Department of Rehabilitation Medicine, Zhongnan Hospital of Wuhan University, Wuhan, China.
Department of Rehabilitation Medicine, West China Hospital, Sichuan University, Chengdu, China.
Brain Res Bull. 2023 Oct 15;203:110778. doi: 10.1016/j.brainresbull.2023.110778. Epub 2023 Oct 7.
Preventing neuronal death after ischemic stroke (IS) is crucial for neuroprotective treatment, yet current management options are limited. Enriched environment (EE) is an effective intervention strategy that promotes the recovery of neurological function after cerebral ischemia/reperfusion (I/R) injury. Ferroptosis has been identified as one of the mechanisms of neuronal death during IS, and inhibiting ferroptosis can reduce cerebral I/R injury. Our previous research has demonstrated that EE reduced ferroptosis by inhibiting lipid peroxidation, but the underlying mechanism still needs to be investigated. This study aims to explore the potential molecular mechanisms by which EE modulates iron metabolism to reduce ferroptosis. The experimental animals were randomly divided into four groups based on the housing environment and the procedure the animals received: the sham-operated + standard environment (SSE) group, the sham-operated + enriched environment (SEE) group, the ischemia/reperfusion + standard environment (ISE) group, and the ischemia/reperfusion + enriched environment (IEE) group. The results showed that EE reduced IL-6 expression during cerebral I/R injury, hence reducing JAK2-STAT3 pathway activation and hepcidin expression. Reduced hepcidin expression led to decreased DMT1 expression and increased FPN1 expression in neurons, resulting in lower neuronal iron levels and alleviated ferroptosis. In addition, EE also reduced the expression of TfR1 in neurons. Our research suggested that EE played a neuroprotective role by modulating iron metabolism and reducing neuronal ferroptosis after cerebral I/R injury, which might be achieved by inhibiting inflammatory response and down-regulating hepcidin expression.
预防缺血性脑卒中（IS）后神经元死亡对于神经保护治疗至关重要，但目前的治疗选择有限。丰富环境（EE）是一种有效的干预策略，可促进脑缺血/再灌注（I/R）损伤后神经功能的恢复。铁死亡已被确定为 IS 期间神经元死亡的机制之一，抑制铁死亡可以减轻脑 I/R 损伤。我们之前的研究表明，EE 通过抑制脂质过氧化来减少铁死亡，但潜在的机制仍需要进一步研究。本研究旨在探讨 EE 通过调节铁代谢来减少铁死亡的潜在分子机制。实验动物根据饲养环境和动物接受的程序随机分为四组：假手术+标准环境（SSE）组、假手术+丰富环境（SEE）组、缺血/再灌注+标准环境（ISE）组和缺血/再灌注+丰富环境（IEE）组。结果表明，EE 降低了脑 I/R 损伤期间的 IL-6 表达，从而减少了 JAK2-STAT3 途径的激活和铁调素的表达。铁调素表达降低导致神经元中 DMT1 表达降低和 FPN1 表达增加，导致神经元中铁水平降低和铁死亡减轻。此外，EE 还降低了神经元中 TfR1 的表达。我们的研究表明，EE 通过调节铁代谢和减轻脑 I/R 损伤后的神经元铁死亡发挥神经保护作用，这可能是通过抑制炎症反应和下调铁调素表达来实现的。
