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

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.

Transcriptomic analysis reveals novel age-independent immunomodulatory proteins as a mode of cerebroprotection in P2X4R KO mice after ischemic stroke

“…Although the pro-in ammatory role of IL-6 is well-de ned after acute stroke injury, reduced IL-6 levels may indicate cerebroprotective effects of P2X4R KO during early stroke injury timepoints. Although the exact mechanism of how P2X4R activates IL-6 is not clear, we and others have shown that pro-in ammatory effects of P2X4R activation might indirectly contribute in stroke injury [23].…”

Purinergic Receptors P2X7 and P2X4 as Markers of Disease Progression in the rd10 Mouse Model of Inherited Retinal Dystrophy

“…Purinergic receptors have a complex role both in promoting and preventing inflammation. For instance, the potentiation of P2X4R signaling favors a switch to an anti-inflammatory phenotype in microglia [ 58 ], but P2X4R overexpression is also related to an upregulation of cytokines such as IL-6 and inflammation [ 14 , 59 ].…”

“…It has also been shown that these receptors can influence each other’s expression (reviewed in [ 11 ]). The role of P2X4R in neurodegeneration is less clear, although it is considered a central player in the pathogenesis of chronic and neuropathic pain and allodynia [ 14 , 15 ]. It is also involved in multiple pathologies including asthma, rheumatoid arthritis, Duchenne muscular dystrophy, brain tumors, and neurodegenerative diseases, including PD and amyotrophic lateral sclerosis [ 14 , 16 , 17 , 18 , 19 , 20 , 21 , 22 ].…”

Triggering of Major Brain Disorders by Protons and ATP: The Role of ASICs and P2X Receptors

“…P2X7 receptor inhibition has neuroprotective and neuroregenerative effects in various models of PD through anti-inflammatory actions along with modulation of the microglial activation state and cytokine release [ 202 – 205 ]. Also, overexpression of P2X4 receptors upregulates IL-6 and exacerbates 6-OHDA-induced dopaminergic degeneration in the rat model of PD [ 206 ]. A very recent paper suggests that P2X4 receptor activation might inhibit neuronal autophagy through regulation of the BDNF/TrkB signaling pathway, leading to dopaminergic neuron damage in the substantia nigra and the further inhibition of P2X4-mediated autophagy [ 207 ].…”

“…Overexpression or activation of P2X4Rs is associated with increased dopaminergic degeneration [ 206 , 207 ]…”