TNF-α Mediates the Intrinsic and Extrinsic Pathway in Propofol-Induced Neuronal Apoptosis Via PI3K/Akt Signaling Pathway in Rat Prefrontal Cortical Neurons

Neurotox Res. 2017 Oct;32(3):409-419. doi: 10.1007/s12640-017-9751-8. Epub 2017 May 24.

Abstract

Propofol can cause developing neuronal apoptosis in both in vivo and in vitro studies, and the mechanism is unclear till now. Our previous study has demonstrated that propofol can increase the TNF-α expression in the prefrontal cortex in rat developing brain, the TNF-α antagonist, etanercept, can inhibit propofol-induced neuronal apoptosis, but little is known about how TNF-α mediates that process. This study reveals that propofol at clinically relevant concentrations increases the TNF-α synthesis and release in neurons, and induces neuronal apoptosis; etanercept significantly reduces neuronal apoptosis, the elevation of cleaved caspase-8 and cleaved caspase-9, or the Akt phosphorylation induced by propofol, while the selective PI3K antagonist blocks the neuroprotection of etanercept. Propofol does not change the expression of P2X7 receptor in neurons, and the P2X7 receptor antagonist cannot affect the TNF-α synthesis or release after propofol treatment. These results suggest that propofol can increase the synthesis and release of TNF-α in the primary cultured prefrontal cortical neurons, TNF-α contributes to the intrinsic and extrinsic pathway in propofol-induced neuronal apoptosis via PI3K/Akt signaling pathway, and P2X7R is not involved in the synthesis and release of TNF-α induced by propofol.

Keywords: Apoptosis; Neurotoxicity; P2X7 receptor; PI3K/Akt; Propofol; TNF-α.

MeSH terms

  • Animals
  • Apoptosis / drug effects*
  • Apoptosis / physiology
  • Caspase 8 / metabolism
  • Caspase 9 / metabolism
  • Cells, Cultured
  • Etanercept / pharmacology
  • Hypnotics and Sedatives / toxicity
  • Neurons / drug effects*
  • Neurons / metabolism
  • Neurons / pathology
  • Neuroprotective Agents / pharmacology
  • Phosphatidylinositol 3-Kinases / metabolism
  • Prefrontal Cortex / drug effects*
  • Prefrontal Cortex / metabolism
  • Prefrontal Cortex / pathology
  • Propofol / toxicity*
  • Proto-Oncogene Proteins c-akt / metabolism
  • Rats, Sprague-Dawley
  • Receptors, Purinergic P2X7 / metabolism
  • Signal Transduction / drug effects
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors
  • Tumor Necrosis Factor-alpha / metabolism*

Substances

  • Hypnotics and Sedatives
  • Neuroprotective Agents
  • Receptors, Purinergic P2X7
  • Tumor Necrosis Factor-alpha
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-akt
  • Casp8 protein, rat
  • Casp9 protein, rat
  • Caspase 8
  • Caspase 9
  • Etanercept
  • Propofol