Involvement of P2X7 receptor in neuronal degeneration triggered by traumatic injury.

Francisco M Nadal-Nicolás,Pablo Pelegrín,Marta Agudo-Barriuso,María Barberà-Cremades,Manuel Salinas-Navarro,Carlos Detorre-Minguela,Francisco J Valiente-Soriano,Caridad Galindo-Romero

doi:10.1038/srep38499

Abstract

Axonal injury is a common feature of central nervous system insults that culminates with the death of the affected neurons, and an irreversible loss of function. Inflammation is an important component of the neurodegenerative process, where the microglia plays an important role by releasing proinflammatory factors as well as clearing the death neurons by phagocytosis. Here we have identified the purinergic signaling through the P2X7 receptor as an important component for the neuronal death in a model of optic nerve axotomy. We have found that in P2X7 receptor deficient mice there is a delayed loss of retinal ganglion cells and a decrease of phagocytic microglia at early times points after axotomy. In contralateral to the axotomy retinas, P2X7 receptor controlled the numbers of phagocytic microglia, suggesting that extracellular ATP could act as a danger signal activating the P2X7 receptor in mediating the loss of neurons in contralateral retinas. Finally, we show that intravitreal administration of the selective P2X7 receptor antagonist A438079 also delays axotomy-induced retinal ganglion cell death in retinas from wild type mice. Thus, our work demonstrates that P2X7 receptor signaling is involved in neuronal cell death after axonal injury, being P2X7 receptor antagonism a potential therapeutic strategy.

Highlights

Axonal injury is a common feature of central nervous system insults that culminates with the death of the affected neurons, and an irreversible loss of function
There is a weak expression of P2X7 receptor in retinal ganglion cells (RGCs), in accordance with previous reports[40,44]
We found a staining of blood vessels with the anti-P2X7 receptor antibody, but this signal was observed in retinas from P2rx7−/− mice, suggesting that is a non-specific signal (Fig. 1A).To confirm P2X7 receptor expression in retinas, we performed western blotting detection in extracts from intact, injured and contralateral to the injury retinas

Summary

Introduction

Axonal injury is a common feature of central nervous system insults that culminates with the death of the affected neurons, and an irreversible loss of function. Damage to the optic nerve (ON), formed by the axons of retinal ganglion cells (RGCs) neurons, causes their retrograde death and the consequent loss of vision. Using knock-out mice it has been reported that RGCs survive better after axotomy when the expression of pro-apoptotic genes such as Bax are ablated[7], there is an increase of RGCs survival upon reduction of oxidative damage[8], inflammation[9,10], nuclear atrophy[11] or calpain activity[12], or an activation of autophagy[13] In spite of these works, there is no current treatment to delay neuronal loss after traumatic injury, and no effective therapies for patients. It is known that neuroinflammation, if not the primary cause of this death, has an important role exacerbating it[14]

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Results

Conclusion