The role of muscarinic acetylcholine receptor-mediated activation of extracellular signal-regulated kinase 1/2 in pilocarpine-induced seizures.
Pilocarpine-induced seizures are mediated by the M(1) subtype of muscarinic acetylcholine receptor (mAChR), but little is known about the signaling mechanisms linking the receptor to seizures. The extracellular signal-regulated kinase (ERK) signaling cascade is activated by M(1) mAChR and is elevated during status epilepticus. Yet, the role of ERK activation prior to seizure has not been evaluated. Here, we examine the role of pilocarpine-induced ERK activation in the induction of seizures in mice by pharmacological and behavioral approaches. We show that pilocarpine induces ERK activation prior to the induction of seizures by both western blot and immunocytochemistry with an antibody to phosphorylated ERK. In addition, we show that the ERK pathway inhibitor SL327 effectively blocks the pilocarpine-induced ERK activation. However, SL327 pretreatment has no effect on the initiation of seizures. In fact, animals treated with SL327 had higher seizure-related mortality than vehicle-treated animals, suggesting activated ERK may serve a protective role during seizures. In addition, ERK inhibition had no effect on the development of the long-term sequelae of status epilepticus (SE), including mossy fiber sprouting, neuronal death and spontaneous recurrent seizures.
Berkeley
Jennifer L
JL
Department of Neurology, Center for Neurodegenerative Disease, Emory University, Whitehead Biomedical Research Building, 615 Michael Street, Atlanta, GA 30322, USA.
Decker
Michael J
MJ
Levey
Allan I
AI
D000607:Aminoacetonitrile / Q000031:analogs & derivatives; D000818:Animals; D015153:Blotting, Western; D016923:Cell Death / Q000187:drug effects; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019599:Mossy Fibers, Hippocampal / Q000187:drug effects / Q000473:pathology; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D010862:Pilocarpine; D011480:Protease Inhibitors / Q000494:pharmacology; D011976:Receptors, Muscarinic / Q000378:metabolism*; D012008:Recurrence; D012640:Seizures / Q000139:chemically induced / Q000150:complications / Q000473:pathology / Q000503:physiopathology*; D013226:Status Epilepticus / Q000209:etiology / Q000503:physiopathology; D015996:Survival Rate
D004791:Enzyme Inhibitors; D011480:Protease Inhibitors; D011976:Receptors, Muscarinic; C424127:SL 327; D010862:Pilocarpine; D000607:Aminoacetonitrile; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases