Protein synthesis inhibition occurs in neurons immediately on reperfusion after ischemia and involves at least alterations in eukaryotic initiation factors 2 (eIF2) and 4 (eIF4). Phosphorylation of the α subunit of eIF2 [eIF2(αP)] by the endoplasmic reticulum transmembrane eIF2α kinase PERK occurs immediately on reperfusion and inhibits translation initiation. PERK activation, along with depletion of endoplasmic reticulum Ca²⁺ and inhibition of the endoplasmic reticulum Ca²⁺-ATPase, SERCA2b, indicate that an endoplasmic reticulum unfolded protein response occurs as a consequence of brain ischemia and reperfusion. In mammals, the upstream unfolded protein response components PERK, IRE1, and ATF6 activate prosurvivial mechanisms (e.g., transcription of GRP78, PDI, SERCA2b) and proapoptotic mechanisms (i.e., activation of Jun N-terminal kinases, caspase-12, and CHOP transcription). Sustained eIF2(αP) is proapoptotic by inducing the synthesis of ATF4, the CHOP transcription factor, through “bypass scanning” of 5‘ upstream open-reading frames in ATF4 messenger RNA; these upstream open-reading frames normally inhibit access to the ATF4 coding sequence. Brain ischemia and reperfusion also induce μ-calpain–mediated or caspase-3–mediated proteolysis of eIF4G, which shifts message selection to m⁷G-cap–independent translation initiation of messenger RNAs containing internal ribosome entry sites. This internal ribosome entry site–mediated translation initiation (i.e., for apoptosis-activating factor-1 and death-associated protein-5) can also promote apoptosis. Thus, alterations in eIF2 and eIF4 have major implications for which messenger RNAs are translated by residual protein synthesis in neurons during brain reperfusion, in turn constraining protein expression of changes in gene transcription induced by ischemia and reperfusion. Therefore, our current understanding shifts the focus from protein synthesis inhibition to the molecular pathways that underlie this inhibition, and the role that these pathways play in prosurvival and proapoptotic processes that may be differentially expressed in vulnerable and resistant regions of the reperfused brain.

A persistent translation arrest (TA) correlates precisely with the selective vulnerability of post‐ischemic neurons. Mechanisms of post‐ischemic TA that have been assessed include ribosome biochemistry, the link between TA and stress responses, and the inactivation of translational components via sequestration in subcellular structures. Each of these approaches provides a perspective on post‐ischemic TA. Here, we develop the notion that mRNA regulation via RNA‐binding proteins, or ribonomics, also contributes to post‐ischemic TA. We describe the ribonomic network, or structures involved in mRNA regulation, including nuclear foci, polysomes, stress granules, embryonic lethal abnormal vision/Hu granules, processing bodies, exosomes, and RNA granules. Transcriptional, ribonomic, and ribosomal regulation together provide multiple layers mediating cell reprogramming. Stress gene induction via the heat‐shock response, immediate early genes, and endoplasmic reticulum stress represents significant reprogramming of post‐ischemic neurons. We present a model of post‐ischemic TA in ischemia‐resistant neurons that incorporates ribonomic considerations. In this model, selective translation of stress‐induced mRNAs contributes to translation recovery. This model provides a basis to study dysfunctional stress responses in vulnerable neurons, with a key focus on the inability of vulnerable neurons to selectively translate stress‐induced mRNAs. We suggest a ribonomic approach will shed new light on the roles of mRNA regulation in persistent TA in vulnerable post‐ischemic neurons.