title: Antiepileptic action of c-Jun N-terminal kinase (JNK) inhibition in an animal model of temporal lobe epilepsy.
abstract: Several phosphorylation signaling pathways have been implicated in the pathogenesis of epilepsy arising from both genetic causes and acquired insults to the brain. Identification of dysfunctional signaling pathways in epilepsy may provide novel targets for antiepileptic therapies. We previously described a deficit in phosphorylation signaling mediated by p38 mitogen-activated protein kinase (p38 MAPK) that occurs in an animal model of temporal lobe epilepsy, and that produces neuronal hyperexcitability measured in vitro. We asked whether in vivo pharmacological manipulation of p38 MAPK activity would influence seizure frequency in chronically epileptic animals. Administration of a p38 MAPK inhibitor, SB203580, markedly worsened spontaneous seizure frequency, consistent with prior in vitro results. However, anisomycin, a non-specific p38 MAPK activator, significantly increased seizure frequency. We hypothesized that this unexpected result was due to activation of a related MAPK, c-Jun N-terminal kinase (JNK). Administration of JNK inhibitor SP600125 significantly decreased seizure frequency in a dose-dependent manner without causing overt behavioral abnormalities. Biochemical analysis showed increased JNK expression and activity in untreated epileptic animals. These results show for the first time that JNK is hyperactivated in an animal model of epilepsy, and that phosphorylation signaling mediated by JNK may represent a novel antiepileptic target.
authors.affiliation: Departments of Chemistry and Biochemistry, University of Washington, Seattle, WA, United States.
authors.forename: Tina Y
authors.initials: TY
authors.lastname: Tai
authors.affiliation: Neurobiology Program, University of Washington, Seattle, WA, United States.
authors.forename: Lindsay N
authors.initials: LN
authors.lastname: Warner
authors.affiliation: Department of Neurology, University of Washington, Seattle, WA, United States.
authors.forename: Terrance D
authors.initials: TD
authors.lastname: Jones
authors.affiliation: Department of Neurology, University of Washington, Seattle, WA, United States.
authors.forename: Sangwook
authors.initials: S
authors.lastname: Jung
authors.affiliation: Department of Neurology, University of Washington, Seattle, WA, United States.
authors.forename: Francis A
authors.initials: FA
authors.lastname: Concepcion
authors.affiliation: Department of Chemistry, Seattle University, Seattle, WA, United States.
authors.forename: David W
authors.initials: DW
authors.lastname: Skyrud
authors.affiliation: Department of Neurosurgery, University of Washington, Seattle, WA, United States.
authors.forename: Jason
authors.initials: J
authors.lastname: Fender
authors.affiliation: Departments of Psychiatry and Pharmacology, University of Washington, Seattle, WA, United States.
authors.forename: Yusha
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Physiology and Biophysics, University of Washington, Seattle, WA, United States.
authors.forename: Aaron D
authors.initials: AD
authors.lastname: Williams
authors.affiliation: Departments of Psychiatry and Pharmacology, University of Washington, Seattle, WA, United States.
authors.forename: John F
authors.initials: JF
authors.lastname: Neumaier
authors.affiliation: Department of Neurosurgery, University of Washington, Seattle, WA, United States; Regional Epilepsy Center, University of Washington, Seattle, WA, United States.
authors.forename: Raimondo
authors.initials: R
authors.lastname: D'Ambrosio
authors.affiliation: Department of Neurology, University of Washington, Seattle, WA, United States; Department of Physiology and Biophysics, University of Washington, Seattle, WA, United States; Regional Epilepsy Center, University of Washington, Seattle, WA, United States. Electronic address: npoolos@uw.edu.
authors.forename: Nicholas P
authors.initials: NP
authors.lastname: Poolos
mesh_terms: D000818:Animals; D000841:Anisomycin / Q000494:pharmacology; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D000927:Anticonvulsants / Q000494:pharmacology*; D004195:Disease Models, Animal; D004833:Epilepsy, Temporal Lobe / Q000188:drug therapy* / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D000927:Anticonvulsants; D007093:Imidazoles; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D000841:Anisomycin; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580
keywords: antiepileptic drug; c-Jun N-terminal kinase (JNK); p38 mitogen activated kinase (p38 MAPK); phosphorylation; pilocarpine; temporal lobe epilepsy