No Cover Image

E-Thesis 418 views 362 downloads

Natural and Synthetic GHSR1a Agonists as Neuroprotective Agents in Models of Parkinson's disease / Daniel J. Rees

Swansea University Author: Daniel J. Rees

DOI (Published version): 10.23889/SUthesis.40946

Abstract

Parkinson’s disease (PD) is the second most prevalent neurodegenerative disorder in humans. It is characterised by the progressive loss of the A9 (Girk2+) subpopulation of dopamine (DA) neurones in the Substantia Nigra Pars Compacta (SNpc) resulting in resting tremor, bradykinesia and rigidity. The...

Full description

Published: 2017
Institution: Swansea University
Degree level: Doctoral
Degree name: Ph.D
URI: https://cronfa.swan.ac.uk/Record/cronfa40946
Tags: Add Tag
No Tags, Be the first to tag this record!
first_indexed 2018-07-10T10:31:21Z
last_indexed 2020-09-04T03:02:36Z
id cronfa40946
recordtype RisThesis
fullrecord <?xml version="1.0"?><rfc1807><datestamp>2020-09-03T08:15:45.9661762</datestamp><bib-version>v2</bib-version><id>40946</id><entry>2018-07-06</entry><title>Natural and Synthetic GHSR1a Agonists as Neuroprotective Agents in Models of Parkinson's disease</title><swanseaauthors><author><sid>b616e86eaf57b5fb3526535c36713351</sid><ORCID>NULL</ORCID><firstname>Daniel J.</firstname><surname>Rees</surname><name>Daniel J. Rees</name><active>true</active><ethesisStudent>true</ethesisStudent></author></swanseaauthors><date>2018-07-06</date><abstract>Parkinson&#x2019;s disease (PD) is the second most prevalent neurodegenerative disorder in humans. It is characterised by the progressive loss of the A9 (Girk2+) subpopulation of dopamine (DA) neurones in the Substantia Nigra Pars Compacta (SNpc) resulting in resting tremor, bradykinesia and rigidity. The majority of PD cases are idiopathic. However, environmental toxins that inhibit the mitochondrial electron transport chain cause PD-like symptoms and recent studies of rare familial PD implicate metabolic dysfunction as a possible cause of DA nerve cell loss. We propose that the homeostatic hormone, acyl-ghrelin, may prevent DA neurone loss by preserving nerve cell metabolism during bioenergetics stress. In the in-vivo MPTP-toxin model of PD acyl-ghrelin prevents SNpc DA neurone loss in an acyl-ghrelin receptor (GHSR)-dependent manner (Andrews et al.2009). Here, using the eGFP-GHSR reporter mouse we demonstrate co-localised expression of the GHSR with TH+ and Girk2+ SNpc neurones. This suggests that acyl-ghrelin may exert a direct protective effect on A9 DA neurones via GHSR+ signalling. We show that acyl-ghrelin attenuated the 6-OHDA-induced SN lesion in unilateral lesioned rats. Moreover, this neuroprotection is consistent with the preservation of motor function. Using a mouse-midbrain-derived neuronal cell line (SN4741), immune-positive for TH+/ Girk2+/GHSR+, we assess the neuroprotective potential of acyl-ghrelin and GHSR1a agonist, JMV2894, in an in-vitro rotenone-based PD model. Furthermore, we show acyl-ghrelin as a modulator of intra-cellular AMPK and ACC phosphorylation and investigate the protective effects on mitochondrial health and morphology using automated images analysis and TEM. Acyl-ghrelin activated cellular pathways associated with protecting against energetic stress and promoting healthy aging. These data suggest that Acyl-Ghrelin may be a potential new therapeutic target for PD.</abstract><type>E-Thesis</type><journal/><publisher/><keywords>Ghrelin, Parkinson&amp;apos;s, Neuroprotection, Neurodegeneration</keywords><publishedDay>31</publishedDay><publishedMonth>12</publishedMonth><publishedYear>2017</publishedYear><publishedDate>2017-12-31</publishedDate><doi>10.23889/SUthesis.40946</doi><url/><notes/><college>COLLEGE NANME</college><department>Swansea University Medical School</department><CollegeCode>COLLEGE CODE</CollegeCode><institution>Swansea University</institution><degreelevel>Doctoral</degreelevel><degreename>Ph.D</degreename><apcterm/><lastEdited>2020-09-03T08:15:45.9661762</lastEdited><Created>2018-07-06T12:03:54.6719643</Created><path><level id="1">Faculty of Medicine, Health and Life Sciences</level><level id="2">Swansea University Medical School - Medicine</level></path><authors><author><firstname>Daniel J.</firstname><surname>Rees</surname><orcid>NULL</orcid><order>1</order></author></authors><documents><document><filename>0040946-06072018120450.pdf</filename><originalFilename>Rees_Daniel_J_PhD_Thesis_Final.pdf</originalFilename><uploaded>2018-07-06T12:04:50.0200000</uploaded><type>Output</type><contentLength>8795824</contentLength><contentType>application/pdf</contentType><version>E-Thesis &#x2013; open access</version><cronfaStatus>true</cronfaStatus><embargoDate>2019-07-03T00:00:00.0000000</embargoDate><copyrightCorrect>true</copyrightCorrect></document></documents><OutputDurs/></rfc1807>
spelling 2020-09-03T08:15:45.9661762 v2 40946 2018-07-06 Natural and Synthetic GHSR1a Agonists as Neuroprotective Agents in Models of Parkinson's disease b616e86eaf57b5fb3526535c36713351 NULL Daniel J. Rees Daniel J. Rees true true 2018-07-06 Parkinson’s disease (PD) is the second most prevalent neurodegenerative disorder in humans. It is characterised by the progressive loss of the A9 (Girk2+) subpopulation of dopamine (DA) neurones in the Substantia Nigra Pars Compacta (SNpc) resulting in resting tremor, bradykinesia and rigidity. The majority of PD cases are idiopathic. However, environmental toxins that inhibit the mitochondrial electron transport chain cause PD-like symptoms and recent studies of rare familial PD implicate metabolic dysfunction as a possible cause of DA nerve cell loss. We propose that the homeostatic hormone, acyl-ghrelin, may prevent DA neurone loss by preserving nerve cell metabolism during bioenergetics stress. In the in-vivo MPTP-toxin model of PD acyl-ghrelin prevents SNpc DA neurone loss in an acyl-ghrelin receptor (GHSR)-dependent manner (Andrews et al.2009). Here, using the eGFP-GHSR reporter mouse we demonstrate co-localised expression of the GHSR with TH+ and Girk2+ SNpc neurones. This suggests that acyl-ghrelin may exert a direct protective effect on A9 DA neurones via GHSR+ signalling. We show that acyl-ghrelin attenuated the 6-OHDA-induced SN lesion in unilateral lesioned rats. Moreover, this neuroprotection is consistent with the preservation of motor function. Using a mouse-midbrain-derived neuronal cell line (SN4741), immune-positive for TH+/ Girk2+/GHSR+, we assess the neuroprotective potential of acyl-ghrelin and GHSR1a agonist, JMV2894, in an in-vitro rotenone-based PD model. Furthermore, we show acyl-ghrelin as a modulator of intra-cellular AMPK and ACC phosphorylation and investigate the protective effects on mitochondrial health and morphology using automated images analysis and TEM. Acyl-ghrelin activated cellular pathways associated with protecting against energetic stress and promoting healthy aging. These data suggest that Acyl-Ghrelin may be a potential new therapeutic target for PD. E-Thesis Ghrelin, Parkinson&apos;s, Neuroprotection, Neurodegeneration 31 12 2017 2017-12-31 10.23889/SUthesis.40946 COLLEGE NANME Swansea University Medical School COLLEGE CODE Swansea University Doctoral Ph.D 2020-09-03T08:15:45.9661762 2018-07-06T12:03:54.6719643 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Medicine Daniel J. Rees NULL 1 0040946-06072018120450.pdf Rees_Daniel_J_PhD_Thesis_Final.pdf 2018-07-06T12:04:50.0200000 Output 8795824 application/pdf E-Thesis – open access true 2019-07-03T00:00:00.0000000 true
title Natural and Synthetic GHSR1a Agonists as Neuroprotective Agents in Models of Parkinson's disease
spellingShingle Natural and Synthetic GHSR1a Agonists as Neuroprotective Agents in Models of Parkinson's disease
Daniel J. Rees
title_short Natural and Synthetic GHSR1a Agonists as Neuroprotective Agents in Models of Parkinson's disease
title_full Natural and Synthetic GHSR1a Agonists as Neuroprotective Agents in Models of Parkinson's disease
title_fullStr Natural and Synthetic GHSR1a Agonists as Neuroprotective Agents in Models of Parkinson's disease
title_full_unstemmed Natural and Synthetic GHSR1a Agonists as Neuroprotective Agents in Models of Parkinson's disease
title_sort Natural and Synthetic GHSR1a Agonists as Neuroprotective Agents in Models of Parkinson's disease
author_id_str_mv b616e86eaf57b5fb3526535c36713351
author_id_fullname_str_mv b616e86eaf57b5fb3526535c36713351_***_Daniel J. Rees
author Daniel J. Rees
author2 Daniel J. Rees
format E-Thesis
publishDate 2017
institution Swansea University
doi_str_mv 10.23889/SUthesis.40946
college_str Faculty of Medicine, Health and Life Sciences
hierarchytype
hierarchy_top_id facultyofmedicinehealthandlifesciences
hierarchy_top_title Faculty of Medicine, Health and Life Sciences
hierarchy_parent_id facultyofmedicinehealthandlifesciences
hierarchy_parent_title Faculty of Medicine, Health and Life Sciences
department_str Swansea University Medical School - Medicine{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Medicine
document_store_str 1
active_str 0
description Parkinson’s disease (PD) is the second most prevalent neurodegenerative disorder in humans. It is characterised by the progressive loss of the A9 (Girk2+) subpopulation of dopamine (DA) neurones in the Substantia Nigra Pars Compacta (SNpc) resulting in resting tremor, bradykinesia and rigidity. The majority of PD cases are idiopathic. However, environmental toxins that inhibit the mitochondrial electron transport chain cause PD-like symptoms and recent studies of rare familial PD implicate metabolic dysfunction as a possible cause of DA nerve cell loss. We propose that the homeostatic hormone, acyl-ghrelin, may prevent DA neurone loss by preserving nerve cell metabolism during bioenergetics stress. In the in-vivo MPTP-toxin model of PD acyl-ghrelin prevents SNpc DA neurone loss in an acyl-ghrelin receptor (GHSR)-dependent manner (Andrews et al.2009). Here, using the eGFP-GHSR reporter mouse we demonstrate co-localised expression of the GHSR with TH+ and Girk2+ SNpc neurones. This suggests that acyl-ghrelin may exert a direct protective effect on A9 DA neurones via GHSR+ signalling. We show that acyl-ghrelin attenuated the 6-OHDA-induced SN lesion in unilateral lesioned rats. Moreover, this neuroprotection is consistent with the preservation of motor function. Using a mouse-midbrain-derived neuronal cell line (SN4741), immune-positive for TH+/ Girk2+/GHSR+, we assess the neuroprotective potential of acyl-ghrelin and GHSR1a agonist, JMV2894, in an in-vitro rotenone-based PD model. Furthermore, we show acyl-ghrelin as a modulator of intra-cellular AMPK and ACC phosphorylation and investigate the protective effects on mitochondrial health and morphology using automated images analysis and TEM. Acyl-ghrelin activated cellular pathways associated with protecting against energetic stress and promoting healthy aging. These data suggest that Acyl-Ghrelin may be a potential new therapeutic target for PD.
published_date 2017-12-31T03:52:10Z
_version_ 1763752574168596480
score 11.016258

Similar Items