Department of Central Laboratory, Xi'an Peihua University, Xi'an, China.
Department of Neurosurgery, Bijie Traditional Chinese Medicine Hospital, Bijie, China.
CNS Neurosci Ther. 2023 Jun;29(6):1667-1677. doi: 10.1111/cns.14130. Epub 2023 Feb 27.
Ferroptosis is increasingly becoming to be considered as an important mechanism of pathological cell death during stroke, and specific exogenous ferroptosis inhibitors have the ability to reverse cerebral ischemia/reperfusion injury. However, research on Srs11-92 (AA9), a ferrostatin-1 (Fer-1) analog, in preclinical studies is limited.
In the middle cerebral artery occlusion-reperfusion (MCAO/R) mice model or oxygen-glucose deprivation/reperfusion (OGD/R) cell model, Fer-1, AA9, and/or ML385 were administered, and brain infarct size, neurological deficits, neuronal damage, oxidative stress, and neuroinflammation were determined after the damage, in vitro and in vivo.
Fer-1 and AA9 improved brain infarct size, neuronal damage, and neurological deficits in mice model of MCAO/R, and inhibited the overloaded iron deposition, ROS accumulation, and neuroinflammation response: it also increased the expression of GPx4, Nrf2, and HO-1 and suppressed the expression of HMGB1 and NF-κB p65 in the epicenter of injured hippocampal formation. However, Nrf2 inhibitor ML385 reversed the neuroprotective effect of AA9, including the oxidative stress and neuroinflammation. In vitro studies showed that AA9 relieved OGD/R-induced neuronal oxidative stress and neuroinflammation via the Nrf2 pathway, which was impaired by ML385 in primary neurons.
The findings imply that Fer-1 analog AA9 may be suitable for further translational studies for the protection of neuronal damage via Nrf2 signal pathway-mediated oxidative stress and neuroinflammation in stroke and others neurological diseases.
铁死亡作为中风过程中病理性细胞死亡的一个重要机制，日益受到关注，特定的外源性铁死亡抑制剂能够逆转脑缺血/再灌注损伤。然而，Fer-1 类似物 Srs11-92（AA9）在临床前研究中的研究还很有限。
在大脑中动脉闭塞/再灌注（MCAO/R）小鼠模型或氧葡萄糖剥夺/再灌注（OGD/R）细胞模型中，给予 Fer-1、AA9 和/或 ML385，在损伤后，在体外和体内测定脑梗死面积、神经功能缺损、神经元损伤、氧化应激和神经炎症。
Fer-1 和 AA9 改善了 MCAO/R 小鼠模型的脑梗死面积、神经元损伤和神经功能缺损，并抑制了铁超载沉积、ROS 积累和神经炎症反应：还增加了 GPx4、Nrf2 和 HO-1 的表达，抑制了损伤海马区中心 HMGB1 和 NF-κB p65 的表达。然而，Nrf2 抑制剂 ML385 逆转了 AA9 的神经保护作用，包括氧化应激和神经炎症。体外研究表明，AA9 通过 Nrf2 通路缓解了 OGD/R 诱导的神经元氧化应激和神经炎症，而 ML385 则损害了原代神经元中的这一通路。
这些发现表明，Fer-1 类似物 AA9 可能适合进一步进行转化研究，通过 Nrf2 信号通路介导的氧化应激和神经炎症来保护中风和其他神经疾病中的神经元损伤。
