Inhibiting of RIPK3 attenuates early brain injury following subarachnoid hemorrhage: Possibly through alleviating necroptosis

Biomed Pharmacother. 2018 Nov:107:563-570. doi: 10.1016/j.biopha.2018.08.056. Epub 2018 Aug 14.


Necroptosis is an inflammatory form of cell death that depends on receptor-interacting serine-threonine kinase 3 (RIPK3) and mixed lineage kinase domain-like (MLKL) and displays the morphological characteristics of necrosis. To date, it is unclear to what extent necroptosis contributes to subarachnoid hemorrhage (SAH) induced brain injury. The present study aimed to investigate the RIPK3-mediated necroptosis and the effects of the RIPK3 selective inhibitor GSK'872 in early brain injury following SAH. After SAH, RIPK3 expression increased as early as 6 h and peaked at 72 h. Double immunofluorescence staining revealed that RIPK3 was mainly located in neurons. Most necrotic cells were neurons, which were further confirmed by TEM. Intracerebroventricular injection of GSK'872 (25 mM) could attenuate brain edema and improve neurological function following SAH and reduce the number of necrotic cells. In addition, GSK'872 could also decrease the protein levels of RIPK3 and MLKL, and cytoplasmic translocation and expression of HMGB1, an important pro-inflammatory protein. Taken together, the current study provides the new evidence that RIPK3-mediated necroptosis is involved in early brain injury and GSK'872 decreases the RIPK3-mediated necroptosis and subsequent cytoplasmic translocation and expression of HMGB1, as well as ameliorates brain edema and neurological deficits.

Keywords: Early brain injury; GSK’872; Necroptosis; RIPK3; Subarachnoid hemorrhage.

MeSH terms

  • Animals
  • Apoptosis* / drug effects
  • Brain Injuries / etiology*
  • Brain Injuries / pathology*
  • Cytoplasm / metabolism
  • HMGB1 Protein / metabolism
  • Male
  • Necrosis
  • Neurons / metabolism
  • Neurons / pathology
  • Neurons / ultrastructure
  • Protein Kinase Inhibitors / administration & dosage
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinases / metabolism
  • Protein Transport / drug effects
  • Rats, Sprague-Dawley
  • Receptor-Interacting Protein Serine-Threonine Kinases / antagonists & inhibitors*
  • Receptor-Interacting Protein Serine-Threonine Kinases / metabolism
  • Subarachnoid Hemorrhage / complications*


  • HMGB1 Protein
  • Protein Kinase Inhibitors
  • MLKL protein, rat
  • Protein Kinases
  • Receptor-Interacting Protein Serine-Threonine Kinases