P2X(7) receptor blockade prevents ATP excitotoxicity in oligodendrocytes and ameliorates experimental autoimmune encephalomyelitis.
Oligodendrocyte death and demyelination are hallmarks of multiple sclerosis (MS). Here we show that ATP signaling can trigger oligodendrocyte excitotoxicity via activation of calcium-permeable P2X(7) purinergic receptors expressed by these cells. Sustained activation of P2X(7) receptors in vivo causes lesions that are reminiscent of the major features of MS plaques, i.e., demyelination, oligodendrocyte death, and axonal damage. In addition, treatment with P2X(7) antagonists of chronic experimental autoimmune encephalomyelitis (EAE), a model of MS, reduces demyelination and ameliorates the associated neurological symptoms. Together, these results indicate that ATP can kill oligodendrocytes via P2X(7) activation and that this cell death process contributes to EAE. Importantly, P2X(7) expression is elevated in normal-appearing axon tracts in MS patients, suggesting that signaling through this receptor in oligodendrocytes may be enhanced in this disease. Thus, P2X(7) receptor antagonists may be beneficial for the treatment of MS.
Matute
Carlos
C
Departamento de Neurociencias, Universidad del País Vasco, 48940 Leioa, Spain. carlos.matute@ehu.es
Torre
Iratxe
I
Pérez-Cerdá
Fernando
F
Pérez-Samartín
Alberto
A
Alberdi
Elena
E
Etxebarria
Estibaliz
E
Arranz
Amaia M
AM
Ravid
Rivka
R
Rodríguez-Antigüedad
Alfredo
A
Sánchez-Gómez
MaríaVictoria
M
Domercq
María
M
D000255:Adenosine Triphosphate / Q000633:toxicity*; D000818:Animals; D000831:Animals, Newborn; D002118:Calcium / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000139:chemically induced / Q000628:therapy*; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006023:Glycoproteins; D006801:Humans; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D051379:Mice; D016253:Microscopy, Immunoelectron / Q000379:methods; D004676:Myelin Basic Protein / Q000378:metabolism; D063308:Myelin-Oligodendrocyte Glycoprotein; D009836:Oligodendroglia / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D009900:Optic Nerve / Q000166:cytology / Q000473:pathology / Q000648:ultrastructure; D018408:Patch-Clamp Techniques / Q000379:methods; D010446:Peptide Fragments; D010975:Platelet Aggregation Inhibitors; D058919:Purinergic P2 Receptor Antagonists; D051381:Rats; D017207:Rats, Sprague-Dawley; D018048:Receptors, Purinergic P2 / Q000502:physiology*; D058486:Receptors, Purinergic P2X7
D005904:Glial Fibrillary Acidic Protein; D006023:Glycoproteins; D004676:Myelin Basic Protein; D063308:Myelin-Oligodendrocyte Glycoprotein; C546468:P2RX7 protein, human; C546469:P2rx7 protein, mouse; D010446:Peptide Fragments; D010975:Platelet Aggregation Inhibitors; D058919:Purinergic P2 Receptor Antagonists; D018048:Receptors, Purinergic P2; D058486:Receptors, Purinergic P2X7; C445081:myelin oligodendrocyte glycoprotein (35-55); D000255:Adenosine Triphosphate; D002118:Calcium