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The Journal of Neuroscience, August 29, 2007, 27(35):9525-9533; doi:10.1523/JNEUROSCI.0579-07.2007

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 Previous Article

Neurobiology of Disease
P2X7 Receptor Blockade Prevents ATP Excitotoxicity in Oligodendrocytes and Ameliorates Experimental Autoimmune Encephalomyelitis

Carlos Matute,1 Iratxe Torre,1 Fernando Pérez-Cerdá,1 Alberto Pérez-Samartín,1 Elena Alberdi,1 Estibaliz Etxebarria,1 Amaia M. Arranz,1 Rivka Ravid,2 Alfredo Rodríguez-Antigüedad,3 MaríaVictoria Sánchez-Gómez,1 and María Domercq1

1Departamento de Neurociencias, Universidad del País Vasco, 48940 Leioa, Spain, 2Netherland Brain Bank, 1105 AZ Amsterdam ZO, The Netherlands, and 3Servicio de Neurología, Hospital de Basurto, 48008 Bilbao, Spain

Correspondence should be addressed to Carlos Matute, Departamento de Neurociencias, Universidad del País Vasco, 48940 Leioa, Spain. Email: carlos.matute{at}ehu.es

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 P2X7 purinergic receptors expressed by these cells. Sustained activation of P2X7 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 P2X7 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 P2X7 activation and that this cell death process contributes to EAE. Importantly, P2X7 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, P2X7 receptor antagonists may be beneficial for the treatment of MS.

Key words: oligodendrocytes; ATP; excitotoxicity; demyelination; EAE; multiple sclerosis

Received Feb. 9, 2007; revised July 12, 2007; accepted July 13, 2007.

Correspondence should be addressed to Carlos Matute, Departamento de Neurociencias, Universidad del País Vasco, 48940 Leioa, Spain. Email: carlos.matute{at}ehu.es


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