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

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Abstract

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.

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Abbreviations

PD:

Parkinson's disease

DPP-4:

dipeptidyl peptidase-4

6-OHDA:

6-hydroxydopamine

SIRT1:

NAD dependent deacetylase sirtuin-1

SIRT3:

NAD-dependent deacetylase sirtuin-3

ELISA:

enzyme-linked immunosorbent assay

mTOR:

The mammalian target of rapamycin

PGC-1α:

Peroxisome proliferator-activated receptor-γ coactivator1 α

PTEN:

Phosphatase and tensin homolog

TH:

tyrosine hydroxylase

BBG:

brilliant blue G

lin:

linagliptin

SNC:

nigra pars compacta

NF-κB:

nuclear factor kappa B

Nrf2:

Nuclear factor erythroid-2-related factor 2

FOXO3a:

Forkhead box class O 3a

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Acknowledgments

The present study was financially supported by research affairs of Iran University of Medical Sciences.

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Authors and Affiliations

  1. Department of Physiology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran

    Nida Jamali-Raeufy, Zahra Mojarrab, Tourandokht Baluchnejadmojarad, Javad Fahanik-Babaei & Mina Goudarzi

  2. Student Research Committee, Iran University of Medical Sciences, Tehran, Iran

    Zahra Mojarrab

  3. Neurophysiology Research Center, Shahed University, Tehran, Iran

    Mehrdad Roghani

Authors
  1. Nida Jamali-Raeufy
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  2. Zahra Mojarrab
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  3. Tourandokht Baluchnejadmojarad
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  4. Mehrdad Roghani
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  5. Javad Fahanik-Babaei
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  6. Mina Goudarzi
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Correspondence to Nida Jamali-Raeufy.

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Jamali-Raeufy, N., Mojarrab, Z., Baluchnejadmojarad, T. et al. The effects simultaneous inhibition of dipeptidyl peptidase-4 and P2X7 purinoceptors in an in vivo Parkinson’s disease model. Metab Brain Dis 35, 539–548 (2020). https://doi.org/10.1007/s11011-020-00538-x

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  • DOI: https://doi.org/10.1007/s11011-020-00538-x

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