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...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2021-04-01
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| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/22/9/4674 |
| Summary: | 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. |
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| ISSN: | 1661-6596 1422-0067 |