Over-Activated Proteasome Mediates Neuroinflammation on Acute Intracerebral Hemorrhage in Rats

Abstract

Background: Neuroinflammation is a hallmark in intracerebral hemorrhage (ICH) that induces secondary brain injury, leading to neuronal cell death. ER stress-triggered apoptosis and proteostasis disruption caused neuroinflammation to play an important role in various neurological disorders. The consequences of ER stress and proteostasis disruption have rarely been studied during the course of ICH development. Methods: ICH was induced by collagenase VII-S intrastriatal infusion. Animals were sacrificed at 0, 3, 6, 24, and 72 h post-ICH. Rats were determined for body weight changes, hematoma volume, and neurological deficits. Brain tissues were harvested for molecular signaling analysis either for ELISA, immunoblotting, immunoprecipitation, RT-qPCR, protein aggregation, or for histological examination. A non-selective proteasome inhibitor, MG132, was administered into the right striatum three hours prior to ICH induction. Results: ICH-induced acute proteasome over-activation caused the early degradation of the endoplasmic reticulum (ER) chaperone GRP78 and IκB protein. These exacerbations were accompanied by the elevation of pro-apoptotic CCAAT-enhancer-binding protein homologous protein (CHOP) and pro-inflammatory cytokines expression via nuclear factor-kappa B (NF-κB) signal activation. Pre-treatment with proteasome inhibitor MG132 significantly ameliorated the ICH-induced ER stress/proteostasis disruption, pro-inflammatory cytokines, neuronal cells apoptosis, and neurological deficits. Conclusions: ICH induced rapid proteasome over-activation, leading to an exaggeration of the ER stress/proteostasis disruption, and neuroinflammation might be a critical event in acute ICH pathology.

Selective Activation of Cannabinoid Receptor-2 Reduces White Matter Injury via Perk Signaling in a Rat Model of Traumatic Brain Injury

“…Thus, we further explored the mechanism of the interaction between microglia and OLs. Recently, ER stress has attracted much attention for its involvement in many CNS diseases, including amyotrophic lateral sclerosis (ALS), Parkinson's disease and TBI [45]. The ER is a structure in which misfolded and nascent proteins are accurately folded by various chaperones (such as GRP78) before transport by secretory vesicles.…”

A Role for Endoplasmic Reticulum Stress in Intracerebral Hemorrhage

“…On the other hand, ER dysfunction caused by protein misfolding and oxidative stress has led to acute central nervous system damage [80,81]. Recently, we have elucidated that acute phase of ICH has exacerbated the ER stress through proteasome overactivation, which also lead to neuroinflammation [82]. Although the studies to describe the relationship between ER stress and ICH are minimal, it is necessary to analyze the role of ER stress in ICH because of the crucial interplay between ER stress and various other factors involved in ICH pathophysiology including microglial activation, oxidative stress, neuroinflammation, and heme release [83][84][85].…”

The Role of Urocortins in Intracerebral Hemorrhage

“…Neuroinflammation is a hallmark in ICH that triggered by the endoplasmic reticulum (ER) stress and proteostasis disruption through early degradation of chaperone GRP78 and IkB protein, leading inflammatory response and increased cytokine expression [109]. Interestingly, a study has shown that the receptor of UCN, CRFR1, is involved in CRH-induced neuron apoptosis through the increased GRP78 in a concentration-dependent manner.…”