Cargando…

The GLP‐1/GIP dual‐receptor agonist DA5‐CH inhibits the NF‐κB inflammatory pathway in the MPTP mouse model of Parkinson's disease more effectively than the GLP‐1 single‐receptor agonist NLY01

The GLP‐1 receptor agonist exendin‐4 has recently shown good effects in a phase II clinical trial in Parkinson's disease (PD) patients. Here, a comparison of the new GLP‐1/GIP dual receptor agonist DA5‐CH and NLY01, a 40 kDa pegylated form of exendin‐4, on motor impairments and reducing inflamm...

Descripción completa

Detalles Bibliográficos
Autores principales: Lv, MiaoJun, Xue, GuoFang, Cheng, HuiFeng, Meng, PengFei, Lian, Xia, Hölscher, Christian, Li, DongFang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8413783/
https://www.ncbi.nlm.nih.gov/pubmed/34125470
http://dx.doi.org/10.1002/brb3.2231
_version_ 1783747701112832000
author Lv, MiaoJun
Xue, GuoFang
Cheng, HuiFeng
Meng, PengFei
Lian, Xia
Hölscher, Christian
Li, DongFang
author_facet Lv, MiaoJun
Xue, GuoFang
Cheng, HuiFeng
Meng, PengFei
Lian, Xia
Hölscher, Christian
Li, DongFang
author_sort Lv, MiaoJun
collection PubMed
description The GLP‐1 receptor agonist exendin‐4 has recently shown good effects in a phase II clinical trial in Parkinson's disease (PD) patients. Here, a comparison of the new GLP‐1/GIP dual receptor agonist DA5‐CH and NLY01, a 40 kDa pegylated form of exendin‐4, on motor impairments and reducing inflammation in the 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) PD mouse model is provided. The drug groups received either DA5‐CH or NLY01 (25 nmol/kg) i.p. after daily MPTP intraperitoneal injection. Both drugs showed improvements in motor activity, open field experiments, rotarod tests, and gait analysis, but DA5‐CH was more potent. Tyrosine hydroxylase expression in dopaminergic neurons was much reduced by MPTP and improved by DA5‐CH, while NLY01 showed weak effects. When analyzing levels of α‐synuclein (α‐Syn), DA5‐CH reduced levels effectively while NLY01 had no effect. When measuring the levels of the inflammation markers Toll‐like receptor 4 (TLR4), specific markers of microglia activation (Iba‐1), the marker of astrocyte activation glial fibrillary acidic protein (GFAP), nuclear factor‐κB (NF‐κB), tumor necrosis factor (TNF‐α), and transforming growth factor β1 (TGF‐β1), DA5‐CH was very effective in reducing the chronic inflammation response, while NLY01 did not show significant effects. Levels of key growth factors such as Glial cell‐derived neurotrophic factor (GDNF) and Brain‐derived neurotrophic factor (BDNF) were much reduced by MPTP, and DA5‐CH was able to normalize levels in the brain, while NLY01 showed little effect. The levels of pro‐inflammatory cytokines (IL‐6 and IL‐Iβ) were much reduced by DA5‐CH, too, while NLY01 showed no effect. In a separate experiment, we tested the ability of the two drugs to cross the blood‐brain barrier. After injecting fluorescin‐labelled peptides peripherally, the fluorescence in brain tissue was measured. It was found that the pegylated NLY01 peptide did not cross the BBB in meaningful quantities while exendin‐4 and the dual agonist DA5‐CH did. The results show that DA5‐CH shows promise as a therapeutic drug for PD.
format Online
Article
Text
id pubmed-8413783
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher John Wiley and Sons Inc.
record_format MEDLINE/PubMed
spelling pubmed-84137832021-09-07 The GLP‐1/GIP dual‐receptor agonist DA5‐CH inhibits the NF‐κB inflammatory pathway in the MPTP mouse model of Parkinson's disease more effectively than the GLP‐1 single‐receptor agonist NLY01 Lv, MiaoJun Xue, GuoFang Cheng, HuiFeng Meng, PengFei Lian, Xia Hölscher, Christian Li, DongFang Brain Behav Original Research The GLP‐1 receptor agonist exendin‐4 has recently shown good effects in a phase II clinical trial in Parkinson's disease (PD) patients. Here, a comparison of the new GLP‐1/GIP dual receptor agonist DA5‐CH and NLY01, a 40 kDa pegylated form of exendin‐4, on motor impairments and reducing inflammation in the 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) PD mouse model is provided. The drug groups received either DA5‐CH or NLY01 (25 nmol/kg) i.p. after daily MPTP intraperitoneal injection. Both drugs showed improvements in motor activity, open field experiments, rotarod tests, and gait analysis, but DA5‐CH was more potent. Tyrosine hydroxylase expression in dopaminergic neurons was much reduced by MPTP and improved by DA5‐CH, while NLY01 showed weak effects. When analyzing levels of α‐synuclein (α‐Syn), DA5‐CH reduced levels effectively while NLY01 had no effect. When measuring the levels of the inflammation markers Toll‐like receptor 4 (TLR4), specific markers of microglia activation (Iba‐1), the marker of astrocyte activation glial fibrillary acidic protein (GFAP), nuclear factor‐κB (NF‐κB), tumor necrosis factor (TNF‐α), and transforming growth factor β1 (TGF‐β1), DA5‐CH was very effective in reducing the chronic inflammation response, while NLY01 did not show significant effects. Levels of key growth factors such as Glial cell‐derived neurotrophic factor (GDNF) and Brain‐derived neurotrophic factor (BDNF) were much reduced by MPTP, and DA5‐CH was able to normalize levels in the brain, while NLY01 showed little effect. The levels of pro‐inflammatory cytokines (IL‐6 and IL‐Iβ) were much reduced by DA5‐CH, too, while NLY01 showed no effect. In a separate experiment, we tested the ability of the two drugs to cross the blood‐brain barrier. After injecting fluorescin‐labelled peptides peripherally, the fluorescence in brain tissue was measured. It was found that the pegylated NLY01 peptide did not cross the BBB in meaningful quantities while exendin‐4 and the dual agonist DA5‐CH did. The results show that DA5‐CH shows promise as a therapeutic drug for PD. John Wiley and Sons Inc. 2021-06-14 /pmc/articles/PMC8413783/ /pubmed/34125470 http://dx.doi.org/10.1002/brb3.2231 Text en © 2021 The Authors. Brain and Behavior published by Wiley Periodicals LLC https://creativecommons.org/licenses/by/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Research
Lv, MiaoJun
Xue, GuoFang
Cheng, HuiFeng
Meng, PengFei
Lian, Xia
Hölscher, Christian
Li, DongFang
The GLP‐1/GIP dual‐receptor agonist DA5‐CH inhibits the NF‐κB inflammatory pathway in the MPTP mouse model of Parkinson's disease more effectively than the GLP‐1 single‐receptor agonist NLY01
title The GLP‐1/GIP dual‐receptor agonist DA5‐CH inhibits the NF‐κB inflammatory pathway in the MPTP mouse model of Parkinson's disease more effectively than the GLP‐1 single‐receptor agonist NLY01
title_full The GLP‐1/GIP dual‐receptor agonist DA5‐CH inhibits the NF‐κB inflammatory pathway in the MPTP mouse model of Parkinson's disease more effectively than the GLP‐1 single‐receptor agonist NLY01
title_fullStr The GLP‐1/GIP dual‐receptor agonist DA5‐CH inhibits the NF‐κB inflammatory pathway in the MPTP mouse model of Parkinson's disease more effectively than the GLP‐1 single‐receptor agonist NLY01
title_full_unstemmed The GLP‐1/GIP dual‐receptor agonist DA5‐CH inhibits the NF‐κB inflammatory pathway in the MPTP mouse model of Parkinson's disease more effectively than the GLP‐1 single‐receptor agonist NLY01
title_short The GLP‐1/GIP dual‐receptor agonist DA5‐CH inhibits the NF‐κB inflammatory pathway in the MPTP mouse model of Parkinson's disease more effectively than the GLP‐1 single‐receptor agonist NLY01
title_sort glp‐1/gip dual‐receptor agonist da5‐ch inhibits the nf‐κb inflammatory pathway in the mptp mouse model of parkinson's disease more effectively than the glp‐1 single‐receptor agonist nly01
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8413783/
https://www.ncbi.nlm.nih.gov/pubmed/34125470
http://dx.doi.org/10.1002/brb3.2231
work_keys_str_mv AT lvmiaojun theglp1gipdualreceptoragonistda5chinhibitsthenfkbinflammatorypathwayinthemptpmousemodelofparkinsonsdiseasemoreeffectivelythantheglp1singlereceptoragonistnly01
AT xueguofang theglp1gipdualreceptoragonistda5chinhibitsthenfkbinflammatorypathwayinthemptpmousemodelofparkinsonsdiseasemoreeffectivelythantheglp1singlereceptoragonistnly01
AT chenghuifeng theglp1gipdualreceptoragonistda5chinhibitsthenfkbinflammatorypathwayinthemptpmousemodelofparkinsonsdiseasemoreeffectivelythantheglp1singlereceptoragonistnly01
AT mengpengfei theglp1gipdualreceptoragonistda5chinhibitsthenfkbinflammatorypathwayinthemptpmousemodelofparkinsonsdiseasemoreeffectivelythantheglp1singlereceptoragonistnly01
AT lianxia theglp1gipdualreceptoragonistda5chinhibitsthenfkbinflammatorypathwayinthemptpmousemodelofparkinsonsdiseasemoreeffectivelythantheglp1singlereceptoragonistnly01
AT holscherchristian theglp1gipdualreceptoragonistda5chinhibitsthenfkbinflammatorypathwayinthemptpmousemodelofparkinsonsdiseasemoreeffectivelythantheglp1singlereceptoragonistnly01
AT lidongfang theglp1gipdualreceptoragonistda5chinhibitsthenfkbinflammatorypathwayinthemptpmousemodelofparkinsonsdiseasemoreeffectivelythantheglp1singlereceptoragonistnly01
AT lvmiaojun glp1gipdualreceptoragonistda5chinhibitsthenfkbinflammatorypathwayinthemptpmousemodelofparkinsonsdiseasemoreeffectivelythantheglp1singlereceptoragonistnly01
AT xueguofang glp1gipdualreceptoragonistda5chinhibitsthenfkbinflammatorypathwayinthemptpmousemodelofparkinsonsdiseasemoreeffectivelythantheglp1singlereceptoragonistnly01
AT chenghuifeng glp1gipdualreceptoragonistda5chinhibitsthenfkbinflammatorypathwayinthemptpmousemodelofparkinsonsdiseasemoreeffectivelythantheglp1singlereceptoragonistnly01
AT mengpengfei glp1gipdualreceptoragonistda5chinhibitsthenfkbinflammatorypathwayinthemptpmousemodelofparkinsonsdiseasemoreeffectivelythantheglp1singlereceptoragonistnly01
AT lianxia glp1gipdualreceptoragonistda5chinhibitsthenfkbinflammatorypathwayinthemptpmousemodelofparkinsonsdiseasemoreeffectivelythantheglp1singlereceptoragonistnly01
AT holscherchristian glp1gipdualreceptoragonistda5chinhibitsthenfkbinflammatorypathwayinthemptpmousemodelofparkinsonsdiseasemoreeffectivelythantheglp1singlereceptoragonistnly01
AT lidongfang glp1gipdualreceptoragonistda5chinhibitsthenfkbinflammatorypathwayinthemptpmousemodelofparkinsonsdiseasemoreeffectivelythantheglp1singlereceptoragonistnly01