Inhibition of ferroptosis attenuates tissue damage and improves long‐term outcomes after traumatic brain injury in mice

Xie, Baoshu; Wang, Yi‐Qin; Lin, Yong; Mao, Qing; Feng, Junfeng; Gao, Guoyi; Jiang, Jiyao

doi:10.1111/cns.13069

Cited by 261 publications

(211 citation statements)

References 42 publications

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“…In our study, we observed accumulation of MDA and Fe 2+ and alternation of the above-mentioned metabolism-related molecules after CCI. Our findings together with previous reports indicate that ferroptosis is involved in the pathogenesis of CCI [35]. Many of our results are consistent with previous studies [11,35,36], with some exceptions.…”

Section: Discussionsupporting

confidence: 94%

“…Our findings together with previous reports indicate that ferroptosis is involved in the pathogenesis of CCI [35]. Many of our results are consistent with previous studies [11,35,36], with some exceptions. Gpx4 (converts toxic lipid hydroperoxides to non-toxic lipid alcohols) was reported to decrease after TBI [10], but in our study, its expression was barely changed compared to the sham group at all indicated time points except for the 6 h group in which an increased level of Gpx4 was observed.…”

Section: Discussionsupporting

confidence: 94%

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miR-212-5p attenuates ferroptotic neuronal death after traumatic brain injury by targeting Ptgs2

et al. 2019

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Ferroptosis, a newly discovered form of iron-dependent regulated cell death, has been implicated in traumatic brain injury (TBI). MiR-212-5p has previously been reported to be downregulated in extracellular vesicles following TBI. To investigate whether miR-212-5p is involved in the ferroptotic neuronal death in TBI mice, we first examined the accumulation of malondialdehyde (MDA) and ferrous ion, and the expression of ferroptosis-related molecules at 6 h, 12 h, 24 h, 48 h and 72 h following controlled cortical impact (CCI) in mice. There was a significant upregulation in the expression of Gpx4 and Acsl4 at 6 h, Slc7a11 from 12 h to 72 h, and Nox2 and Sat1 from 6 h to 72 h post injury. Similarly, an upregulation in the expression of Gpx4 at 6 h, Nox2 from 6 h to 72 h, xCT from 12 h to 72 h, and Sat1 at 72 h after CCI was observed at the protein level. Interestingly, MDA and ferrous ion were increased whereas miR-212-5p was decreased in the CCI group compared to the sham group. Furthermore, we found that overexpression of miR-212-5p attenuated ferroptosis while downregulation of miR-212-5p promoted ferroptotic cell death partially by targeting prostaglandin-endoperoxide synthase-2 (Ptgs2) in HT-22 and Neuro-2a cell lines. In addition, administration of miR-212-5p in CCI mice significantly improved learning and spatial memory. Collectively, these findings indicate that miR-212-5p may protect against ferroptotic neuronal death in CCI mice partially by targeting Ptgs2.

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Section: Discussionsupporting

confidence: 94%

Section: Discussionsupporting

confidence: 94%

miR-212-5p attenuates ferroptotic neuronal death after traumatic brain injury by targeting Ptgs2

et al. 2019

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“…The evolution of TBI is accompanied by biological processes, such as iron accumulation, disordered iron metabolism, upregulation of ferroptosis-related genes, decreased GPX activity and ROS accumulation 75 . The application of the ferroptosis inhibitor Fer-1 significantly reduces iron deposition, neuronal degeneration, and injury and improves the prognosis of patients, thus providing an experimental basis for TBI treatment targeting ferroptosis 75 .…”

Section: Traumatic Brain Injury (Tbi)mentioning

confidence: 99%

Ferroptosis: past, present and future

et al. 2020

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Ferroptosis is a new type of cell death that was discovered in recent years and is usually accompanied by a large amount of iron accumulation and lipid peroxidation during the cell death process; the occurrence of ferroptosis is iron-dependent. Ferroptosis-inducing factors can directly or indirectly affect glutathione peroxidase through different pathways, resulting in a decrease in antioxidant capacity and accumulation of lipid reactive oxygen species (ROS) in cells, ultimately leading to oxidative cell death. Recent studies have shown that ferroptosis is closely related to the pathophysiological processes of many diseases, such as tumors, nervous system diseases, ischemia-reperfusion injury, kidney injury, and blood diseases. How to intervene in the occurrence and development of related diseases by regulating cell ferroptosis has become a hotspot and focus of etiological research and treatment, but the functional changes and specific molecular mechanisms of ferroptosis still need to be further explored. This paper systematically summarizes the latest progress in ferroptosis research, with a focus on providing references for further understanding of its pathogenesis and for proposing new targets for the treatment of related diseases. Facts Ferroptosis is a new type of programmed cell death, which occurs with iron dependence. Ferroptosis plays an important regulatory role in the occurrence and development of many diseases, such as tumors, neurological diseases, acute kidney injury, ischemia/reperfusion, etc. Activating or blocking the ferroptosis pathway to alleviate the progression of the disease, which provides a promising therapeutic strategy for many diseases. Open questions What is the relationship between ferroptosis and other types of cell death? Is it synergy or antagonism? Is iron necessary to promote the production of lipid peroxides, or can other substances take the place of iron in ferroptosis? What is the downstream regulation mechanism of iron in ferroptosis? How can ferroptosis promote the development of inflammation?

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“…Recently, Do Van B etc. confirmed that ferroptosis was a new way of cell death in Parkinson's disease [25] . Ferroptosis also makes contribution to the neuronal loss in Alzheimer's disease [26] .…”

Section: Ferroptosis Inhibitor Ferrostatin-1 Can Protect Cell Death Imentioning

confidence: 84%

Sodium valproate protects against neuronal ferroptosis in epilepsy via suppressing lysyl oxidase

Qin

Jia

et al. 2020

Preprint

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Background and purpose:Epilepsy is a chronic neurological disease that is characterized by repetitive seizures. Seizures-related complications such as cognitive deficits, anxiety and sleep disorders seriously impact the life quality of patients.Antiepileptic drugs are widely used for the treatment of epilepsy. Sodium valproate is served as the first-line antiepileptic drugs and possesses various pharmacological effects on the brain. Sodium valproate exerts neuroprotective effects in acute nervous system diseases such as ischemic brain damage by inhibiting oxidative stress.However, the mechanism of neuroprotection of sodium valproate in epilepsy is unclear. Lysyl oxidase (Lox) is a monoamine oxidase that acts on extracellular matrix collagen and elastin and it can promote accumulation of oxidative stress. Our previous studies have confirmed that Lox is involved in ferroptosis, a novel iron-dependent and lipid peroxidation-mediated cell death pathway, during epilepsy. In this study, we would like to investigate whether sodium valproate can exert neuroprotective effects on kainic acid-induced epileptic seizures by inhibiting Lox-mediated ferroptosis. Methods: Epileptic mouse models were established by intracranial injection of 250 ng/μl kainic acid on right hippocampus. Sodium valproate and ferroptosis inhibitors were administrated by intraperitoneal injecting. The epileptic behavior of the mice within 4 hours was recorded after intracranial injection of kainic acid. Mouse hippocampus was acquired to analyze the mRNA expression of prostaglandin-endoperoxide synthase 2 (PTGS2) and the production of 4-hydroxynonenal (4-HNE). In vitro, the protective effects of sodium valproate on glutamate-induced HT22 cell damage model was assessed by PI/Hoechst staining; The levels of PTGS2, 4-HNE and lipid ROS were analyzed by RT-qPCR, western blot and flow cytometry, respectively. RT-qPCR and Western blot analysis the mRNA and protein expression of Lox in the glutamate-induced HT22 cell damage model. The Lox overexpression model was established by intracranial injection of AAV on right hippocampus. Results: Pretreatment with sodium valproate and ferroptosis inhibitors could significantly alleviate the epileptic seizures in the kainic acid induced epilepsy mouse model. Western blot and RT-qPCR results showed that sodium valproate and ferroptosis inhibitors significantly inhibited the levels of 4-HNE and PTGS2. PI/Hoechst staining showed that 1 mM sodium valproate exerted protective effect on glutamate-induced HT22 cell injury model. There was no significant difference observed between sodium valproate and ferroptosis inhibitors co-intervention group and sodium valproate intervention group on glutamate-induced cell injury model. And sodium valproate could significantly inhibit the production of lipid reactive oxygen species and 4-HNE. The expression of Lox was significantly increased in the glutamate-induced HT22 cell injury model, which could be reversed by pretreatment of sodium valproate. And β -aminopropionitrile (a specific inh...

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Inhibition of ferroptosis attenuates tissue damage and improves long‐term outcomes after traumatic brain injury in mice

Cited by 261 publications

References 42 publications

miR-212-5p attenuates ferroptotic neuronal death after traumatic brain injury by targeting Ptgs2

miR-212-5p attenuates ferroptotic neuronal death after traumatic brain injury by targeting Ptgs2

Ferroptosis: past, present and future

Sodium valproate protects against neuronal ferroptosis in epilepsy via suppressing lysyl oxidase

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