The Fas Ligand/Fas Death Receptor Pathways Contribute to Propofol-Induced Apoptosis and Neuroinflammation in the Brain of Neonatal Rats
- 446 Downloads
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.
KeywordsPropofol toxicity FasL/Fas receptor Bcl-2 gene family Caspasa-1 IL-1β cytokine Microglia activation
This work was supported by the Grant ON173056 from the Ministry of Education, Science and Technological Development of the Republic of Serbia.
Compliance with ethical standards
Conflict of interest
No conflict of interest to declare.
- Clark RS, Kochanek PM, Chen M, Watkins SC, Marion DW, Chen J, Hamilton RL, Loeffert JE, Graham SH (1999) Increases in bcl-2 and cleavage of caspase-1 and caspase-3 in human brain after head injury. FASEB J 8:813–821Google Scholar
- Fredriksson A, Ponten E, Gordh T, Eriksson P (2007) Neonatal exposure to a combination of N-methyl-d-aspartate and gamma-aminobutyric acid type A receptor anesthetic agents potentiates apoptotic neurodegeneration and persistent behavioral deficits. Anesthesiology 107:427–436PubMedCrossRefGoogle Scholar
- Lei X, Guo Q, Zhang J (2012) Mechanistic insights into neurotoxicity induced by anesthetics in the developing brain. Int J Med Sci 13(6):6772–6799Google Scholar
- Milanovic D, Popic J, Pesic V, Loncarevic-Vasiljkovic N, Kanazir S, Jevtovic-Todorovic V, Ruzdijic S (2010) Regional and temporal profiles of calpain and caspase-3 activities in postnatal rat brain following repeated propofol administration. Dev Neurosci 32:288–301PubMedPubMedCentralCrossRefGoogle Scholar
- Milanovic D, Pesic V, Popic J, Tanic N, Kanazir S, Jevtovic-Todorovic V, Ruzdijic S (2014) Propofol anesthesia induces proapoptotic tumor necrosis factor-α and pro-nerve growth factor signaling as well as prosurvival Akt and XIAP expression in neonatal rat brain. J Neurosci Res 92:1362–1373PubMedPubMedCentralCrossRefGoogle Scholar
- Pesic V, Milanovic D, Popic J, Smiljanic K, Tesic V, Kanazir S, Jevtovic-Todorovic V, Ruzidijic S (2015) Neonatal propofol anesthesia modifies activity-dependent processes and induces transient hyperlocomotor response to d-amphetamine during adolescence in rats. Int J Devl neuroscience 47:266–277CrossRefGoogle Scholar
- Sprung J, Flick R, Katusic S, Colligan RC, Barbaresi WJ, Bojanic K, Welch TL, Olson MD, Hanson AC, Schroeder DR, Wilder RT, Warner DO (2012) Attention-deficit/hyperactivity disorder after early exposure to procedures requiring general anesthesia. Mayo Clin Proc 87(2):120–129PubMedPubMedCentralCrossRefGoogle Scholar