Brain injury triggers cell‐type‐specific and time‐dependent endoplasmic reticulum stress responses

Abstract

The unfolded protein response (UPR) is a signal transduction network that responds to endoplasmic reticulum (ER) stress by coordinating protein homeostasis to maintain cell viability. The UPR can also trigger cell death when adaptive responses fail to improve protein homeostasis. Despite accumulating evidence suggesting that the UPR plays a role in neurodegenerative diseases and brain insults, our understanding of how ER stress is induced under neuropathological conditions is limited. Here, we investigated the celland time-specific patterns of the ER stress response after brain injury using ER stressactivated indicator (ERAI) mice, which enable monitoring of the UPR in vivo via increased fluorescence of a spliced XBP-1 protein fused with the green fluorescent protein (GFP) variant Venus. Following cortical stab injury of ERAI mice, the GFP signal and number of GFP + cells increased in the ipsilateral cortex throughout the observation period (6 h to 7 days post-injury), confirming the induction of the UPR. GFP signals were observed in injured neurons early (from 6 h) after brain injury. However, non-neuronal cells, mainly endothelial cells followed by astrocytes, accounted for the majority of GFP + cells after brain injury. Similar results were obtained in a mouse model of focal cerebral ischemia. These findings suggest that activation of the UPR in both neuronal and non-neuronal cells, especially endothelial cells and astrocytes, may play an important role in and could be a potential therapeutic target for acute brain injuries.

Prenatal alcohol alters inflammatory signatures in enteric portal tissues following adult-onset cerebrovascular ischemic stroke

“…An important limitation of this study relates to experimental design considerations in that we elected to not perform a sham surgery (including anesthesia and needle insertion into the brain) on our stroke-naive animals. We chose this strategy because needle insertion recapitulates the “stab injury” model of traumatic brain injury 44 and is by itself an acute adult-onset disease model. Therefore, in this study, the stroke exposure experience included the effects of both needle insertion and endothelin-1.…”

“…A potential limitation to this complex experimental design comparing the effects of a single ‘hit’, PAE, to a double ‘hit’, i.e., PAE + Stroke, is that we did not include animals in this study which were subject to a sham stroke surgery which would have included the insertion of a needle intracerebrally in an anesthetized animal. The surgical insertion of a needle into the brain, equivalent to a stab-injury model for traumatic brain injury, 44 possibly constitutes a second hit by itself. To address the possibility that surgery procedure itself could elicit a systemic inflammatory response, a separate cohort of adult male and female rats that were either stroke naïve (6 females, 5 males) or exposed to sham surgery (6 females, 5 males), i.e., anesthesia followed by needle insertion into the brain to the same stereotaxic coordinates as above were assessed.…”