Up-regulation of P2X2, P2X4 receptor and ischemic cell death: Prevention by P2 antagonists

• Published in: Neuroscience Vol. 120; no. 1; pp. 85 - 98
• Main Authors: CAVALIERE, F, FLORENZANO, F, VOLONTE, C, AMADIO, S, FUSCO, F. R, VISCOMI, M. T, D'AMBROSI, N, VACCA, F, SANCESARIO, G, BERNARDI, G, MOLINARI, M
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier 01-08-2003
• Subjects: Animals; Biological and medical sciences; Cell Death - drug effects; Cell Death - physiology; Cell Hypoxia - drug effects; Cell Hypoxia - physiology; Gerbillinae; Hippocampus - drug effects; Hippocampus - metabolism; Medical sciences; Neurology; Organ Culture Techniques; Purinergic P2 Receptor Antagonists; Rats; Rats, Wistar; Receptors, Purinergic P2 - biosynthesis; Receptors, Purinergic P2X2; Receptors, Purinergic P2X4; Up-Regulation - drug effects; Up-Regulation - physiology; Vascular diseases and vascular malformations of the nervous system; Nervous system diseases; Neuroglia; Rodentia; Organotypic culture; P2 Purinergic receptor; Cardiovascular disease; Cerebral disorder; Microglia; Vascular disease; carotid occlusion; Vertebrata; Experimental disease; Mammalia; Ischemia; Cell death; Animal; Central nervous system disease; Antagonist; organotypic cultures; Gerbil; Cerebrovascular disease; Brain (vertebrata)
• ISSN: 0306-4522; 1873-7544
• DOI: 10.1016/s0306-4522(03)00228-8

In the present work we examined the involvement of selected P2X receptors for extracellular ATP in the onset of neuronal cell death caused by glucose/oxygen deprivation. The in vitro studies of organotypic cultures from hippocampus evidenced that P2X2 and P2X4 were up-regulated by glucose/oxygen deprivation. Moreover, we showed that ischemic conditions induced specific neuronal loss not only in hippocampal, but also in cortical and striatal organotypic cultures and the P2 receptor antagonists basilen blue and suramin prevented these detrimental effects. In the in vivo experiments we confirmed the induction of P2X receptors in the hippocampus of gerbils subjected to bilateral common carotid occlusion. In particular, P2X2 and P2X4 proteins became significantly up-regulated, although to different extent and in different cellular phenotypes. The induction was confined to the pyramidal cell layer of the CA1 subfield and to the transition zone of the CA2 subfield and it was coincident with the area of neuronal damage. P2X2 was expressed in neuronal cell bodies and fibers in the CA1 pyramidal cell layer and in the strata oriens and radiatum. Intense P2X4 immunofluorescence was localized to microglia cells. Our results indicate a direct involvement of P2X receptors in the mechanisms sustaining cell death evoked by metabolism impairment and suggest the use of selected P2 antagonists as effective neuroprotecting agents.