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Neuroprotection of NRF2 against Ferroptosis after Traumatic Brain Injury in Mice.

ABSTRACT: Ferroptosis and iron-related redox imbalance aggravate traumatic brain injury (TBI) outcomes. NRF2 is the predominant transcription factor regulating oxidative stress and neuroinflammation in TBI, but its role in iron-induced post-TBI damage is unclear. We investigated ferroptotic neuronal damage in the injured cortex and observed neurological deficits post-TBI. These were ameliorated by the iron chelator deferoxamine (DFO) in wild-type mice. In Nrf2-knockout (Nrf2^-/-) mice, more sever ferroptosis and neurological deficits were detected. Dimethyl fumarate (DMF)-mediated NRF2 activation alleviated neural dysfunction in TBI mice, partly due to TBI-induced ferroptosis mitigation. Additionally, FTH-FTL and FSP1 protein levels, associated with iron metabolism and the ferroptotic redox balance, were highly NRF2-dependent post-TBI. Thus, NRF2 is neuroprotective against TBI-induced ferroptosis through both the xCT-GPX4- and FTH-FTL-determined free iron level and the FSP1-regulated redox status. This yields insights into the neuroprotective role of NRF2 in TBI-induced neuronal damage and its potential use in TBI treatment.

SUBMITTER: Cheng H

PROVIDER: S-EPMC10044792 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature

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Neuroprotection of NRF2 against Ferroptosis after Traumatic Brain Injury in Mice.

Cheng Hao H Wang Pengfei P Wang Ning N Dong Wenwen W Chen Ziyuan Z Wu Mingzhe M Wang Ziwei Z Yu Ziqi Z Guan Dawei D Wang Linlin L Zhao Rui R

Antioxidants (Basel, Switzerland) 20230316 3

Ferroptosis and iron-related redox imbalance aggravate traumatic brain injury (TBI) outcomes. NRF2 is the predominant transcription factor regulating oxidative stress and neuroinflammation in TBI, but its role in iron-induced post-TBI damage is unclear. We investigated ferroptotic neuronal damage in the injured cortex and observed neurological deficits post-TBI. These were ameliorated by the iron chelator deferoxamine (DFO) in wild-type mice. In Nrf2-knockout (Nrf2-/-) m ...[more]

PMID: 36978979

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Project description:ImportanceTraumatic brain injury (TBI) is a significant public health concern that affects individuals in all demographics. With increasing interest in the medical and public communities, understanding the inflammatory mechanisms that drive the pathologic and consequent cognitive outcomes can inform future research and clinical decisions for patients with TBI.ObjectivesTo review known inflammatory mechanisms in TBI and to highlight clinical trials and neuroprotective therapeutic manipulations of pathologic and inflammatory mechanisms of TBI.Evidence reviewWe searched articles in PubMed published between 1960 and August 1, 2014, using the following keywords: traumatic brain injury, sterile injury, inflammation, astrocytes, microglia, monocytes, macrophages, neutrophils, T cells, reactive oxygen species, alarmins, danger-associated molecular patterns, purinergic receptors, neuroprotection, and clinical trials. Previous clinical trials or therapeutic studies that involved manipulation of the discussed mechanisms were considered for inclusion. The final list of selected studies was assembled based on novelty and direct relevance to the primary focus of this review.FindingsTraumatic brain injury is a diverse group of sterile injuries induced by primary and secondary mechanisms that give rise to cell death, inflammation, and neurologic dysfunction in patients of all demographics. Pathogenesis is driven by complex, interacting mechanisms that include reactive oxygen species, ion channel and gap junction signaling, purinergic receptor signaling, excitotoxic neurotransmitter signaling, perturbations in calcium homeostasis, and damage-associated molecular pattern molecules, among others. Central nervous system resident and peripherally derived inflammatory cells respond to TBI and can provide neuroprotection or participate in maladaptive secondary injury reactions. The exact contribution of inflammatory cells to a TBI lesion is dictated by their anatomical positioning as well as the local cues to which they are exposed.Conclusions and relevanceThe mechanisms that drive TBI lesion development as well as those that promote repair are exceedingly complex and often superimposed. Because pathogenic mechanisms can diversify over time or even differ based on the injury type, it is important that neuroprotective therapeutics be developed and administered with these variables in mind. Due to its complexity, TBI has proven particularly challenging to treat; however, a number of promising therapeutic approaches are now under pre-clinical development, and recent clinical trials have even yielded a few successes. Given the worldwide impact of TBI on the human population, it is imperative that research remains active in this area and that we continue to develop therapeutics to improve outcome in afflicted patients.

Project description:ObjectiveTo provide an overview of the preclinical literature on progesterone for neuroprotection after traumatic brain injury and to describe unique features of developmental brain injury that should be considered when evaluating the therapeutic potential for progesterone treatment after pediatric traumatic brain injury.Data sourcesNational Library of Medicine PubMed literature review.Study selectionThe mechanisms of neuroprotection by progesterone are reviewed, and the preclinical literature using progesterone treatment in adult animal models of traumatic brain injury is summarized. Unique features of the developing brain that could either enhance or limit the efficacy of neuroprotection by progesterone are discussed, and the limited preclinical literature using progesterone after acute injury to the developing brain is described. Finally, the current status of clinical trials of progesterone for adult traumatic brain injury is reviewed.Data extraction and data synthesisProgesterone is a pleiotropic agent with beneficial effects on secondary injury cascades that occur after traumatic brain injury, including cerebral edema, neuroinflammation, oxidative stress, and excitotoxicity. More than 40 studies have used progesterone for treatment after traumatic brain injury in adult animal models, with results summarized in tabular form. However, very few studies have evaluated progesterone in pediatric animal models of brain injury. To date, two human phase II trials of progesterone for adult traumatic brain injury have been published, and two multicenter phase III trials are underway.ConclusionsThe unique features of the developing brain from that of a mature adult brain make it necessary to independently study progesterone in clinically relevant, immature animal models of traumatic brain injury. Additional preclinical studies could lead to the development of a novel neuroprotective therapy that could reduce the long-term disability in head-injured children and could potentially provide benefit in other forms of pediatric brain injury (global ischemia, stroke, and statue epilepticus).

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Neuroprotection of NRF2 against Ferroptosis after Traumatic Brain Injury in Mice.

Publications

Neuroprotection of NRF2 against Ferroptosis after Traumatic Brain Injury in Mice.

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