PLoS ONE ◽  
2018 ◽  
Vol 13 (9) ◽  
pp. e0202597 ◽  
Author(s):  
Vincent Perlbarg ◽  
Justine Lambert ◽  
Benjamin Butler ◽  
Mehdi Felfli ◽  
Romain Valabrègue ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Rat Model ◽  
Nigrostriatal Pathway ◽  
Multimodal Mri

scholarly journals Microglial exosomes facilitate α-synuclein transmission in Parkinson’s disease

Brain ◽  
2020 ◽  
Vol 143 (5) ◽  
pp. 1476-1497 ◽  
Author(s):  
Min Guo ◽  
Jian Wang ◽  
Yanxin Zhao ◽  
Yiwei Feng ◽  
Sida Han ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Protein Aggregation ◽  
Brain Regions ◽  
Dependent Manner ◽  
Nigrostriatal Pathway ◽  
Stereotaxic Injection ◽  
Promising Therapeutic Target ◽  
The Brain

Abstract Accumulation of neuronal α-synuclein is a prominent feature in Parkinson’s disease. More recently, such abnormal protein aggregation has been reported to spread from cell to cell and exosomes are considered as important mediators. The focus of such research, however, has been primarily in neurons. Given the increasing recognition of the importance of non-cell autonomous-mediated neurotoxicity, it is critical to investigate the contribution of glia to α-synuclein aggregation and spread. Microglia are the primary phagocytes in the brain and have been well-documented as inducers of neuroinflammation. How and to what extent microglia and their exosomes impact α-synuclein pathology has not been well delineated. We report here that when treated with human α-synuclein preformed fibrils, exosomes containing α-synuclein released by microglia are fully capable of inducing protein aggregation in the recipient neurons. Additionally, when combined with microglial proinflammatory cytokines, these exosomes further increased protein aggregation in neurons. Inhibition of exosome synthesis in microglia reduced α-synuclein transmission. The in vivo significance of these exosomes was demonstrated by stereotaxic injection of exosomes isolated from α-synuclein preformed fibrils treated microglia into the mouse striatum. Phosphorylated α-synuclein was observed in multiple brain regions consistent with their neuronal connectivity. These animals also exhibited neurodegeneration in the nigrostriatal pathway in a time-dependent manner. Depleting microglia in vivo dramatically suppressed the transmission of α-synuclein after stereotaxic injection of preformed fibrils. Mechanistically, we report here that α-synuclein preformed fibrils impaired autophagy flux by upregulating PELI1, which in turn, resulted in degradation of LAMP2 in activated microglia. More importantly, by purifying microglia/macrophage derived exosomes in the CSF of Parkinson’s disease patients, we confirmed the presence of α-synuclein oligomer in CD11b+ exosomes, which were able to induce α-synuclein aggregation in neurons, further supporting the translational aspect of this study. Taken together, our study supports the view that microglial exosomes contribute to the progression of α-synuclein pathology and therefore, they may serve as a promising therapeutic target for Parkinson’s disease.

scholarly journals Impact of Aging on the 6-OHDA-Induced Rat Model of Parkinson’s Disease

2020 ◽  
Vol 21 (10) ◽  
pp. 3459 ◽  
Author(s):  
Sandra Barata-Antunes ◽  
Fábio G. Teixeira ◽  
Bárbara Mendes-Pinheiro ◽  
Ana V. Domingues ◽  
Helena Vilaça-Faria ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Animal Welfare ◽  
Neurodegenerative Disorder ◽  
Negative Impact ◽  
Substantia Nigra Pars Compacta ◽  
Nigrostriatal Pathway ◽  
Aged Rats ◽  
Age Related ◽  
The Impact

Parkinson’s disease (PD) is the second most common age-related neurodegenerative disorder. The neurodegeneration leading to incapacitating motor abnormalities mainly occurs in the nigrostriatal pathway due to the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). Several animal models have been developed not only to better understand the mechanisms underlying neurodegeneration but also to test the potential of emerging disease-modifying therapies. However, despite aging being the main risk factor for developing idiopathic PD, most of the studies do not use aged animals. Therefore, this study aimed at assessing the effect of aging in the unilateral 6-hydroxydopamine (6-OHDA)-induced animal model of PD. For this, female young adult and aged rats received a unilateral injection of 6-OHDA into the medial forebrain bundle. Subsequently, the impact of aging on 6-OHDA-induced effects on animal welfare, motor performance, and nigrostriatal integrity were assessed. The results showed that aging had a negative impact on animal welfare after surgery. Furthermore, 6-OHDA-induced impairments on skilled motor function were significantly higher in aged rats when compared with their younger counterparts. Nigrostriatal histological analysis further revealed an increased 6-OHDA-induced dopaminergic cell loss in the SNpc of aged animals when compared to young animals. Overall, our results demonstrate a higher susceptibility of aged animals to 6-OHDA toxic insult.

scholarly journals Therapeutic Potential of Repeated Intravenous Transplantation of Human Adipose-Derived Stem Cells in Subchronic MPTP-Induced Parkinson’s Disease Mouse Model

2020 ◽  
Vol 21 (21) ◽  
pp. 8129
Author(s):  
Hyunjun Park ◽  
Keun-A Chang
Keyword(s):  
Parkinson’S Disease ◽  
Stem Cells ◽  
Parkinson's Disease ◽  
Neurodegenerative Disease ◽  
Neurotrophic Factor ◽  
Dopaminergic Neurons ◽  
Therapeutic Potential ◽  
Adipose Derived Stem Cells ◽  
Nigrostriatal Pathway

Parkinson’s disease (PD) is the second most common neurodegenerative disease, which is clinically and pathologically characterized by motor dysfunction and the loss of dopaminergic neurons in the substantia nigra, respectively. PD treatment with stem cells has long been studied by researchers; however, no adequate treatment strategy has been established. The results of studies so far have suggested that stem cell transplantation can be an effective treatment for PD. However, PD is a progressively deteriorating neurodegenerative disease that requires long-term treatment, and this has been insufficiently studied. Thus, we aimed to investigate the therapeutic potential of human adipose-derived stem cells (hASC) for repeated vein transplantation over long-term in an animal model of PD. In 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD model mice, hASCs were administered on the tail vein six times at two-week intervals. After the last injection of hASCs, motor function significantly improved. The number of dopaminergic neurons present in the nigrostriatal pathway was recovered using hASC transplantation. Moreover, the administration of hASC restored altered dopamine transporter expression and increased neurotrophic factors, such as brain-derived neurotrophic factor (BDNF) and glial cell-derived neurotrophic factor (GDNF), in the striatum. Overall, this study suggests that repeated intravenous transplantation of hASC may exert therapeutic effects on PD by restoring BDNF and GDNF expressions, protecting dopaminergic neurons, and maintaining the nigrostriatal pathway.

Sign in / Sign up

Export Citation Format

Share Document