DA5-CH and Semaglutide Protect against Neurodegeneration and Reduce α-Synuclein Levels in the 6-OHDA Parkinson’s Disease Rat Model
Insulin desensitization has been observed in the brains of patients with Parkinson’s disease (PD), which is a progressive neurodegenerative disorder for which there is no cure. Semaglutide is a novel long-actingglucagon-likepeptide-1 (GLP-1) receptor agonist that is on the market as a treatment for...
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| Format: | Article |
| Language: | English |
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Wiley
2022-01-01
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| Series: | Parkinson's Disease |
| Online Access: | http://dx.doi.org/10.1155/2022/1428817 |
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| author | Lingyu Zhang Chun Li Zijuan Zhang Zhenqiang Zhang Qian-Qian Jin Lin Li Christian Hölscher |
| author_facet | Lingyu Zhang Chun Li Zijuan Zhang Zhenqiang Zhang Qian-Qian Jin Lin Li Christian Hölscher |
| author_sort | Lingyu Zhang |
| collection | DOAJ |
| description | Insulin desensitization has been observed in the brains of patients with Parkinson’s disease (PD), which is a progressive neurodegenerative disorder for which there is no cure. Semaglutide is a novel long-actingglucagon-likepeptide-1 (GLP-1) receptor agonist that is on the market as a treatment for type 2 diabetes. It is in a phase II clinical trial in patients with PD. Two previous phase II trials in PD patients showed good effects with the older GLP-1 receptor agonists, exendin-4 and liraglutide. We have developed a dual GLP-1/GIP receptor agonist (DA5-CH) that can cross the blood-brain barrier (BBB) at a higher rate than semaglutide. We tested semaglutide and DA5-CH in the 6-OHDA-lesion rat model of PD. Treatment was semaglutide or DA5-CH (25 nmol/kg, i.p.) daily for 30 days postlesion. Both drugs reduced the apomorphine-induced rotational behavior and alleviated dopamine depletion and the inflammation response in the lesioned striatum as shown in reduced IL-1β and TNF-α levels, with DA5-CH being more effective. In addition, both drugs protected dopaminergic neurons and increased TH expression in the substantia nigra. Furthermore, the level of monomer and aggregated α-synuclein was reduced by the drugs, and insulin resistance as shown in reduced pIRS-1ser312 phosphorylation was also attenuated after drug treatment, with DA5-CH being more effective. Therefore, while semaglutide showed good effects in this PD model, DA5-CH was superior and may be a better therapeutic drug for neurodegenerative disorders such as PD than GLP-1 receptor agonists that do not easily cross the BBB. |
| format | Article |
| id | doaj-art-7ac6d3f15c864394b75c087e9a631704 |
| institution | Kabale University |
| issn | 2042-0080 |
| language | English |
| publishDate | 2022-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Parkinson's Disease |
| spelling | doaj-art-7ac6d3f15c864394b75c087e9a6317042025-02-03T05:57:55ZengWileyParkinson's Disease2042-00802022-01-01202210.1155/2022/1428817DA5-CH and Semaglutide Protect against Neurodegeneration and Reduce α-Synuclein Levels in the 6-OHDA Parkinson’s Disease Rat ModelLingyu Zhang0Chun Li1Zijuan Zhang2Zhenqiang Zhang3Qian-Qian Jin4Lin Li5Christian Hölscher6Key Laboratory of Cellular PhysiologyDepartment of Forensic PathologyAcademy of Chinese Medical SciencesAcademy of Chinese Medical SciencesDepartment of Forensic PathologyKey Laboratory of Cellular PhysiologySecond Hospital Neurology DepartmentInsulin desensitization has been observed in the brains of patients with Parkinson’s disease (PD), which is a progressive neurodegenerative disorder for which there is no cure. Semaglutide is a novel long-actingglucagon-likepeptide-1 (GLP-1) receptor agonist that is on the market as a treatment for type 2 diabetes. It is in a phase II clinical trial in patients with PD. Two previous phase II trials in PD patients showed good effects with the older GLP-1 receptor agonists, exendin-4 and liraglutide. We have developed a dual GLP-1/GIP receptor agonist (DA5-CH) that can cross the blood-brain barrier (BBB) at a higher rate than semaglutide. We tested semaglutide and DA5-CH in the 6-OHDA-lesion rat model of PD. Treatment was semaglutide or DA5-CH (25 nmol/kg, i.p.) daily for 30 days postlesion. Both drugs reduced the apomorphine-induced rotational behavior and alleviated dopamine depletion and the inflammation response in the lesioned striatum as shown in reduced IL-1β and TNF-α levels, with DA5-CH being more effective. In addition, both drugs protected dopaminergic neurons and increased TH expression in the substantia nigra. Furthermore, the level of monomer and aggregated α-synuclein was reduced by the drugs, and insulin resistance as shown in reduced pIRS-1ser312 phosphorylation was also attenuated after drug treatment, with DA5-CH being more effective. Therefore, while semaglutide showed good effects in this PD model, DA5-CH was superior and may be a better therapeutic drug for neurodegenerative disorders such as PD than GLP-1 receptor agonists that do not easily cross the BBB.http://dx.doi.org/10.1155/2022/1428817 |
| spellingShingle | Lingyu Zhang Chun Li Zijuan Zhang Zhenqiang Zhang Qian-Qian Jin Lin Li Christian Hölscher DA5-CH and Semaglutide Protect against Neurodegeneration and Reduce α-Synuclein Levels in the 6-OHDA Parkinson’s Disease Rat Model Parkinson's Disease |
| title | DA5-CH and Semaglutide Protect against Neurodegeneration and Reduce α-Synuclein Levels in the 6-OHDA Parkinson’s Disease Rat Model |
| title_full | DA5-CH and Semaglutide Protect against Neurodegeneration and Reduce α-Synuclein Levels in the 6-OHDA Parkinson’s Disease Rat Model |
| title_fullStr | DA5-CH and Semaglutide Protect against Neurodegeneration and Reduce α-Synuclein Levels in the 6-OHDA Parkinson’s Disease Rat Model |
| title_full_unstemmed | DA5-CH and Semaglutide Protect against Neurodegeneration and Reduce α-Synuclein Levels in the 6-OHDA Parkinson’s Disease Rat Model |
| title_short | DA5-CH and Semaglutide Protect against Neurodegeneration and Reduce α-Synuclein Levels in the 6-OHDA Parkinson’s Disease Rat Model |
| title_sort | da5 ch and semaglutide protect against neurodegeneration and reduce α synuclein levels in the 6 ohda parkinson s disease rat model |
| url | http://dx.doi.org/10.1155/2022/1428817 |
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