The Fas Ligand/Fas Death Receptor Pathways Contribute to Propofol-Induced Apoptosis and Neuroinflammation in the Brain of Neonatal Rats

Neurotox Res. 2016 Oct;30(3):434-52. doi: 10.1007/s12640-016-9629-1. Epub 2016 May 17.

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.

Keywords: Bcl-2 gene family; Caspasa-1; FasL/Fas receptor; IL-1β cytokine; Microglia activation; Propofol toxicity.

MeSH terms

  • Anesthetics, Intravenous / toxicity
  • Animals
  • Animals, Newborn
  • Apoptosis / drug effects*
  • Apoptosis / physiology
  • Brain / drug effects*
  • Brain / growth & development*
  • Brain / immunology
  • Brain / pathology
  • Caspase 1 / metabolism
  • Caspase 8 / metabolism
  • Caspase 9 / metabolism
  • Fas Ligand Protein / metabolism*
  • Interleukin-1beta / metabolism
  • Male
  • Microglia / drug effects
  • Microglia / immunology
  • Microglia / pathology
  • Motor Activity / drug effects
  • Motor Activity / physiology
  • Neuroimmunomodulation / drug effects
  • Neuroimmunomodulation / physiology
  • Propofol / toxicity*
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • RNA, Messenger / metabolism
  • Rats, Wistar
  • Time Factors
  • fas Receptor / metabolism*

Substances

  • Anesthetics, Intravenous
  • Bcl2 protein, rat
  • Fas Ligand Protein
  • Fas protein, rat
  • Faslg protein, rat
  • IL1B protein, rat
  • Interleukin-1beta
  • Proto-Oncogene Proteins c-bcl-2
  • RNA, Messenger
  • fas Receptor
  • Casp8 protein, rat
  • Casp9 protein, rat
  • Caspase 8
  • Caspase 9
  • Caspase 1
  • Propofol