The effects simultaneous inhibition of dipeptidyl peptidase-4 and P2X7 purinoceptors in an in vivo Parkinson’s disease model

• Published in: Metabolic brain disease 2020-03, Vol.35 (3), p.539-548
• Main Authors: Jamali-Raeufy, Nida, Mojarrab, Zahra, Baluchnejadmojarad, Tourandokht, Roghani, Mehrdad, Fahanik-Babaei, Javad, Goudarzi, Mina
• Format: Article
• Language: English
• Subjects: 6-Hydroxydopamine; Animals; Apomorphine; Biochemistry; Biomedical and Life Sciences; Biomedicine; Brain; Corpus Striatum - drug effects; Corpus Striatum - metabolism; Density; Dipeptidyl-peptidase IV; Dipeptidyl-Peptidase IV Inhibitors - pharmacology; Dipeptidyl-Peptidase IV Inhibitors - therapeutic use; Disease Models, Animal; DNA fragmentation; DNA Fragmentation - drug effects; Dopamine; Dopamine - biosynthesis; Dopamine receptors; Dopaminergic Neurons - drug effects; Dopaminergic Neurons - metabolism; Drug Therapy, Combination; Enzyme-linked immunosorbent assay; Hydroxylase; Immunohistochemistry; In vivo methods and tests; Metabolic Diseases; Mitochondria; Motor Activity - drug effects; Movement disorders; Neostriatum; Neurodegenerative diseases; Neurology; Neurons; Neurosciences; Oncology; Original Article; Oxidopamine; p53 Protein; Parkinson Disease, Secondary - chemically induced; Parkinson Disease, Secondary - drug therapy; Parkinson Disease, Secondary - metabolism; Parkinson's disease; Peptidase; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha - metabolism; PTEN Phosphohydrolase - metabolism; PTEN protein; Purine P2X receptors; Purinergic P2X Receptor Antagonists - pharmacology; Purinergic P2X Receptor Antagonists - therapeutic use; Quality of life; Rats; Rats, Wistar; Rodents; SIRT1 protein; Sirtuin 1 - metabolism; Sirtuin 3 - metabolism; Substantia Nigra - drug effects; Substantia Nigra - metabolism; TOR protein; TOR Serine-Threonine Kinases - metabolism; Tyrosine; Tyrosine 3-monooxygenase; Tyrosine 3-Monooxygenase - metabolism
• ISSN: 0885-7490; 1573-7365
• DOI: 10.1007/s11011-020-00538-x

Loss of dopaminergic neurons following Parkinson’s disease (PD) diminishes quality of life in patients. The present study was carried out to investigate the protective effects of simultaneous inhibition of dipeptidyl peptidase-4 (DPP-4) and P2X7 purinoceptors in a PD model and explore possible mechanisms. The 6-hydroxydopamine (6-OHDA) was used as a tool to establish PD model in male Wister rats. The expressions of SIRT1, SIRT3, mTOR, PGC-1α, PTEN, P53 and DNA fragmentation were evaluated by ELISA assay. Behavioral impairments were determined using apomorphine-induced rotational and narrow beam tests. Dopamine synthesis and TH-positive neurons were detected by tyrosine hydroxylase (TH) immunohistochemistry. Neuronal density was determined by Nissl staining. OHDA-lesioned rats exhibited behavioral impairments that reversed by BBG, lin and lin + BBG. We found significant reduced levels of SIRT1, SIRT3, PGC-1α and mTOR in both mid brain and striatum from OHDA-lesioned rats that reversed by BBG, lin and lin + BBG. Likewise, significant increased levels of PTEN and P53 were found in both mid brain and striatum from OHDA-lesioned rats that was reversed by BBG, lin and lin + BBG. TH-positive neurons and neuronal density were markedly reduced OHDA-lesioned rats that reversed by BBG, lin and lin + BBG. Collectively, our results showed protective effects of simultaneous inhibition of DPP-4 and P2X7 purinoceptors in a rat model of PD can be linked to targeting SIRT1/SIRT3, PTEN-mTOR pathways. Moreover, our findings demonstrated that simultaneous inhibition of DPP-4 and P2X7 purinoceptors might have stronger effect on mitochondrial biogenesis compared to only one.