Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

The Neuroprotective Effect of GPR4 Inhibition through Attenuation of Caspase Mediated Apoptotic Cell Death in MPTP Induced Mouse Model of Parkinson’s Disease

Version 1 : Received: 7 April 2021 / Approved: 8 April 2021 / Online: 8 April 2021 (09:12:06 CEST)

A peer-reviewed article of this Preprint also exists.

Haque, M.E.; Azam, S.; Akther, M.; Cho, D.-Y.; Kim, I.-S.; Choi, D.-K. 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. Int. J. Mol. Sci. 2021, 22, 4674. Haque, M.E.; Azam, S.; Akther, M.; Cho, D.-Y.; Kim, I.-S.; Choi, D.-K. 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. Int. J. Mol. Sci. 2021, 22, 4674.

Journal reference: Int. J. Mol. Sci. 2021, 22, 4674
DOI: 10.3390/ijms22094674

Abstract

GPR4, a member of proton activated GPCRs group. Previously we have reported that GPR4 is constitutively active at physiological pH and knockout of GPR4 has shown to protect dopaminergic neuronal cells from caspase-dependent mitochondrial apoptotic cell death. In this study we have investigated the role of GPR4 in 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) treated mice model of Parkinson’s disease. Subchronic administration of MPTP in mice produces oxidative stress induced apoptotic cell death of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and motor deficits. Treatment with NE52-QQ57, a selective antagonist of GPR4 reduced dopaminergic neuronal loss MPTP-intoxicated C57BL6/J mice and improved motor deficit and memory impairment. Co-treatment with NE52-QQ57 significantly decreases the protein level of proapoptotic marker (Bax), and increases the antiapoptotic marker (Bcl-2) in the SNpc and striatum tissue collected from the brain of MPTP inflicted mice. Further, MPTP induced activation of caspase 3 and cleavage of poly (ADP-ribose) polymerase (PARP) was significantly decreased in the SNpc and striatum tissue of NE52-QQ57 cotreated mice. Further mice receiving both MPTP and NE52-QQ57 mice showed significantly higher TH positive cells in the SNpc and striatum than MPTP treated mice alone. Moreover, NE52-QQ57 cotreatment improved the motor activity in the rotarod test and pole test and also improved spatial memory in Y maze test. Our findings suggest GPR4 as a potential therapeutic target for PD whereas the activation GPR4 is involved in the caspase mediated apoptotic cell death in SNpc and striatum of MPTP-intoxicated mice.

Keywords

Apoptosis; PARP; Caspase 3; Neurodegeneration; GPR4 receptor; MPTP; Parkinson’s disease

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