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<p>Oxidative damage induced by glutamate triggers neuronal death in cerebral ischemic/reperfusion injury. BTB and CNC homology 1 (BACH1) is a major link between the cellular heme level, the redox state and the transcriptional response. <i>p</i>-Coumaric acid (<i>p</i>-CA) is a natural antioxidant that has been shown to ameliorate ischemic/reperfusion injury. In this study, we investigated whether and how <i>p</i>-CA regulated BACH1 in ischemic/reperfusion injury from the perspective of BACH1 subcellular localization and function. Middle cerebral artery occlusion (MCAO) model was established in male mice. MCAO mice were treated with <i>p</i>-CA (50, 100 mg/kg, ip) twice 5 min after MCAO and 5 h after reperfusion operation, respectively. We showed that <i>p</i>-CA treatment exerted dramatic neuroprotective effects, which were associated with the inhibition of BACH1. In HT22 cells, treatment with <i>p</i>-CA (20 μM) ameliorated OGD/R or glutamate-induced oxidative damage and mitochondrial dysfunction through decreasing the protein level of BACH1, the beneficial effect of <i>p</i>-CA was blocked by BACH1 overexpression. We demonstrated that BACH1 level was markedly elevated in the nucleus of HT22 cells under glutamate stimulation, and transcriptionally regulated NADPH oxidase 4 (NOX4) expression, thus mediating ROS outbreak. <i>p</i>-CA treatment activated the activated Cdc42-associated kinase 1 (ACK1)/protein kinase B (AKT) cascade to facilitate the phosphorylation of BACH1, augmented its interaction with chromosome region maintenance 1 (CRM1), thereby leading to the export of BACH1 from the nucleus and degradation mediated by heme-oxidized IRP2 ubiquitin ligase-1 (HOIL-1). In accord with this, administration of ACK1 inhibitor AIM-100 (20 mg/kg, ip) 5 min after MCAO significantly attenuated the neuroprotective effects of <i>p</i>-CA in MCAO mice. We concluded that ACK1/AKT/BACH1 axis may serve as a promising therapeutic approach for the management of ischemic stroke, thereby broadening the clinical utility of <i>p</i>-CA.</p><p><b>Keywords:</b> ischemic/reperfusion injury; <i>p</i>-Coumaric acid; BACH1; NOX4; ACK1/AKT; AIM-100</p>

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p-Coumaric acid alleviates neuronal damage in ischemic stroke mice by promoting BACH1 nuclear export and degradation

  • 期刊论文

  • 发表日期：

    2025年3月14日

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  • Meng-lu Song,
  • Yun-yun Sun,
  • Hai-jun Yin,
  • Yi Li,
  • Hua Yang

摘要

Oxidative damage induced by glutamate triggers neuronal death in cerebral ischemic/reperfusion injury. BTB and CNC homology 1 (BACH1) is a major link between the cellular heme level, the redox state and the transcriptional response. p-Coumaric acid (p-CA) is a natural antioxidant that has been shown to ameliorate ischemic/reperfusion injury. In this study, we investigated whether and how p-CA regulated BACH1 in ischemic/reperfusion injury from the perspective of BACH1 subcellular localization and function. Middle cerebral artery occlusion (MCAO) model was established in male mice. MCAO mice were treated with p-CA (50, 100 mg/kg, ip) twice 5 min after MCAO and 5 h after reperfusion operation, respectively. We showed that p-CA treatment exerted dramatic neuroprotective effects, which were associated with the inhibition of BACH1. In HT22 cells, treatment with p-CA (20 μM) ameliorated OGD/R or glutamate-induced oxidative damage and mitochondrial dysfunction through decreasing the protein level of BACH1, the beneficial effect of p-CA was blocked by BACH1 overexpression. We demonstrated that BACH1 level was markedly elevated in the nucleus of HT22 cells under glutamate stimulation, and transcriptionally regulated NADPH oxidase 4 (NOX4) expression, thus mediating ROS outbreak. p-CA treatment activated the activated Cdc42-associated kinase 1 (ACK1)/protein kinase B (AKT) cascade to facilitate the phosphorylation of BACH1, augmented its interaction with chromosome region maintenance 1 (CRM1), thereby leading to the export of BACH1 from the nucleus and degradation mediated by heme-oxidized IRP2 ubiquitin ligase-1 (HOIL-1). In accord with this, administration of ACK1 inhibitor AIM-100 (20 mg/kg, ip) 5 min after MCAO significantly attenuated the neuroprotective effects of p-CA in MCAO mice. We concluded that ACK1/AKT/BACH1 axis may serve as a promising therapeutic approach for the management of ischemic stroke, thereby broadening the clinical utility of p-CA.

Keywords: ischemic/reperfusion injury; p-Coumaric acid; BACH1; NOX4; ACK1/AKT; AIM-100