Ischemic stroke induced neuronal apoptosis via IRE1α/ASK1 signaling in mice

Neuronal apoptosis mediated by endoplasmic reticulum (ER) stress exerts crucial pathophysiological functions in the central nervous system. Inositol-requiring kinase 1α (IRE1α), a transmembrane sensor in the ER, triggers the unfolded protein response (UPR) to maintain ER function and cell homeostasis. Hence, the aim of this study was to investigate the role and mechanism of endoplasmic reticulum stress-mediated neuronal apoptosis-related signaling pathway IRE1α/ASK1 in ischemic stroke.

A focal cortical ischemic stroke model was established to detect the expression levels of IRE1α, ASK1 and their related signaling molecules in ischemic brain tissue and cultured neurons in vitro. IRE1α antagonist (4μ8C) and ASK1 inhibitor (NQDI-1) were used for intervention, and the effects on infarct volume, neuronal death and neurological impairment were evaluated.

The levels of IRE1α, ASK1, TRAF2, p-p38, CHOP, Bax, and caspase-3 were significantly elevated in the ischemic brain tissue after stroke. Notably, treatment with an IRE1α antagonist (4μ8C) or an ASK1 inhibitor (NQDI-1) reduced the levels of TRAF2, p-p38, CHOP, Bax, and caspase-3. The medications also substantially reduced the infarct volume, the quantity of neuronal death, and neurological impairment. In vitro experimental data confirmed that the activity of primary neurons is also regulated by IRE1α/ASK1 signaling.

IRE1α/ASK1 signaling plays a crucial role in endoplasmic reticulum stress during ischemic stroke by modulating the p38 - CHOP pathway and regulating caspase - 3-dependent neuronal apoptosis, providing a new target for the treatment of ischemic stroke.