Endoplasmic Reticulum Stress and the Unfolded Protein Response in Cerebral Ischemia/Reperfusion Injury
Open accessAbstract
Ischemic stroke is an acute cerebrovascular disease characterized by sudden interruption of blood flow in a certain part of the brain, leading to serious disability and death. At present, treatment methods for ischemic stroke are limited to thrombolysis or thrombus removal, but the treatment window is very narrow. However, recovery of cerebral blood circulation further causes cerebral ischemia/reperfusion injury (CIRI). The endoplasmic reticulum (ER) plays an important role in protein secretion, membrane protein folding, transportation, and maintenance of intracellular calcium homeostasis. Endoplasmic reticulum stress (ERS) plays a crucial role in cerebral ischemia pathophysiology. Mild ERS helps improve cell tolerance and restore cell homeostasis; however, excessive or long-term ERS causes apoptotic pathway activation. Specifically, the protein kinase R-like endoplasmic reticulum kinase (PERK), activating transcription factor 6 (ATF6), and inositol-requiring enzyme 1 (IRE1) pathways are significantly activated following initiation of the unfolded protein response (UPR). CIRI-induced apoptosis leads to nerve cell death, which ultimately aggravates neurological deficits in patients. Therefore, it is necessary and important to comprehensively explore the mechanism of ERS in CIRI to identify methods for preserving brain cells and neuronal function after ischemia.
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GRP78 has previously exhibited several neuroprotective roles within endoplasmic reticulum-stress response pathways, by guarding against oxidative stress and glutamate excitotoxicity due to prolonged cerebral ischemia.
“whereas GRP78 has previously exhibited several neuroprotective roles within endoplasmic reticulum–stress response pathways, by guarding against oxidative stress and glutamate excitotoxicity due to prolonged cerebral ischemia.”
From High vulnerability of medial prefrontal pyramidal neurons in post-stroke, vascular, Alzheimer's disease, and aging-related dementias (2026) · cites this paper as [22]
The IRE1 Pathway section describes GRP78’s role in the endoplasmic-reticulum stress response, and the cerebral ischemia/reperfusion section discusses GRP78 expression during injury. Neither section says GRP78 protects neurons from oxidative stress or glutamate excitotoxicity during prolonged ischemia; the latter instead reports reduced apoptosis when a treatment lowers GRP78 expression. Page numbers are unavailable in our copy. (LLM, conf=0.82)
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Jobson, D. D., Hase, Y., Walker, L., Polvikoski, T., Khundakar, A. A., Allan, L., & Kalaria, R. N. (2026) · Alzheimer's & Dementia · doi:10.1002/alz.71151 · Cited by 2 · see citing works
- Authors
- Wang, L., Liu, Y., Zhang, X., Ye, Y., Xiong, X., Zhang, S., Gu, L., Jian, Z., & Wang, H.
- Affiliations
- Renmin Hospital of Wuhan University (CN)
- Zhejiang Provincial People's Hospital (CN)
- Corresponding author
- Jian, Zhihong
- Wang, Hongfa
- ORCID
- Venue
- Frontiers in Cellular Neuroscience
- Publisher
- Frontiers Media SA
- Published
- 2022-05-04
- Volume
- 16
- Pages
- 864426-864426
- ISSN
- 1662-5102 (ISSN-L)
- PMC
- PMC9114642
- OpenAlex
- W4225426224
- Cited by
- 121
- References
- 254
- Citations by year
- 2026: 20 · 2025: 32 · 2024: 48 · 2023: 16 · 2022: 5
- FWCI
- 3.63
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Frontiers in Cellular Neuroscience (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- Fundamental Research Funds for the Central Universities (2042020kf0079)
- Health Commission of Hubei Province
- National Natural Science Foundation of China (82171336, 81870939, 82071339, 81771283)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
- Health Sciences › Medicine › Epidemiology › Acute Ischemic Stroke Management
- Life Sciences › Neuroscience › Sensory Systems › Ion Channels and Receptors
- Keywords
- endoplasmic reticulum stress, unfolded protein response, cerebral ischemia-reperfusion injury, ischemic stroke, PERK pathway, ATF6 pathway, IRE1 pathway, apoptosis, neuronal cell death, neurological deficit, neuroprotection
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