The endoplasmic reticulum stress inhibitor salubrinal inhibits the activation of autophagy and neuroprotection induced by brain ischemic preconditioning

Acta Pharmacol Sin. 2013 May;34(5):657-66. doi: 10.1038/aps.2013.34. Epub 2013 Apr 22.


Aim: To investigate whether endoplasmic reticulum (ER) stress participates in the neuroprotective effects of ischemic preconditioning (IPC)-induced neuroprotection and autophagy activation in rat brains.

Methods: The right middle cerebral artery in SD rats was occluded for 10 min to induce focal cerebral IPC, and was occluded permanently 24 h later to induce permanent focal ischemia (PFI). ER stress inhibitor salubrinal (SAL) was injected via intracerebral ventricle infusion 10 min before the onset of IPC. Infarct volume and motor behavior deficits were examined after the ischemic insult. The protein levels of LC3, p62, HSP70, glucose-regulated protein 78 (GRP 78), p-eIF2α and caspase-12 in the ipsilateral cortex were analyzed using immunoblotting. LC3 expression pattern in the sections of ipsilateral cortex was observed with immunofluorescence.

Results: Pretreatment with SAL (150 pmol) abolished the neuroprotective effects of IPC, as evidenced by the significant increases in mortality, infarct volume and motor deficits after PFI. At the molecular levels, pretreatment with SAL (150 pmol) significantly increased p-eIF2α level, and decreased GRP78 level after PFI, suggesting that SAL effectively inhibited ER stress in the cortex. Furthermore, the pretreatment with SAL blocked the IPC-induced upregulation of LC3-II and downregulation of p62 in the cortex, thus inhibiting the activation of autophagy. Moreover,SAL blocked the upregulation of HSP70, but significantly increased the cleaved caspase-12 level, thus promoting ER stress-dependent apoptotic signaling in the cortex.

Conclusion: ER stress-induced autophagy might contribute to the neuroprotective effect of brain ischemic preconditioning.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Autophagy / drug effects*
  • Brain / blood supply
  • Brain / drug effects
  • Brain / metabolism
  • Brain / pathology*
  • Brain Ischemia / metabolism
  • Brain Ischemia / pathology*
  • Brain Ischemia / therapy*
  • Cinnamates / pharmacology*
  • Endoplasmic Reticulum Stress / drug effects*
  • Ischemic Preconditioning* / methods
  • Male
  • Rats
  • Rats, Sprague-Dawley
  • Signal Transduction / drug effects
  • Thiourea / analogs & derivatives*
  • Thiourea / pharmacology


  • Cinnamates
  • salubrinal
  • Thiourea