Neurotoxicity Research

, Volume 34, Issue 1, pp 79–92 | Cite as

Temporal Pattern and Crosstalk of Necroptosis Markers with Autophagy and Apoptosis Associated Proteins in Ischemic Hippocampus

  • Fari Ryan
  • Fariba Khodagholi
  • Leila Dargahi
  • Dariush Minai-Tehrani
  • Abolhassan Ahmadiani


Necroptosis, a novel type of programmed cell death, has been recently implicated as a possible mechanism for cerebral ischemia-reperfusion (I/R) injury. We herein studied time-dependent changes of necroptosis markers along with apoptosis- and autophagy-associated proteins in rat hippocampus at 1, 3, 6, 12, 24, and 48 h after global cerebral I/R injury. Furthermore, to determine the cross talk between autophagy and necroptosis, we examined the effects of pretreatment with bafilomycin-A1 (Baf-A1), as a late-stage autophagy inhibitor, on necroptosis. Highest levels of receptor-interacting protein 1 and 3 (RIP1 and RIP3), as key mediators of necroptosis, were observed at 24 h after reperfusion. Alongside, activity of glutamate dehydrogenase (GLUD1), downstream enzyme of RIP3, was increased. Peak time of necroptosis was subsequent to caspase-3-dependent cell death that peaked at 12 h of reperfusion but concurrent with autophagy. Administration of Baf-A1 could attenuate necroptosis, verified by decrease in RIP1 and RIP3 protein levels, as well as GLUD1 activity. However, there was no significant change in caspase-3-dependent cell death. Taken together, our results highlight that global cerebral I/R activates necroptosis that could be triggered by autophagy and interacts reversely with caspase-3-dependent apoptosis.


Necroptosis Autophagy Apoptosis Global cerebral ischemia-reperfusion Bafilomycin-A1 Neural cell death 



This work is part of Ph.D. thesis carried out by the first author at Shahid Beheshti University of Medical Sciences.

Compliance with Ethical Standards

All experiments used in this study were performed in accordance with Ethics Committee of Shahid Beheshti University of Medical Sciences in accordance with the international guidelines for animal experiments (NIH publication No. 80-23, revised 1996).


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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Fari Ryan
    • 1
  • Fariba Khodagholi
    • 1
  • Leila Dargahi
    • 2
  • Dariush Minai-Tehrani
    • 3
  • Abolhassan Ahmadiani
    • 1
  1. 1.Neuroscience Research CenterShahid Beheshti University of Medical SciencesTehranIran
  2. 2.NeuroBiology Research CenterShahid Beheshti University of Medical SciencesTehranIran
  3. 3.Bioresearch Lab, Faculty of Biological SciencesShahid Beheshti University G.CTehranIran

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