P2X4R Overexpression Upregulates Interleukin-6 and Exacerbates 6-OHDA-Induced Dopaminergic Degeneration in a Rat Model of PD.

Jiangnan Ma,Jiangnan Ma,Mengyue Niu,Jinzhao Gao,Jinzhao Gao,Xiaona Zhang,Xiaona Zhang,Jing Wang,Jing Wang,Anmu Xie,Anmu Xie

doi:10.3389/fnagi.2020.580068

Jiangnan Ma, Jiangnan Ma + Show 9 more

Open Access

https://doi.org/10.3389/fnagi.2020.580068

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Abstract

The pathogenesis of Parkinson’s disease (PD) remains elusive. Current thinking suggests that the activation of microglia and the subsequent release of inflammatory factors, including interleukin-6 (IL-6), are involved in the pathogenesis of PD. P2X4 receptor (P2X4R) is a member of the P2X superfamily of ion channels activated by ATP. To study the possible effect of the ATP-P2X4R signal axis on IL-6 in PD, lentivirus carrying the P2X4R-overexpression gene or empty vector was injected into the substantia nigra (SN) of rats, followed by treatment of 6-hydroxydopamine (6-OHDA) or saline 1 week later. The research found the relative expression of P2X4R in the 6-OHDA-induced PD rat models was notably higher than that in the normal. And P2X4R overexpression could upregulate the expression of IL-6, reduce the amount of dopaminergic (DA) neurons in the SN of PD rats, suggesting that P2X4R may mediate the production of IL-6 to damage DA neurons in the SN. Our data revealed the important role of P2X4R in modulating IL-6, which leads to neuroinflammation involved in PD pathogenesis.

Highlights

Parkinson’s disease (PD) is a common neurodegenerative disease, which has been recognized as presenting with a broad spectrum of the motorand non-motor symptoms, and varying disease progression (Weintraub et al, 2008; Ma et al, 2019; Tao et al, 2019; LeWitt et al, 2020; Zhang et al, 2020)
Detection of P2X4 receptor (P2X4R) Expression in the substantia nigra (SN) by Western Blot Compared to the control group, the expression of P2X4R in the 6-OHDA group and P2X4R-OE group was significantly increased (P < 0.001)
There was no significant difference in the expression of P2X4R between the 6-OHDA group and P2X4R-NC + 6-OHDA group (P > 0.05); compared with the 6-OHDA group, the expression of P2X4R

Summary

INTRODUCTION

PD is a common neurodegenerative disease, which has been recognized as presenting with a broad spectrum of the motor (including bradykinesia, resting tremor, and rigidity)and non-motor symptoms (including olfactory dysfunction, cognitive impairment, psychiatric symptoms, rapid eye movement sleep behavior disorder, and orthostatic hypotension), and varying disease progression (Weintraub et al, 2008; Ma et al, 2019; Tao et al, 2019; LeWitt et al, 2020; Zhang et al, 2020). The abnormal inflammatory signaling modulates the activation of astrocytes and microglia, the release of inflammatory factors, the degeneration of DA neurons (Hunot and Hirsch, 2003; McGeer and McGeer, 2004; Frank-Cannon et al, 2009; Phani et al, 2012; Pradhan and Andreasson, 2013) Plasma antioxidants, such as the superoxide dismutase (SOD), are significantly reduced in PD, while inflammatory factors, such as high-sensitivity C-reactive protein (hsCRP), are increased (Jin et al, 2020), which suggested that oxidative stress and inflammation in the peripheral blood may be involved in the pathogenesis of PD (Adav and Sze, 2020; Yang et al, 2020). The objective of the experiment is to explore the role of P2X4R and inflammatory response in the pathogenesis of PD

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DISCUSSION

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