Structure-activity relationship studies of phenothiazine derivatives as a new class of ferroptosis inhibitors together with the therapeutic effect in an ischemic stroke model

Yang, Wei; Liu, Xiaolong; Song, Chunli; Ji, Songbai; Yang, Jianhong; Liu, Yang; You, Jianxin; Zhang, Jie; Huang, Shenzhen; Cheng, Wei; Shao, Zhenhua; Li, Linli; Yang, Shengyong

doi:10.1016/j.ejmech.2020.112842

Cited by 47 publications

(33 citation statements)

References 52 publications

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“… 26 , 40 Current studies indicate that ferroptotic pathways have been involved in the pathological process of ischemic stroke, and the inhibition of ferroptosis can ameliorate ischemic brain injury in vivo . 1 , 24 , 26 , 41 , 42 …”

Section: Resultsmentioning

confidence: 99%

Inhibiting Ferroptosis through Disrupting the NCOA4–FTH1 Interaction: A New Mechanism of Action

et al. 2021

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Ferroptosis is an iron-dependent form of oxidative cell death, and the inhibition of ferroptosis is a promising strategy with which to prevent and treat neurological diseases. Herein we report a new ferroptosis inhibitor 9a with a novel mechanism of action. It is demonstrated that nuclear receptor coactivator 4 (NCOA4), a cargo receptor for ferritinophagy, is the target of 9a . Compound 9a blocks ferroptosis by reducing the amount of bioavailable intracellular ferrous iron through disrupting the NCOA4–FTH1 protein–protein interaction. Further studies indicate that 9a directly binds to recombinant protein NCOA4 383–522 and effectively blocks the NCOA4 383–522 –FTH1 interaction. In a rat model of ischemic stroke, 9a significantly ameliorates the ischemic-refusion injury. With the first ligand 9a , this work reveals that NCOA4 is a promising drug target. Additionally, 9a is the first NCOA4–FTH1 interaction inhibitor. This work paves a new road to the development of ferroptosis inhibitors against neurological diseases.

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Section: Resultsmentioning

confidence: 99%

Inhibiting Ferroptosis through Disrupting the NCOA4–FTH1 Interaction: A New Mechanism of Action

et al. 2021

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“…The changes are beneficial to inhibit ferroptosis, protect the integrity of endothelial cells and the BBB, promote neural repair, and improve recovery in ischemic stroke [ 25 , 176 , 177 ]. In addition to vitamin B12, the most potent compound 2-(1-(4-(4-methylpiperazin-1-yl) phenyl) ethyl)-10H-phenothiazine (51) of promethazine has a good ability to permeate the BBB and good therapeutic effect in MCAO model [ 178 ]. Meanwhile, it also suppresses erastin-induced ferroptosis [ 178 ].…”

Section: Pharmacotherapies For Ischemic Stroke Targeting Ferroptosis and Necroptosismentioning

confidence: 99%

“…In addition to vitamin B12, the most potent compound 2-(1-(4-(4-methylpiperazin-1-yl) phenyl) ethyl)-10H-phenothiazine (51) of promethazine has a good ability to permeate the BBB and good therapeutic effect in MCAO model [ 178 ]. Meanwhile, it also suppresses erastin-induced ferroptosis [ 178 ]. Leptin is an adipocyte-derived hormone that acts as inhibiting glutamate release in the hippocampal CA3 field [ 179 ], which attenuates ferroptosis induced by glutamate excitotoxicity [ 180 ], increases cerebral blood flow in hypoperfused rat brains, protects neurologic function, and reduces infarct size [ 181 , 182 ].…”

Section: Pharmacotherapies For Ischemic Stroke Targeting Ferroptosis and Necroptosismentioning

confidence: 99%

Insight into Crosstalk between Ferroptosis and Necroptosis: Novel Therapeutics in Ischemic Stroke

Zhou

Liao

Mei

et al. 2021

Oxidative Medicine and Cellular Longevity

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Ferroptosis is a nonapoptotic form of cell death characterized by iron-dependent accumulation of lipid hydroperoxides to lethal levels. Necroptosis, an alternative form of programmed necrosis, is regulated by receptor-interacting protein (RIP) 1 activation and by RIP3 and mixed-lineage kinase domain-like (MLKL) phosphorylation. Ferroptosis and necroptosis both play important roles in the pathological progress in ischemic stroke, which is a complex brain disease regulated by several cell death pathways. In the past few years, increasing evidence has suggested that the crosstalk occurs between necroptosis and ferroptosis in ischemic stroke. However, the potential links between ferroptosis and necroptosis in ischemic stroke have not been elucidated yet. Hence, in this review, we overview and analyze the mechanism underlying the crosstalk between necroptosis and ferroptosis in ischemic stroke. And we find that iron overload, one mechanism of ferroptosis, leads to mitochondrial permeability transition pore (MPTP) opening, which aggravates RIP1 phosphorylation and contributes to necroptosis. In addition, heat shock protein 90 (HSP90) induces necroptosis and ferroptosis by promoting RIP1 phosphorylation and suppressing glutathione peroxidase 4 (GPX4) activation. In this work, we try to deliver a new perspective in the exploration of novel therapeutic targets for the treatment of ischemic stroke.

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“…We did not find thrombolysis complications due to DFO or any other DFO-induced change in the number and type of adverse events (see Table 2 ). This safety DFO data in ischemic stroke patients set the groundwork for a larger clinical trial given the recently reported role of iron-induced ferroptosis as a main contributor of brain damage in experimental stroke models [ 1 , 4 , 5 , 6 , 31 , 32 , 33 ] and of previous reports in which DFO treatment is associated with lower infarct volume, less mitochondrial free radicals [ 24 ], less hemorrhagic transformation, and improved neurological status in experimental ischemic stroke models [ 4 , 20 , 21 , 24 , 34 , 35 , 36 , 37 ]. Of note, either treatment with DFO or prevention of cellular iron uptake have been reported to protect neuronal phenotype cells from excitotoxic cell death through a reduction of oxidative stress [ 12 , 38 , 39 ].…”

Section: Discussionmentioning

confidence: 99%

“…This cell death is known as ferroptosis, which is iron- and lipid peroxidation-dependent, and associated with reduced cellular antioxidant activity. In support of this concept, ferroptosis has been recently reported to drive the acute neurodegeneration observed in ischemic and hemorrhagic stroke [ 1 , 2 , 3 , 4 , 5 , 6 ]; in traumatic brain injury [ 7 ]; or in long-term neurodegeneration observed in pathologies such as Alzheimer’s disease, Parkinson’s disease, or Huntington’s disease [ 8 ].…”

Section: Introductionmentioning

confidence: 99%

Targeting Pro-Oxidant Iron with Deferoxamine as a Treatment for Ischemic Stroke: Safety and Optimal Dose Selection in a Randomized Clinical Trial

Millán

DeGregorio-Rocasolano

Ossa

et al. 2021

Antioxidants

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A role of iron as a target to prevent stroke-induced neurodegeneration has been recently revisited due to new evidence showing that ferroptosis inhibitors are protective in experimental ischemic stroke and might be therapeutic in other neurodegenerative brain pathologies. Ferroptosis is a new form of programmed cell death attributed to an overwhelming lipidic peroxidation due to excessive free iron and reactive oxygen species (ROS). This study aims to evaluate the safety and tolerability and to explore the therapeutic efficacy of the iron chelator and antioxidant deferoxamine mesylate (DFO) in ischemic stroke patients. Administration of placebo or a single DFO bolus followed by a 72 h continuous infusion of three escalating doses was initiated during the tPA infusion, and the impact on blood transferrin iron was determined. Primary endpoint was safety and tolerability, and secondary endpoint was good clinical outcome (clinicalTrials.gov NCT00777140). DFO was found safe as adverse effects were not different between placebo and DFO arms. DFO (40–60 mg/Kg/day) reduced the iron saturation of blood transferrin. A trend to efficacy was observed in patients with moderate-severe ischemic stroke (NIHSS > 7) treated with DFO 40–60 mg/Kg/day. A good outcome was observed at day 90 in 31% of placebo vs. 50–58% of the 40–60 mg/Kg/day DFO-treated patients.

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Structure-activity relationship studies of phenothiazine derivatives as a new class of ferroptosis inhibitors together with the therapeutic effect in an ischemic stroke model

Cited by 47 publications

References 52 publications

Inhibiting Ferroptosis through Disrupting the NCOA4–FTH1 Interaction: A New Mechanism of Action

Inhibiting Ferroptosis through Disrupting the NCOA4–FTH1 Interaction: A New Mechanism of Action

Insight into Crosstalk between Ferroptosis and Necroptosis: Novel Therapeutics in Ischemic Stroke

Targeting Pro-Oxidant Iron with Deferoxamine as a Treatment for Ischemic Stroke: Safety and Optimal Dose Selection in a Randomized Clinical Trial

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