title: The Fas Ligand/Fas Death Receptor Pathways Contribute to Propofol-Induced Apoptosis and Neuroinflammation in the Brain of Neonatal Rats.
abstract: A number of experimental studies have reported that exposure to common, clinically used anesthetics induce extensive neuroapoptosis and cognitive impairment when applied to young rodents, up to 2 weeks old, in phase of rapid synaptogenesis. Propofol is the most used general anesthetic in clinical practice whose mechanisms of neurotoxicity on the developing brain remains to be examined in depth. This study investigated effects of different exposures to propofol anesthesia on Fas receptor and Fas ligand expressions, which mediate proapoptotic and proinflammation signaling in the brain. Propofol (20 mg/kg) was administered to 7-day-old rats in multiple doses sufficient to maintain 2-, 4- and 6-h duration of anesthesia. Animals were sacrificed at 0, 4, 16 and 24 h after termination of anesthesia. It was found that propofol anesthesia induced Fas/FasL and downstream caspase-8 expression more prominently in the thalamus than in the cortex. Opposite, Bcl-2 and caspase-9, markers of intrinsic pathway activation, were shown to be more influenced by propofol treatment in the cortex. Further, we have established upregulation of caspase-1 and IL-1β cytokine transcription as well as subsequent activation of microglia that is potentially associated with brain inflammation. Behavioral analyses revealed that P35 and P60 animals, neonatally exposed to propofol, had significantly higher motor activity during three consecutive days of testing in the open field, though formation of the intersession habituation was not prevented. This data, together with our previous results, contributes to elucidation of complex mechanisms of propofol toxicity in developing brain.
authors.affiliation: Institute for Biological Research, Department of Neurobiology, University of Belgrade, Bulevar Despota Stefana 142, 11060, Belgrade, Serbia. desan@ibiss.bg.ac.rs.
authors.forename: Desanka
authors.initials: D
authors.lastname: Milanovic
authors.affiliation: Institute for Biological Research, Department of Neurobiology, University of Belgrade, Bulevar Despota Stefana 142, 11060, Belgrade, Serbia.
authors.forename: Vesna
authors.initials: V
authors.lastname: Pesic
authors.affiliation: Institute for Biological Research, Department of Neurobiology, University of Belgrade, Bulevar Despota Stefana 142, 11060, Belgrade, Serbia.
authors.forename: Natasa
authors.initials: N
authors.lastname: Loncarevic-Vasiljkovic
authors.affiliation: Institute for Biological Research, Department of Neurobiology, University of Belgrade, Bulevar Despota Stefana 142, 11060, Belgrade, Serbia.
authors.forename: Zeljko
authors.initials: Z
authors.lastname: Pavkovic
authors.affiliation: Department of Biochemistry and Goodman Cancer Research Centre, McGill University, Montreal, QC, Canada.
authors.forename: Jelena
authors.initials: J
authors.lastname: Popic
authors.affiliation: Institute for Biological Research, Department of Neurobiology, University of Belgrade, Bulevar Despota Stefana 142, 11060, Belgrade, Serbia.
authors.forename: Selma
authors.initials: S
authors.lastname: Kanazir
authors.affiliation: Department of Anesthesiology, University of Virginia Health System, Charlottesville, VA, 22908, USA.
authors.forename: Vesna
authors.initials: V
authors.lastname: Jevtovic-Todorovic
authors.affiliation: Institute for Biological Research, Department of Neurobiology, University of Belgrade, Bulevar Despota Stefana 142, 11060, Belgrade, Serbia.
authors.forename: Sabera
authors.initials: S
authors.lastname: Ruzdijic
mesh_terms: D018686:Anesthetics, Intravenous / Q000633:toxicity; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D001921:Brain / Q000187:drug effects* / Q000254:growth & development* / Q000276:immunology / Q000473:pathology; D020170:Caspase 1 / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D053222:Fas Ligand Protein / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism; D008297:Male; D017628:Microglia / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D015213:Neuroimmunomodulation / Q000187:drug effects / Q000502:physiology; D015742:Propofol / Q000633:toxicity*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D017208:Rats, Wistar; D013997:Time Factors; D019014:fas Receptor / Q000378:metabolism*
chemical_list: D018686:Anesthetics, Intravenous; C000617196:Bcl2 protein, rat; D053222:Fas Ligand Protein; C491898:Fas protein, rat; C505662:Faslg protein, rat; C000594089:IL1B protein, rat; D053583:Interleukin-1beta; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D019014:fas Receptor; C505528:Casp8 protein, rat; C506435:Casp9 protein, rat; D053181:Caspase 8; D053453:Caspase 9; D020170:Caspase 1; D015742:Propofol
keywords: Bcl-2 gene family; Caspasa-1; FasL/Fas receptor; IL-1β cytokine; Microglia activation; Propofol toxicity