D-Penicillamine Reveals the Amelioration of Seizure-Induced Neuronal Injury via Inhibiting Aqp11-Dependent Ferroptosis

Yang, Nan; Zhang, Kai; Guan, Qi-Wen; Wang, Zhaojun; Chen, Kang-Ni; Mao, Xiao‐Yuan

doi:10.3390/antiox11081602

Cited by 10 publications

(5 citation statements)

References 64 publications

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“…As such, the use of male animals would help minimize this confounding factor. In addition, it is of note that several recent studies have shown that the kainic acid-neuronal cell death in the mouse brain closely resembles ferroptosis (64)(65)(66). It was reported that the brain tissue of kainic acidtreated mice has decreased levels of GSH, which is accompanied by increased levels of MDA, intracellular superoxide and lipid peroxides, increased PTGS2 expression and decreased GPX expression (64)(65)(66).…”

Section: Discussionmentioning

confidence: 98%

Strong Protection by Bazedoxifene Against Chemically-Induced Ferroptotic Neuronal DeathIn VitroandIn Vivo

Hao,

Wang,

Yang

et al. 2024

Preprint

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Ferroptosis is a form of regulated cell death characterized by excessive iron-dependent lipid peroxidation. Ferroptosis can be induced in cultured cells by exposure to certain chemicals (e.g., erastin and RSL3). Recently it was shown that protein disulfide isomerase (PDI) is a mediator of chemically-induced ferroptosis and also a target for ferroptosis protection. In this study, we find that bazedoxifene (BAZ), a selective estrogen receptor modulator with reported neuroprotective actions in humans, can inhibit PDI function and also strongly protect against chemically-induced ferroptosis in cultured neuronal cells. We find that BAZ can directly bind to PDIin vitroand in intact neuronal cells, and also can inhibit PDI’s catalytic activity. Computational modeling analysis reveals that BAZ forms a hydrogen bond with PDI-His256. Inhibition of PDI by BAZ markedly reduces nNOS and iNOS dimerization and NO accumulation, which have recently been shown to play a crucial role in mediating chemically-induced ferroptosis. In addition, the direct antioxidant activity of BAZ may also partially contribute to its protective effect against chemically-induced ferroptosis. Behavioral analysis shows that mice treated with BAZ are strongly protected against kainic acid-induced memory deficits and hippocampal neuronal damagein vivo. In conclusion, the results of this study demonstrate that BAZ is an inhibitor of PDI and can strongly prevent chemically-induced ferroptosis in hippocampal neurons bothin vitroandin vivo. These observations offer a novel, estrogen receptor-independent mechanism for the recently-reported neuroprotective actions of BAZ in humans.SIGNIFICANCE STATEMENTFerroptosis is an iron- and lipid peroxidation-dependent form of regulated cell death. Recent evidence has shown that protein disulfide isomerase (PDI) is an important mediator of chemically-induced ferroptosis and also a new target for ferroptosis protection. We find that bazedoxifene is an inhibitor of PDI, which can strongly protect against chemically-induced ferroptotic neuronal deathin vitroandin vivo. Additionally, the molecular mechanism of PDI□bazedoxifene binding interaction is defined. This work provides evidence for an estrogen receptor-independent, PDI-mediated mechanism of neuroprotection by bazedoxifene.

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Section: Discussionmentioning

confidence: 98%

Strong Protection by Bazedoxifene Against Chemically-Induced Ferroptotic Neuronal DeathIn VitroandIn Vivo

Hao,

Wang,

Yang

et al. 2024

Preprint

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“…[36,37] Real-Time Quantitative Polymerase Chain Reaction: Real-time quantitative polymerase chain reaction (RT-qPCR) was performed as previously described. [38] In brief, the extraction of total RNA from hippocampal tissue samples was carried out using TRIzol reagent. The quantities and qualities of total RNA were assessed using Nanodrop 2000 spectrophotometer (Thermo Scientific, USA).…”

Section: Methodsmentioning

confidence: 99%

Calcium Phosphate‐Based Nanoformulation Selectively Abolishes Phenytoin Resistance in Epileptic Neurons for Ceasing Seizures

Guan

Wang

Cao

et al. 2023

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to temporally block the sodium-dependent action potentials for inhibiting seizure activities. However, the unique pathological features of epilepsy create additional challenges for PHT-based seizure treatment. Typically, the blood-brain-barrier (BBB) is a formidable obstacle that severely limits the translocation of PHT from the bloodstream to epileptic neurons, which often warrants large PHT dosage to ensure sufficient brain PHT accumulation and causes unneglectable side effects. [2] The prevalent adverse reactions with PHT treatment for epilepsy include gingival hyperplasia and hirsutism and rare but serious cutaneous eruptions such as Stevens-Johnson syndrome. [3] These toxic effects bring great clinical challenges regarding the usage of PHT. Moreover, epileptic neurons are usually overexpressed with p-glycoprotein (P-gp) (coded by the gene Abcb1 in mice) drug efflux pumps, leading to the rapid excretion of internalized PHT molecules and compromising their therapeutic efficacy. [4][5][6] Consequently, it is important to develop new strategies to improve the brain-targeted delivery efficacy of PHT for enhanced epilepsy treatment efficacy.The P-gp-mediated drug efflux is a well-recognized adenosine triphosphate (ATP)-consuming process. [7][8][9][10] Therefore, an ideal PHT delivery system should be able to simultaneously inhibit the P-gp expression in epileptic neurons, as well Phenytoin (PHT) is a first-line antiepileptic drug in clinics, which could decrease neuronal bioelectric activity by blocking the voltage-operated sodium channels. However, the intrinsically low blood-brain-barrier (BBB)-crossing capability of PHT and upregulated expression level of the efflux transporter p-glycoprotein (P-gp) coded by the gene Abcb1 in epileptic neurons limit its efficacy in vivo. Herein, a nanointegrated strategy to overcome PHT resistance mechanisms for enhanced antiepileptic efficacy is reported. Specifically, PHT is first incorporated into calcium phosphate (CaP) nanoparticles through biomineralization, followed by the surface modification of the PEGylated BBB-penetrating TAT peptide. The CaP@PHT-PEG-TAT nanoformulation could effectively cross the BBB to be taken in by epileptic neurons. Afterward, the acidic lysosomal environment would trigger their complete degradation to release Ca 2+ and PHT into the cytosol. Ca 2+ ions would inhibit mitochondrial oxidative phosphorylation to reverse cellular hypoxia to block hypoxia-inducible factor-1α (Hif1α)-Abcb1-axis, as well as disrupt adenosine triphosphate generation, leading to simultaneous suppression of the expression and drug efflux capacity of P-gp to enhance PHT retention. This study offers an approach for effective therapeutic intervention against drug-resistant epilepsy.

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“…Treatment for Wilson's disease involves the use of the medication D-penicillamine [135]. It inactivates ACSL4 by activating aquaporin 11 (Aqp11) and inhibiting ferroptosis in hippocampal neurons [136].…”

Section: Ferroptosis-based Epilepsy Managementmentioning

confidence: 99%

Insight into the Role of Ferroptosis in Epilepsy

Huang,

Liu,

Liu

2024

J. Integr. Neurosci.

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D-Penicillamine Reveals the Amelioration of Seizure-Induced Neuronal Injury via Inhibiting Aqp11-Dependent Ferroptosis

Cited by 10 publications

References 64 publications

Strong Protection by Bazedoxifene Against Chemically-Induced Ferroptotic Neuronal DeathIn VitroandIn Vivo

Strong Protection by Bazedoxifene Against Chemically-Induced Ferroptotic Neuronal DeathIn VitroandIn Vivo

Calcium Phosphate‐Based Nanoformulation Selectively Abolishes Phenytoin Resistance in Epileptic Neurons for Ceasing Seizures

Insight into the Role of Ferroptosis in Epilepsy

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