title: Inhibition of ERK1/2 signaling prevents epileptiform behavior in rats prone to audiogenic seizures.
abstract: It has recently been proposed that extracellular signal-regulated kinases 1 and 2 (ERK1/2) are one of the factors mediating seizure development. We hypothesized that inhibition of ERK1/2 activity could prevent audiogenic seizures by altering GABA and glutamate release mechanisms. Krushinsky-Molodkina rats, genetically prone to audiogenic seizure, were recruited in the experiments. Animals were i.p. injected with an inhibitor of ERK1/2 SL 327 at different doses 60 min before audio stimulation. We demonstrated for the first time that inhibition of ERK1/2 activity by SL 327 injections prevented seizure behavior and this effect was dose-dependent and correlated with ERK1/2 activity. The obtained data also demonstrated unchanged levels of GABA production, and an increase in the level of vesicular glutamate transporter 2. The study of exocytosis protein expression showed that SL 327 treatment leads to downregulation of vesicle-associated membrane protein 2 and synapsin I, and accumulation of synaptosomal-associated protein 25 (SNAP-25). The obtained data indicate that the inhibition of ERK1/2 blocks seizure behavior presumably by altering the exocytosis machinery, and identifies ERK1/2 as a potential target for the development of new strategies for seizure treatment. Extracellular signal-regulated kinases 1 and 2 (ERK1/2) are one of the factors mediating seizure development. Here we report that inhibition of ERK1/2 by SL 327 prevented seizure behavior and this effect was dose-dependent and correlated with ERK1/2 activity. Accumulation of VGLUT2 was associated with differential changing of synaptic proteins VAMP2, SNAP-25 and synapsin I. The obtained data indicate that the inhibition of ERK1/2 alters neurotransmitter release by changing the exocytosis machinery, thus preventing seizures.
authors.affiliation: Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, Saint-Petersburg, Russia.
authors.forename: Margarita V
authors.initials: MV
authors.lastname: Glazova
authors.forename: Liubov S
authors.initials: LS
authors.lastname: Nikitina
authors.forename: Kirill A
authors.initials: KA
authors.lastname: Hudik
authors.forename: Olga D
authors.initials: OD
authors.lastname: Kirillova
authors.forename: Nadezhda A
authors.initials: NA
authors.lastname: Dorofeeva
authors.forename: Anatoly A
authors.initials: AA
authors.lastname: Korotkov
authors.forename: Elena V
authors.initials: EV
authors.lastname: Chernigovskaya
mesh_terms: D000161:Acoustic Stimulation / Q000009:adverse effects; D000607:Aminoacetonitrile / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D001921:Brain / Q000378:metabolism; D050882:CREB-Binding Protein / Q000378:metabolism; D020195:Epilepsy, Reflex / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D005089:Exocytosis / Q000187:drug effects; D005260:Female; D018698:Glutamic Acid / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects* / Q000502:physiology; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors* / Q000502:physiology; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors* / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000502:physiology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D051381:Rats; D011922:Rats, Mutant Strains; D011930:Reaction Time / Q000187:drug effects; D013569:Synapses / Q000187:drug effects / Q000378:metabolism; D016704:Synapsins / Q000378:metabolism; D050825:Synaptosomal-Associated Protein 25 / Q000378:metabolism; D050988:Vesicle-Associated Membrane Protein 2 / Q000378:metabolism; D050599:Vesicular Glutamate Transport Protein 2 / Q000096:biosynthesis / Q000235:genetics; D005680:gamma-Aminobutyric Acid / Q000096:biosynthesis / Q000378:metabolism
chemical_list: D009419:Nerve Tissue Proteins; D047428:Protein Kinase Inhibitors; C424127:SL 327; C493475:Slc17a6 protein, rat; C494210:Snap25 protein, rat; D016704:Synapsins; D050825:Synaptosomal-Associated Protein 25; C494706:Vamp2 protein, rat; D050988:Vesicle-Associated Membrane Protein 2; D050599:Vesicular Glutamate Transport Protein 2; D000607:Aminoacetonitrile; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D050882:CREB-Binding Protein; C494365:Crebbp protein, rat; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3
keywords: SL 327; SNAP25; VAMP2; VGLUT2; synapsin I