RESUMO
Delayed treatment of cholinergic seizure results in benzodiazepine-refractory status epilepticus (SE) that is thought, at least in part, to result from maladaptive trafficking of N-methyl-d-aspartate (NMDA) and gamma-aminobutyric acid type A (GABAA) receptors, the effects of which may be ameliorated by combination therapy with the NMDA receptor antagonist ketamine. Our objective was to establish whether ketamine and midazolam dual therapy would improve outcome over midazolam monotherapy following soman (GD) exposure when evaluated in a mouse model that, similar to humans, lacks plasma carboxylesterase, greatly reducing endogenous scavenging of GD. In the current study, continuous cortical electroencephalographic activity was evaluated in male and female plasma carboxylesterase knockout mice exposed to a seizure-inducing dose of GD and treated with midazolam or with midazolam and ketamine combination at 40â¯min after seizure onset. Ketamine and midazolam combination reduced GD-induced lethality, seizure severity, and the number of mice that developed spontaneous recurrent seizure (SRS) compared with midazolam monotherapy. In addition, ketamine-midazolam combination treatment reduced GD-induced neuronal degeneration and microgliosis. These results support that combination of antiepileptic drug therapies aimed at correcting the maladaptive GABAA and NMDA receptor trafficking reduces the detrimental effects of GD exposure. Ketamine may be a beneficial adjunct to midazolam in reducing the epileptogenesis and neuroanatomical damage that follows nerve agent exposure and pharmacoresistant SE.
Assuntos
Encéfalo/patologia , Carboxilesterase/sangue , Ketamina/administração & dosagem , Midazolam/administração & dosagem , Soman/toxicidade , Estado Epiléptico/sangue , Animais , Anticonvulsivantes/administração & dosagem , Encéfalo/efeitos dos fármacos , Carboxilesterase/deficiência , Quimioterapia Combinada , Eletroencefalografia/métodos , Feminino , Masculino , Camundongos , Camundongos Knockout , Convulsões/sangue , Convulsões/induzido quimicamente , Convulsões/tratamento farmacológico , Estado Epiléptico/induzido quimicamente , Estado Epiléptico/tratamento farmacológicoRESUMO
Eukaryotes employ complex immune mechanisms for protection against microbial pathogens. Here, we identified SCD1 (Stomatal Cytokinesis-Defective 1), previously implicated in growth and development through its role in cytokinesis and polarized cell expansion (Falbel, T. G., Koch, L. M., Nadeau, J. A., Segui-Simarro, J. M., Sack, F. D., and Bednarek, S. Y. (2003) Development 130, 4011-4024) as a novel component of innate immunity. In Arabidopsis, SCD1 is a unique gene encoding for the only protein containing a complete DENN (Differentially Expressed in Normal and Neoplastic cells) domain. The DENN domain is a largely uncharacterized tripartite protein motif conserved among eukaryotic proteins. We show that conditional scd1-1 plants containing a point mutation in a conserved DENN residue affected a subset of signaling responses to some bacterial pathogen-associated molecular patterns (PAMPs). Consistent with increased transcript accumulation of Pathogen-related (PR) genes, scd1-1 plants were more resistant to Pseudomonas syringae pathovar tomato (Pst) DC3000 infection implicating SCD1 as a negative regulator of basal resistance against bacteria. scd1-1 plants were different from known mutants exhibiting constitutive expressor of PR (cpr)-like phenotypes, in that growth impairment of scd1-1 plants was genetically independent of constitutive immune response activation. For scd1-1, shift to elevated temperature or introduction of a mutant allele in Salicylic acid Induction-Deficient 2 (SID2) suppressed constitutive defense response activation. sid2-2 also repressed the resistance phenotype of scd1-1. Temperature shift and sid2-2, however, did not rescue conditional growth and sterility defects of scd1-1. These results implicate SCD1 in multiple cellular pathways, possibly by affecting different proteins. Overall, our studies identified a novel role for eukaryotic DENN proteins in immunity against bacteria.