Necroptosis in global cerebral ischemia: a role for endoplasmic reticulum stress

The use of salubrinal, an agent that promotes the unfolded protein response (UPR) and alleviates endoplasmic reticulum (ER) stress, has been reported to maintain a neuroprotective effect after 7 days of ischemia (Anuncibay-Soto et al., 2016). [...]data extracted from Font-Belmonte et al. In this regard, salubrinal has been reported to decrease inflammation in different models of brain damage (Logsdon et al., 2016), including a global cerebral ischemia model (Anuncibay-Soto et al., 2016). [...]the decrease observed in necroptosis following salubrinal treatment could be a consequence of the UPR-dependent reduction in inflammation or because UPR decreases ER stress, resulting in the alleviation of the necroptosis pathway (Font-Belmonte et al., 2019). The analysis of the necroptosis markers provides some interesting hints on the time course of the necroptotic pathway. [...]RIPK3 phosphorylation, which represents a crucial stage in necroptosome formation and MLKL activation (Galluzzi et al., 2018), decreases from 48 to 72 hours after ischemia and supports the idea of a relatively long temporal sequence in the activation of MLKL rather than a simultaneous response to the activation of the necroptosome. [...]the report of Font-Belmonte highlights the differences in the necroptotic response in cerebral cortex and CA1, where data on current necroptosis markers are less consistent in the hippocampus.