title: Regulation of hippocampal Fas receptor and death-inducing signaling complex after kainic acid treatment in mice.
abstract: Kainic acid (KA)-induced brain neuronal cell death (especially in the hippocampus) was shown to be mainly mediated by the intrinsic (mitochondrial) apoptotic pathway. This study investigated the regulation of the extrinsic apoptotic pathway mediated by Fas ligand/Fas receptor and components of the indispensable death-inducing signaling complex (DISC) in the hippocampus (marked changes) and cerebral cortex (modest changes) of KA-treated mice. KA (45mg/kg) induced a severe behavioral syndrome with recurrent motor seizures (scores; maximal at 60-90min; minimal at 72h) with activation of hippocampal pro-apoptotic JNK (+2.5 fold) and increased GFAP (+57%) and nuclear PARP-1 fragmentation (+114%) 72h post-treatment (delayed neurotoxicity). In the extrinsic apoptotic pathway (hippocampus), KA (72h) reduced Fas ligand (-92%) and Fas receptor aggregates (-24%). KA (72h) also altered the contents of major DISC components: decreased FADD adaptor (-44%), reduced activation of initiator caspase-8 (-47%) and increased survival FLIP-S (+220%). Notably, KA (72h) upregulated the content of anti-apoptotic p-Ser191 FADD (+41%) and consequently the expression of p-FADD/FADD ratio (+1.9-fold), a neuroplastic index. Moreover, the p-FADD dependent transcription factor NF-κB was also increased (+61%) in the hippocampus after KA (72h). The convergent adaptation of the extrinsic apoptotic machinery 72h after KA in mice (with otherwise normal gross behavior) is a novel finding which suggests the induction of survival mechanisms to partly counteract the delayed neuronal death in the hippocampus.
authors.affiliation: Laboratori de Neurofarmacologia, IUNICS-IdISPa, Universitat de les Illes Balears (UIB), Palma de Mallorca, Spain; Redes Temáticas de Investigación Cooperativa en Salud-Red de Trastornos Adictivos (RETICS-RTA), Spain.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Keller
authors.affiliation: Laboratori de Neurofarmacologia, IUNICS-IdISPa, Universitat de les Illes Balears (UIB), Palma de Mallorca, Spain; Redes Temáticas de Investigación Cooperativa en Salud-Red de Trastornos Adictivos (RETICS-RTA), Spain. Electronic address: jesus.garcia-sevilla@uib.es.
authors.forename: Jesús A
authors.initials: JA
authors.lastname: García-Sevilla
mesh_terms: D000818:Animals; D001526:Behavioral Symptoms / Q000139:chemically induced; D053418:Death Domain Receptor Signaling Adaptor Proteins / Q000378:metabolism*; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects*; D006624:Hippocampus / Q000187:drug effects*; D007608:Kainic Acid / Q000494:pharmacology*; D008297:Male; D051379:Mice; D009419:Nerve Tissue Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013347:Subcellular Fractions / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors; D019014:fas Receptor / Q000378:metabolism*
chemical_list: D053418:Death Domain Receptor Signaling Adaptor Proteins; D018690:Excitatory Amino Acid Agonists; D009419:Nerve Tissue Proteins; D019014:fas Receptor; D007608:Kainic Acid
keywords: Cerebral cortex; Extrinsic apoptotic pathway; Hippocampus; Kainic acid; Mouse