Premium
Mechanisms of neuroprotection against ischemic insult by stress‐inducible phosphoprotein‐1/prion protein complex
Author(s) -
Beraldo Flavio H.,
Ostapchenko Valeriy G.,
Xu Jason Z.,
Di Guglielmo Gianni M.,
Fan Jue,
Nicholls Peter J.,
Caron Marc G.,
Prado Vania F.,
Prado Marco A. M.
Publication year - 2018
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.14281
Subject(s) - neuroprotection , phosphoprotein , microbiology and biotechnology , receptor , ischemia , neuroscience , medicine , pharmacology , biology , phosphorylation
Stress‐inducible phosphoprotein 1 ( STI 1) acts as a neuroprotective factor in the ischemic brain and its levels are increased following ischemia. Previous work has suggested that some of these STI 1 actions in a stroke model depend on the recruitment of bone marrow‐derived stem cells to improve outcomes after ischemic insult. However, STI 1 can directly increase neuroprotective signaling in neurons by engaging with the cellular prion protein (Pr P C ) and activating α7 nicotinic acetylcholine receptors (α7n AC hR). Given that α7n AC hR activation has also been involved in neuroprotection in stroke, it is possible that STI 1 can have direct actions on neurons to prevent deleterious consequences of ischemic insults. Here, we tested this hypothesis by exposing primary neuronal cultures to 1‐h oxygen‐glucose deprivation ( OGD ) and reperfusion and assessing signaling pathways activated by STI 1/Pr P C . Our results demonstrated that STI 1 treatment significantly decreased apoptosis and cell death in mouse neurons submitted to OGD in a manner that was dependent on Pr P C and α7n AC hR, but also on the activin A receptor 1 ( ALK 2), which has emerged as a signaling partner of STI 1. Interestingly, pharmacological inhibition of the ALK 2 receptor prevented neuroprotection by STI 1, while activation of ALK 2 receptors by bone morphogenetic protein 4 ( BMP 4) either before or after OGD was effective in decreasing neuronal death induced by ischemia. We conclude that Pr P C / STI 1 engagement and its subsequent downstream signaling cascades involving α7n AC hR as well as the ALK 2 receptor may be activated in neurons by increased levels of STI 1. This signaling pathway protects neurons from ischemic insults.