Cargando…

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

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 kno...

Descripción completa

Detalles Bibliográficos
Autores principales: Kelly, Rachel, Bemelmans, Alexis-Pierre, Joséphine, Charlène, Brouillet, Emmanuel, McKernan, Declan P., Dowd, Eilís
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8778740/
https://www.ncbi.nlm.nih.gov/pubmed/35056822
http://dx.doi.org/10.3390/molecules27020507
_version_ 1784637397143650304
author Kelly, Rachel
Bemelmans, Alexis-Pierre
Joséphine, Charlène
Brouillet, Emmanuel
McKernan, Declan P.
Dowd, Eilís
author_facet Kelly, Rachel
Bemelmans, Alexis-Pierre
Joséphine, Charlène
Brouillet, Emmanuel
McKernan, Declan P.
Dowd, Eilís
author_sort Kelly, Rachel
collection PubMed
description 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 CB(1) or CB(2) 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.
format Online
Article
Text
id pubmed-8778740
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-87787402022-01-22 Time-Course of Alterations in the Endocannabinoid System after Viral-Mediated Overexpression of α-Synuclein in the Rat Brain Kelly, Rachel Bemelmans, Alexis-Pierre Joséphine, Charlène Brouillet, Emmanuel McKernan, Declan P. Dowd, Eilís Molecules Article 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 CB(1) or CB(2) 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. MDPI 2022-01-14 /pmc/articles/PMC8778740/ /pubmed/35056822 http://dx.doi.org/10.3390/molecules27020507 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Kelly, Rachel
Bemelmans, Alexis-Pierre
Joséphine, Charlène
Brouillet, Emmanuel
McKernan, Declan P.
Dowd, Eilís
Time-Course of Alterations in the Endocannabinoid System after Viral-Mediated Overexpression of α-Synuclein in the Rat Brain
title Time-Course of Alterations in the Endocannabinoid System after Viral-Mediated Overexpression of α-Synuclein in the Rat Brain
title_full Time-Course of Alterations in the Endocannabinoid System after Viral-Mediated Overexpression of α-Synuclein in the Rat Brain
title_fullStr Time-Course of Alterations in the Endocannabinoid System after Viral-Mediated Overexpression of α-Synuclein in the Rat Brain
title_full_unstemmed Time-Course of Alterations in the Endocannabinoid System after Viral-Mediated Overexpression of α-Synuclein in the Rat Brain
title_short Time-Course of Alterations in the Endocannabinoid System after Viral-Mediated Overexpression of α-Synuclein in the Rat Brain
title_sort time-course of alterations in the endocannabinoid system after viral-mediated overexpression of α-synuclein in the rat brain
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8778740/
https://www.ncbi.nlm.nih.gov/pubmed/35056822
http://dx.doi.org/10.3390/molecules27020507
work_keys_str_mv AT kellyrachel timecourseofalterationsintheendocannabinoidsystemafterviralmediatedoverexpressionofasynucleinintheratbrain
AT bemelmansalexispierre timecourseofalterationsintheendocannabinoidsystemafterviralmediatedoverexpressionofasynucleinintheratbrain
AT josephinecharlene timecourseofalterationsintheendocannabinoidsystemafterviralmediatedoverexpressionofasynucleinintheratbrain
AT brouilletemmanuel timecourseofalterationsintheendocannabinoidsystemafterviralmediatedoverexpressionofasynucleinintheratbrain
AT mckernandeclanp timecourseofalterationsintheendocannabinoidsystemafterviralmediatedoverexpressionofasynucleinintheratbrain
AT dowdeilis timecourseofalterationsintheendocannabinoidsystemafterviralmediatedoverexpressionofasynucleinintheratbrain