A Role for Endoplasmic Reticulum Stress in Intracerebral Hemorrhage

Abstract

The endoplasmic reticulum (ER) is an intracellular organelle that performs multiple functions, such as lipid biosynthesis, protein folding, and maintaining intracellular calcium homeostasis. Thus, conditions wherein the ER is unable to fold proteins is defined as ER stress, and an inbuilt quality control mechanism, called the unfolded protein response (UPR), is activated during ER stress, which serves as a recovery system that inhibits protein synthesis. Further, based on the severity of ER stress, the response could involve both proapoptotic and antiapoptotic phases. Intracerebral hemorrhage (ICH) is the second most common subtype of cerebral stroke and many lines of evidence have suggested a role for the ER in major neurological disorders. The injury mechanism during ICH includes hematoma formation, which in turn leads to inflammation, elevated intracranial pressure, and edema. a proper understanding of the injury mechanism(s) is required to effectively treat ICH and closing the gap between our current understanding of ER stress mechanisms and ICH injury can lead to valuable advances in the clinical management of ICH.Cells 2020, 9, 750 2 of 20 because of cardiovascular conditions, with hypertension playing a major role. PBI is characterized by mechanical injury followed by a mass effect with the initial ictus causing physical tissue disruption that then leads to pathophysiological conditions in the brain.A sudden rise in intracranial hematoma volume causes an increase in barotrauma and reduces blood flow to the area of the ictus [4,5]. Typically, PBI is followed by SBI, which is considered as a devastating stage after ICH, and the severity of SBI depends on the rate of recovery and location of the ICH. SBI involves the neuroinflammatory response to the triggering of the coagulation cascade through activation of the immune system. The inflammation size is based on the volume and position of the hematoma [5][6][7]. The various pathological factors responsible for SBI include the host immune response, release of thrombin, release of clot components (iron and heme)

Molecular Correlates of Hemorrhage and Edema Volumes Following Human Intracerebral Hemorrhage Implicate Inflammation, Autophagy, mRNA Splicing, and T Cell Receptor Signaling

“…The Blue module, positively correlated with rPHE, was overrepresented by major protein translation, stress response, and cell death pathways, including Eukaryotic Initiation Factor (EIF), p70S6K, mTOR, Nucleotide Excision Repair (NER), protein ubiquitination, Unfolded Protein Response (UPR), Endoplasmic Reticulum Stress Pathway, and Necroptosis Signaling (Fig. 5 f, Table S2 O)—many of which have been implicated in ICH [ 97 ]. The inability to properly fold proteins leads to UPR and often programmed cell death including necroptosis [ 65 , 97 ].…”

Neuroprotective Effects of Exercise Postconditioning After Stroke via SIRT1-Mediated Suppression of Endoplasmic Reticulum (ER) Stress

“…Prolonged environmental stress triggers signal transduction pathways that lead to apoptosis and thereby heighten pathological processes, leading to cerebral damage (Chi et al, 2019 ). Endoplasmic reticulum stress exerts its vital role in stroke-induced neural apoptosis (Mohammed Thangameeran et al, 2020 ) through activation of downstream CCAATenhancer-binding protein homologous protein (CHOP) and caspase-12 (Chi et al, 2019 ; Chu et al, 2019 ; Li Y. et al, 2020 ). SIRT1 is a nicotine adenine dinucleotide (NAD+)-dependent enzyme that deacetylates numerous transcription factors in response to ischemic stress and is involved in various biological pathways (Chen et al, 2005 ).…”

Effects of homocysteine-induced endoplasmic reticulum protein on endoplasmic reticulum stress, autophagy, and neuronal apoptosis following intracerebral hemorrhage

“…Previous studies had indicated that autophagy, ER stress and apoptosis were involved in various physiological and pathological conditions in stroke, especially in intracerebral hemorrhage ( Durocher et al, 2019 ; Mohammed Thangameeran et al, 2020 ; Yang et al, 2018 ). HERP has been described as a ubiquitin-like membrane protein induced by endoplasmic reticulum stress, however, whether HERP plays a positive or negative role in the intracerebral hemorrhage remains controversial and the role of HERP in the autophagy, ER stress, apoptosis is largely unknown.…”

“…A number of works in recent years indicate that the pathological process of ICH is complex, including brain edema, hematoma formation, and the activation of cytotoxic, inflammatory, oxidative, autophagy and endoplasmic reticulum (ER) stress pathways. Therefore, it is necessary to elucidate these cellular and molecular mechanisms of ICH ( Li et al, 2020 ; Mohammed Thangameeran et al, 2020 ).…”