Abstract
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.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Adenosine Triphosphate / toxicity*
-
Animals
-
Animals, Newborn
-
Calcium / metabolism
-
Cell Survival / drug effects
-
Cell Survival / physiology
-
Cells, Cultured
-
Encephalomyelitis, Autoimmune, Experimental / chemically induced
-
Encephalomyelitis, Autoimmune, Experimental / therapy*
-
Glial Fibrillary Acidic Protein / metabolism
-
Glycoproteins
-
Humans
-
Membrane Potentials / drug effects
-
Membrane Potentials / physiology
-
Membrane Potentials / radiation effects
-
Mice
-
Microscopy, Immunoelectron / methods
-
Myelin Basic Protein / metabolism
-
Myelin-Oligodendrocyte Glycoprotein
-
Oligodendroglia / drug effects*
-
Oligodendroglia / metabolism
-
Oligodendroglia / ultrastructure
-
Optic Nerve / cytology
-
Optic Nerve / pathology
-
Optic Nerve / ultrastructure
-
Patch-Clamp Techniques / methods
-
Peptide Fragments
-
Platelet Aggregation Inhibitors
-
Purinergic P2 Receptor Antagonists*
-
Rats
-
Rats, Sprague-Dawley
-
Receptors, Purinergic P2 / physiology*
-
Receptors, Purinergic P2X7
Substances
-
Glial Fibrillary Acidic Protein
-
Glycoproteins
-
Myelin Basic Protein
-
Myelin-Oligodendrocyte Glycoprotein
-
P2RX7 protein, human
-
P2rx7 protein, mouse
-
Peptide Fragments
-
Platelet Aggregation Inhibitors
-
Purinergic P2 Receptor Antagonists
-
Receptors, Purinergic P2
-
Receptors, Purinergic P2X7
-
myelin oligodendrocyte glycoprotein (35-55)
-
Adenosine Triphosphate
-
Calcium