Selective Ferroptosis Inhibitor Liproxstatin-1 Attenuates Neurological Deficits and Neuroinflammation After Subarachnoid Hemorrhage

Cao, Yang; Li, Yin; He, Chao; Yan, Feng; Li, Jianru; Xu, Hangzhe; Zhuang, Jianfeng; Zhou, Hang; Peng, Yucong; Fu, Xiongjie; Lü, Xin; Yao, Yuan; Wei, Yuyu; Tong, Yongxi; Zhou, Yifu; Wang, Lin

doi:10.1007/s12264-020-00620-5

Cited by 137 publications

(80 citation statements)

References 51 publications

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“…Importantly, increasing evidence suggests that ferroptosis could be the leading factor to induce ICH secondary injury. The ferroptosis inhibitors have become increasingly popular in ICH therapy recently (Cao et al, 2021).…”

Section: Discussionmentioning

confidence: 99%

Baicalin Inhibits Ferroptosis in Intracerebral Hemorrhage

et al. 2021

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Intracerebral hemorrhage (ICH) is a subtype of stroke characterized by high mortality and disability rates. To date, the exact etiology of ICH-induced brain injury is still unclear. Moreover, there is no effective treatment to delay or prevent disease progression currently. Increasing evidence suggests that ferroptosis plays a dominant role in the pathogenesis of ICH injury. Baicalin is a main active ingredient of Chinese herbal medicine Scutellaria baicalensis. It has been reported to exhibit neuroprotective effects against ICH-induced brain injury as well as reduce iron deposition in multiple tissues. Therefore, in this study, we focused on the protective mechanisms of baicalin against ferroptosis caused by ICH using a hemin-induced in vitro model and a Type IV collagenase-induced in vivo model. Our results revealed that baicalin enhanced cell viability and suppressed ferroptosis in rat pheochromocytoma PC12 cells treated with hemin, erastin and RSL3. Importantly, baicalin showed anti-ferroptosis effect on primary cortical neurons (PCN). Furthermore, baicalin alleviated motor deficits and brain injury in ICH model mice through inhibiting ferroptosis. Additionally, baicalin existed no obvious toxicity towards the liver and kidney of mice. Evidently, ferroptosis is a key pathological feature of ICH and baicalin can prevent the development of ferroptosis in ICH. As such, baicalin is a potential therapeutic drug for ICH treatment.

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Section: Discussionmentioning

confidence: 99%

Baicalin Inhibits Ferroptosis in Intracerebral Hemorrhage

et al. 2021

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“…Currently, methods to monitor ferroptosis rely mainly on measuring ROS production, lipid peroxidation, iron accumulation, and abilities of ferroptosis inhibitors to block cell death [34][35][36]. According to the previous research results, the ferroptosis inhibitors, ferrostatin-1 and liproxstatin-1, have shown their therapeutic value in animal models of ICH; however, their "ROS inhibitor" roles hinted that they may inhibit other pathways of cell death at the same time [37][38][39]. It is particularly important to find more selective and safe drugs to promote ICH recovery, and ironchelating agents may be a potential treatment for ICHinduced ferroptosis.…”

Section: Discussionmentioning

confidence: 99%

Pyridoxal Isonicotinoyl Hydrazone Improves Neurological Recovery by Attenuating Ferroptosis and Inflammation in Cerebral Hemorrhagic Mice

Zhang

Wen

Chen

et al. 2021

BioMed Research International

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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.

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“…Ferroptosis also plays an important role in early brain injury after SAH (Li et al, 2021). Cao et al (2021) recently reported that the treatment with lip-1 protected HT22 cells against hemin-induced injury and reduced neurological deficits and neuroinflammation after SAH in mice. Additionally, earlier research has verified that the NF-E2-related factor 2 (Nrf2) pathway, a multifunctional signaling pathway that can control more than 250 genetics (Chang et al, 2014), is activated and provides neuroprotection after SAH (Chen et al, 2020).…”

Section: Ferroptosis In Hemorrhagic Strokementioning

confidence: 99%

Ferroptosis and Its Multifaceted Roles in Cerebral Stroke

Zhang

Lü

Tai

et al. 2021

Front. Cell. Neurosci.

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Ferroptosis is a unique regulated cell death defined by the intracellular iron overload and distinct biological features compared with other well-known programmed cell death. Ferroptosis can be triggered by many causes including decreased expression of glutathione (GSH), inhibition of the function of glutathione-dependent peroxidase 4 (GPX4), and system xc–, all of which finally lead to the over-accumulation of lipid peroxides in the cell. Ferroptosis has been reported to play an important role in the pathophysiological process of various cancers. In recent years, much evidence also proved that ferroptosis is involved in the progress of cerebral stroke. In this review, we summarized the characteristics of ferroptosis and the potential relationship between ferroptosis and ischemic and hemorrhagic stroke, to provide new targets and ideas for the therapy of stroke.

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Selective Ferroptosis Inhibitor Liproxstatin-1 Attenuates Neurological Deficits and Neuroinflammation After Subarachnoid Hemorrhage

Cited by 137 publications

References 51 publications

Baicalin Inhibits Ferroptosis in Intracerebral Hemorrhage

Baicalin Inhibits Ferroptosis in Intracerebral Hemorrhage

Pyridoxal Isonicotinoyl Hydrazone Improves Neurological Recovery by Attenuating Ferroptosis and Inflammation in Cerebral Hemorrhagic Mice

Ferroptosis and Its Multifaceted Roles in Cerebral Stroke

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