Ferroptosis and inflammation induced by cerebral hemorrhage result in an excessive inflammatory response and irreversible neuronal injury. Alleviating ferroptosis might be an effective way to prevent neuroinflammatory injury and promote neural functional recovery. Pyridoxal isonicotinoyl hydrazine (PIH), a lipophilic iron-chelating agent, has been reported to reduce excess iron-induced cytotoxicity. However, whether PIH could ameliorate the effects of hemorrhagic stroke is not completely understood. In the present study, the preventive effects of PIH in an intracerebral hemorrhage (ICH) mouse model were investigated. Neurological score, rotarod test, and immunofluorescence around the hematoma were assessed to evaluate the effects of PIH on hemorrhagic injury. The involvement of ferroptosis and inflammation was also examined in vitro to explore the underlying mechanism. Results showed that administration of PIH prevented neuronal cell death and reduced lipid peroxidation in Erastin-treated PC-12 cells. In vivo, mice treated with PIH after ICH attenuated neurological deficit scores. Additionally, we found PIH reduced ROS production, iron accumulation, and lipid peroxidation around the hematoma peripheral tissue. Meanwhile, ICH mice treated with PIH showed an upregulation of the key ferroptosis enzyme, glutathione peroxidase 4, and downregulation of cyclooxygenase-2. Moreover, PIH administration inhibited proinflammatory polarization and reduced interleukin-1 beta and tumor necrosis factor alpha in ICH mice. Collectively, these results demonstrated that PIH protects mice against hemorrhage stroke, which was associated with mitigation of inflammation and ferroptosis.

中文翻译：

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吡哆醛异烟酰腙通过减轻脑出血小鼠的铁死亡和炎症来改善神经恢复

脑出血引起的铁死亡和炎症导致过度的炎症反应和不可逆的神经元损伤。减轻铁死亡可能是预防神经炎症损伤、促进神经功能恢复的有效方法。吡哆醛异烟酰肼 (PIH) 是一种亲脂性铁螯合剂，据报道可以减少过量铁诱导的细胞毒性。然而，妊娠高血压综合征是否可以改善出血性中风的影响尚不完全清楚。在本研究中，研究了 PIH 对脑出血 (ICH) 小鼠模型的预防作用。通过神经学评分、转棒试验和血肿周围免疫荧光检查来评估 PIH 对出血性损伤的影响。还在体外检查了铁死亡和炎症的参与，以探索潜在的机制。结果表明，给予 Erastin 处理的 PC-12 细胞中，给予 PIH 可防止神经元细胞死亡并减少脂质过氧化。在体内，在 ICH 后接受 PIH 治疗的小鼠可以减轻神经功能缺损评分。此外，我们发现 PIH 减少了血肿周围组织周围的 ROS 产生、铁积累和脂质过氧化。同时，接受 PIH 治疗的 ICH 小鼠表现出关键的铁死亡酶、谷胱甘肽过氧化物酶 4 的上调，以及环氧合酶-2 的下调。此外，PIH 给药可抑制 ICH 小鼠的促炎极化并减少白细胞介素 1 β 和肿瘤坏死因子 α 的水平。总的来说，这些结果表明，PIH 可以保护小鼠免受出血性中风，这与减轻炎症和铁死亡有关。