The Neuroprotective Effects of GPR4 Inhibition through the Attenuation of Caspase Mediated Apoptotic Cell Death in an MPTP Induced Mouse Model of Parkinson’s Disease
The proton-activated G protein-coupled receptor (GPCR) 4 (GPR4) is constitutively active at physiological pH, and GPR4 knockout protected dopaminergic neurons from caspase-dependent mitochondria-associated apoptosis. This study explored the role of GPR4 in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrid...
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MDPI AG
2021-04-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/22/9/4674 |
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| author | Md Ezazul Haque Shofiul Azam Mahbuba Akther Duk-Yeon Cho In-Su Kim Dong-Kug Choi |
| author_facet | Md Ezazul Haque Shofiul Azam Mahbuba Akther Duk-Yeon Cho In-Su Kim Dong-Kug Choi |
| author_sort | Md Ezazul Haque |
| collection | DOAJ |
| description | The proton-activated G protein-coupled receptor (GPCR) 4 (GPR4) is constitutively active at physiological pH, and GPR4 knockout protected dopaminergic neurons from caspase-dependent mitochondria-associated apoptosis. This study explored the role of GPR4 in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mouse model of Parkinson’s disease (PD). In mice, subchronic MPTP administration causes oxidative stress-induced apoptosis in the dopaminergic neurons of the substantia nigra pars compacta (SNpc), resulting in motor deficits. NE52-QQ57, a selective GPR4 antagonist, reduced dopaminergic neuronal loss in MPTP-treated mice, improving motor and memory functions. MPTP and NE52-QQ57 co-treatment in mice significantly decreased pro-apoptotic marker Bax protein levels and increased anti-apoptotic marker Bcl-2 protein levels in the SNpc and striatum. MPTP-induced caspase 3 activation and poly (ADP-ribose) polymerase (PARP) cleavage significantly decreased in the SNpc and striatum of mice co-treated with NE52-QQ57. MPTP and NE52-QQ57 co-treatment significantly increased tyrosine hydroxylase (TH)-positive cell numbers in the SNpc and striatum compared with MPTP alone. NE52-QQ57 and MPTP co-treatment improved rotarod and pole test–assessed motor performance and improved Y-maze test–assessed spatial memory. Our findings suggest GPR4 may represent a potential therapeutic target for PD, and GPR4 activation is involved in caspase-mediated neuronal apoptosis in the SNpc and striatum of MPTP-treated mice. |
| first_indexed | 2024-03-10T11:51:44Z |
| format | Article |
| id | doaj.art-1078d4a0ba864b3fba2deccb7f1e608b |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T11:51:44Z |
| publishDate | 2021-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-1078d4a0ba864b3fba2deccb7f1e608b2023-11-21T17:38:01ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-04-01229467410.3390/ijms22094674The Neuroprotective Effects of GPR4 Inhibition through the Attenuation of Caspase Mediated Apoptotic Cell Death in an MPTP Induced Mouse Model of Parkinson’s DiseaseMd Ezazul Haque0Shofiul Azam1Mahbuba Akther2Duk-Yeon Cho3In-Su Kim4Dong-Kug Choi5Department of Applied Life Science, Graduate School, BK21 Program, Konkuk University, Chungju 27478, KoreaDepartment of Applied Life Science, Graduate School, BK21 Program, Konkuk University, Chungju 27478, KoreaDepartment of Applied Life Science, Graduate School, BK21 Program, Konkuk University, Chungju 27478, KoreaDepartment of Applied Life Science, Graduate School, BK21 Program, Konkuk University, Chungju 27478, KoreaDepartment of Biotechnology, College of Biomedical and Health Science, Research Institute of Inflammatory Disease (RID), Konkuk University, Chungju 27478, KoreaDepartment of Applied Life Science, Graduate School, BK21 Program, Konkuk University, Chungju 27478, KoreaThe proton-activated G protein-coupled receptor (GPCR) 4 (GPR4) is constitutively active at physiological pH, and GPR4 knockout protected dopaminergic neurons from caspase-dependent mitochondria-associated apoptosis. This study explored the role of GPR4 in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mouse model of Parkinson’s disease (PD). In mice, subchronic MPTP administration causes oxidative stress-induced apoptosis in the dopaminergic neurons of the substantia nigra pars compacta (SNpc), resulting in motor deficits. NE52-QQ57, a selective GPR4 antagonist, reduced dopaminergic neuronal loss in MPTP-treated mice, improving motor and memory functions. MPTP and NE52-QQ57 co-treatment in mice significantly decreased pro-apoptotic marker Bax protein levels and increased anti-apoptotic marker Bcl-2 protein levels in the SNpc and striatum. MPTP-induced caspase 3 activation and poly (ADP-ribose) polymerase (PARP) cleavage significantly decreased in the SNpc and striatum of mice co-treated with NE52-QQ57. MPTP and NE52-QQ57 co-treatment significantly increased tyrosine hydroxylase (TH)-positive cell numbers in the SNpc and striatum compared with MPTP alone. NE52-QQ57 and MPTP co-treatment improved rotarod and pole test–assessed motor performance and improved Y-maze test–assessed spatial memory. Our findings suggest GPR4 may represent a potential therapeutic target for PD, and GPR4 activation is involved in caspase-mediated neuronal apoptosis in the SNpc and striatum of MPTP-treated mice.https://www.mdpi.com/1422-0067/22/9/4674apoptosisPARPcaspase 3neurodegenerationGPR4 receptorMPTP |
| spellingShingle | Md Ezazul Haque Shofiul Azam Mahbuba Akther Duk-Yeon Cho In-Su Kim Dong-Kug Choi The Neuroprotective Effects of GPR4 Inhibition through the Attenuation of Caspase Mediated Apoptotic Cell Death in an MPTP Induced Mouse Model of Parkinson’s Disease International Journal of Molecular Sciences apoptosis PARP caspase 3 neurodegeneration GPR4 receptor MPTP |
| title | The Neuroprotective Effects of GPR4 Inhibition through the Attenuation of Caspase Mediated Apoptotic Cell Death in an MPTP Induced Mouse Model of Parkinson’s Disease |
| title_full | The Neuroprotective Effects of GPR4 Inhibition through the Attenuation of Caspase Mediated Apoptotic Cell Death in an MPTP Induced Mouse Model of Parkinson’s Disease |
| title_fullStr | The Neuroprotective Effects of GPR4 Inhibition through the Attenuation of Caspase Mediated Apoptotic Cell Death in an MPTP Induced Mouse Model of Parkinson’s Disease |
| title_full_unstemmed | The Neuroprotective Effects of GPR4 Inhibition through the Attenuation of Caspase Mediated Apoptotic Cell Death in an MPTP Induced Mouse Model of Parkinson’s Disease |
| title_short | The Neuroprotective Effects of GPR4 Inhibition through the Attenuation of Caspase Mediated Apoptotic Cell Death in an MPTP Induced Mouse Model of Parkinson’s Disease |
| title_sort | neuroprotective effects of gpr4 inhibition through the attenuation of caspase mediated apoptotic cell death in an mptp induced mouse model of parkinson s disease |
| topic | apoptosis PARP caspase 3 neurodegeneration GPR4 receptor MPTP |
| url | https://www.mdpi.com/1422-0067/22/9/4674 |
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