Quinpirole ameliorates nigral dopaminergic neuron damage in Parkinson's disease mouse model through activating GHS-R1a/D 2 R heterodimers

• Published in: Acta pharmacologica Sinica 2023-08, Vol.44 (8), p.1564
• Main Authors: Tang, Ting-Ting, Bi, Ming-Xia, Diao, Mei-Ning, Zhang, Xiao-Yi, Chen, Ling, Xiao, Xue, Jiao, Qian, Chen, Xi, Yan, Chun-Ling, Du, Xi-Xun, Jiang, Hong
• Format: Article
• Language: English
• Subjects: Animals; Disease Models, Animal; Dopamine - metabolism; Dopaminergic Neurons - metabolism; Ghrelin - pharmacology; Mice; Parkinson Disease - drug therapy; Parkinson Disease - pathology; Quinpirole - pharmacology; Receptors, Ghrelin - metabolism; Substantia Nigra - metabolism; Substantia Nigra - pathology
• ISSN: 1745-7254

Growth hormone secretagogue receptor 1a (GHS-R1a) is an important G protein-coupled receptor (GPCR) that regulates a variety of functions by binding to ghrelin. It has been shown that the dimerization of GHS-R1a with other receptors also affects ingestion, energy metabolism, learning and memory. Dopamine type 2 receptor (D R) is a GPCR mainly distributed in the ventral tegmental area (VTA), substantia nigra (SN), striatum and other brain regions. In this study we investigated the existence and function of GHS-R1a/D R heterodimers in nigral dopaminergic neurons in Parkinson's disease (PD) models in vitro and in vivo. By conducting immunofluorescence staining, FRET and BRET analyses, we confirmed that GHS-R1a and D R could form heterodimers in PC-12 cells and in the nigral dopaminergic neurons of wild-type mice. This process was inhibited by MPP or MPTP treatment. Application of QNP (10 μM) alone significantly increased the viability of MPP -treated PC-12 cells, and administration of quinpirole (QNP, 1 mg/kg, i.p. once before and twice after MPTP injection) significantly alleviated motor deficits in MPTP-induced PD mice model; the beneficial effects of QNP were abolished by GHS-R1a knockdown. We revealed that the GHS-R1a/D R heterodimers could increase the protein levels of tyrosine hydroxylase in the SN of MPTP-induced PD mice model through the cAMP response element binding protein (CREB) signaling pathway, ultimately promoting dopamine synthesis and release. These results demonstrate a protective role for GHS-R1a/D R heterodimers in dopaminergic neurons, providing evidence for the involvement of GHS-R1a in PD pathogenesis independent of ghrelin.