Antiepileptic action of c-Jun N-terminal kinase (JNK) inhibition in an animal model of temporal lobe epilepsy. (4th May 2017)

• Record Type: Journal Article
• Authors: Tai, Tina Y.; Warner, Lindsay N.; Jones, Terrance D.; Jung, Sangwook; Concepcion, Francis A.; Skyrud, David W.; Fender, Jason; Liu, Yusha; Williams, Aaron D.; Neumaier, John F.; D'Ambrosio, Raimondo; Poolos, Nicholas P.
• Is Part Of: Neuroscience. Volume 349(2017)
• Page Start: 35
• Page End: 47
• Publication Date: 2017-05-04
• Subjects: AED antiepileptic drug -- AMPA α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid -- ANI anisomycin -- C1-5 Racine class 1-5 -- Cav3.2 voltage-gated calcium channel type 3.2 -- CI confidence interval -- CSF cerebrospinal fluid -- EEG electroencephalogram -- GABAA γ-aminobutyric acid type A -- HCN hyperpolarization-activated, cyclic nucleotide-gated -- i.c.v. intracerebroventricular -- i.p. intraperitoneal -- JIP3 JNK-interacting protein -- JNK c-Jun N-terminal kinase -- Kv4.2 voltage-gated potassium channel type 4.2 -- LTG lamotrigine -- mTOR mammalian target of rapamycin -- p38 MAPK p38 mitogen-activated protein kinase -- PB phenobarbital -- pJNK phosphorylated JNK -- SB SB203580 -- SE status epilepticus -- SEM standard error of mean -- Ser serine -- SP SP600125 -- Thr threonine -- TLE temporal lobe epilepsy -- TS tuberous sclerosis -- Tyr tyrosine; c-Jun N-terminal kinase (JNK) -- antiepileptic drug -- p38 mitogen activated kinase (p38 MAPK) -- temporal lobe epilepsy -- pilocarpine -- phosphorylation; Neurochemistry -- Periodicals; Neurophysiology -- Periodicals; Neurology -- Periodicals; Neurochimie -- Périodiques; Neurophysiologie -- Périodiques; Neurochemistry; Neurophysiology; Electronic journals; Periodicals; Electronic journals; 612.8
• DOI: 10.1016/j.neuroscience.2017.02.024
• Languages: English
• ISSNs: 0306-4522

Abstract

Highlights: Inhibition of c-Jun N-terminal kinase (JNK) produces a dose-dependent antiepileptic effect in an animal model of epilepsy. JNK is hyperactivated in hippocampal tissue from chronically epileptic animals. JNK inhibition did not produce behavioral abnormalities. Inhibition of p38 mitogen-activated protein kinase (p38 MAPK) yielded a proconvulsive effect. 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.