Role of Qrich1-mediated endoplasmic reticulum stress pathway in Berberine inhibition of NF-κB activation induced by cerebral ischemia-reperfusion injury.

BACKGROUND

With global population aging, the incidence of ischemic stroke is rising annually. However, its underlying mechanisms and effective clinical preventive and therapeutic measures remain elusive. This study investigated inflammatory mechanisms and therapeutic targets using a rat cerebral ischemia-reperfusion injury (CIRI) model, focusing on endoplasmic reticulum stress (ERS)-mediated inflammation.

METHODS

A rat CIRI model was established. Neurological assessments were performed 24 h post-modeling. Histopathological analysis evaluated inflammatory cytokines (IL-1β, TNF-α) and NF-κB p65 nuclear translocation in the ischemic penumbra. Molecular profiling assessed activation of endoplasmic reticulum stress (ERS) markers (GRP78, p-PERK, p-eIF2α) and the ERS-associated transcription factor Glutamine-rich protein 1 (QRICH1). Pharmacological induction of ERS and treatment with berberine (BBR) were employed, with mechanistic studies including PERK inhibition.

RESULTS

Neurological assessments revealed significant CIRI-induced neural deficits. Histopathology demonstrated upregulated IL-1β/TNF-α and NF-κB p65 nuclear translocation. Molecular profiling identified activation of ERS markers (GRP78, p-PERK, p-eIF2α) and a time-dependent elevation of QRICH1 post-CIRI. Pharmacological ERS induction confirmed QRICH1/PERK/NF-κB pathway activation. BBR administration significantly attenuated IL-1β/TNF-α levels, suppressed IκB-α degradation, and inhibited NF-κB nuclear translocation. Mechanistically, BBR downregulated QRICH1 upregulation and suppressed agonist-induced ERS-inflammatory cascades; these therapeutic effects were partially reversed by PERK inhibitor.

CONCLUSION

These findings propose modulation of the QRICH1-ERS pathway as a promising therapeutic target for CIRI management, with BBR conferring protection by partially suppressing this axis.