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

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 mecha...

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Bibliographic Details
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
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Summary: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.
ISSN:0885-7490
1573-7365
DOI:10.1007/s11011-020-00538-x