Ferroptosis-centered Drug Response Information

General Information of the Drug (ID: ferrodrug0095)
Name
Edaravone
Synonyms
edaravone; 89-25-8; 3-METHYL-1-PHENYL-2-PYRAZOLIN-5-ONE; Radicut; Norphenazone; 1-Phenyl-3-methyl-5-pyrazolone; MCI-186; Developer Z; Methylphenylpyrazolone; C.I. Developer 1; Norantipyrine; Phenyl methyl pyrazolone; Phenylmethylpyrazolone; Radicava; 5-Methyl-2-phenyl-2,4-dihydro-3H-pyrazol-3-one; 3-Methyl-1-phenyl-1H-pyrazol-5(4H)-one; 1-Phenyl-3-methyl-5-oxo-2-pyrazoline; 3H-Pyrazol-3-one, 2,4-dihydro-5-methyl-2-phenyl-; 1-Phenyl-3-methylpyrazolone; 5-methyl-2-phenyl-4H-pyrazol-3-one; 1-Phenyl-3-methylpyrazolone-5; Edaravone (MCI-186); 3-Methyl-1-phenylpyrazol-5-one; 3-Methyl-1-phenyl-2-pyrazoline-5-one; NCI-C03952; 2-Pyrazolin-5-one, 3-methyl-1-phenyl-; 5-Pyrazolone, 3-methyl-1-phenyl-; 2,4-Dihydro-5-methyl-2-phenyl-3H-pyrazol-3-one; Colorex pmp; Jarocol pmp; NSC-2629; 1-Fenyl-3-methyl-2-pyrazolin-5-on; NSC-26139; CHEBI:31530; 3-methyl-1-phenyl-4,5-dihydro-1H-pyrazol-5-one; S798V6YJRP; MLS000069602; 3-METHYL-1-PHENYL-2-PYRAZOLIN-5-ONE (MCI-186); DTXSID9021130; CI Developer 1; NCGC00164015-01; SMR000059020; edaravone(jan); Edaravone [INN]; DTXCID201130; Monopyrazolone; WLN: T5NMV DHJ BR& E1; CAS-89-25-8; CCRIS 512; Radicut (TN); HSDB 4102; 3H-Pyrazol-3-one,4-dihydro-5-methyl-2-phenyl-; SR-01000000135; 1-Fenyl-3-methyl-2-pyrazolin-5-on [Czech]; EINECS 201-891-0; MFCD00003138; UNII-S798V6YJRP; BRN 0609575; AI3-03557; MCI186; (Edaravone); Radicava (TN); (MCI-186); IN1263; CDS1_000986; Spectrum_000267; Tocris-0786; EDARAVONE [JAN]; MCI-186; Edaravone; Edaravone [USAN:INN]; EDARAVONE [HSDB]; EDARAVONE [USAN]; Maybridge1_005738; Opera_ID_1057; Spectrum2_001574; Spectrum3_000971; Spectrum4_001091; Spectrum5_001217; NORPHENAZONE [MI]; M0687; EDARAVONE [MART.]; EC 201-891-0; EDARAVONE [WHO-DD]; SCHEMBL4704; BSPBio_001235; BSPBio_002601; KBioGR_000575; KBioGR_001502; KBioSS_000575; KBioSS_000747; AE-641/00371017; MLS001146878; MLS002415675; MLS006011753; DivK1c_001018; DivK1c_002026; SPECTRUM1503635; SPBio_001508; CHEMBL290916; Edaravone (USAN/JP17/INN); EDARAVONE [ORANGE BOOK]; BCBcMAP01_000127; GTPL11994; HMS503K17; HMS557M18; KBio1_001018; KBio2_000575; KBio2_000747; KBio2_003143; KBio2_003315; KBio2_005711; KBio2_005883; KBio3_001029; KBio3_001030; KBio3_001821; NSC2629; NINDS_001018; BCPP000246; Bio1_000438; Bio1_000927; Bio1_001416; Bio2_000448; Bio2_000928; HMS1362M17; HMS1792M17; HMS1990M17; HMS2234M19; HMS3266F04; HMS3403M17; HMS3411L05; HMS3654L15; HMS3675L05; HMS3884A11; Pharmakon1600-01503635; BCP26336; HY-B0099; NSC26139; Tox21_112077; Tox21_201747; Tox21_302819; BDBM50200541; CCG-39352; NSC758622; s1326; STK201315; 3-methyl-1-phenyl-2-pyrazolin-5one; AKOS000313817; Tox21_112077_1; AC-4745; BCP9000635; CS-1832; DB12243; NSC-758622; PHENYL METHYL PYRAZOLONE [INCI]; SB19128; IDI1_001018; IDI1_002203; NCGC00018218-01; NCGC00018218-02; NCGC00018218-03; NCGC00018218-04; NCGC00018218-05; NCGC00018218-06; NCGC00018218-07; NCGC00018218-08; NCGC00018218-10; NCGC00018218-17; NCGC00022665-02; NCGC00022665-04; NCGC00022665-05; NCGC00022665-06; NCGC00256515-01; NCGC00259296-01; PHENAZONE IMPURITY A [EP IMPURITY]; SBI-0051836.P002; AM20060748; FT-0608243; SW148216-2; 5-methyl-2-phenyl-2,4-dihydro-3-pyrazolone; EN300-16234; 3-Methyl-1-phenyl-2-pyrazoline-5-one, 99%; 4E-901; 5-methyl-2-phenyl-2,4-dihydro-pyrazol-3-one; D01552; D86209; 3-?Methyl-?1-?phenyl-?2-?pyrazolin-?5-?one; AB00375776_14; AB00375776_15; 2 4-Dihydro-5-methyl-2-phenyl-3H-pyrazol-3-one; 2,4-dihydro-2-phenyl-5-methyl-3H-pyrazol-3-one; A843105; Q335099; Q-200386; SR-01000000135-2; SR-01000000135-3; SR-01000000135-5; 5-Methyl-2-phenyl-2,4-dihydro-3H-pyrazol-3-one #; BRD-K35458079-001-04-2; BRD-K35458079-001-12-5; BRD-K35458079-001-23-2; Z50145861; F0391-0021; 3-Methyl-1-phenyl-2-pyrazoline-5-one, SAJ special grade; 3-Methyl-1-phenyl-2-pyrazoline-5-one, purum, >=98.0% (NT); 5-Methyl-2-phenyl-2,4-dihydro-3H-pyrazol-3-one (Edaravone); Phenazone impurity A, European Pharmacopoeia (EP) Reference Standard; 5-Methyl-2-phenyl-1,2-dihydropyrazol-3-one;3-Methyl-1-phenyl-2-pyrazolin-5-one; InChI=1/C10H10N2O/c1-8-7-10(13)12(11-8)9-5-3-2-4-6-9/h2-6H,7H2,1H

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Status
Approved
Drug Type
Small molecular drug
Structure
Formula
C10H10N2O
IUPAC Name
5-methyl-2-phenyl-4H-pyrazol-3-one
Canonical SMILES
CC1=NN(C(=O)C1)C2=CC=CC=C2
InChI
InChI=1S/C10H10N2O/c1-8-7-10(13)12(11-8)9-5-3-2-4-6-9/h2-6H,7H2,1H3
InChIKey
QELUYTUMUWHWMC-UHFFFAOYSA-N
PubChem CID
4021
TTD Drug ID
D06DLI
Full List of Ferroptosis Target Related to This Drug
Nuclear factor erythroid 2-related factor 2 (NFE2L2)
 Target Info 
In total 2 item(s) under this Target
Experiment 1 Reporting the Ferroptosis-centered Drug Act on This Target [1]
Target for Ferroptosis Marker/Suppressor
Responsed Disease Depressive disorder ICD-11: 6A70
 Disease Info 
Responsed Regulator NAD-dependent protein deacetylase sirtuin-1 (SIRT1) Suppressor
 Regulator Info 
Pathway Response Ferroptosis hsa04216
Fatty acid metabolism hsa01212
Cell Process Cell ferroptosis
Cell proliferation
In Vitro Model hBCs (Brain cells)
In Vivo Model
Male C57BL/6J mice (aged 7-8 weeks) and retired male CD-1 mice (aged 16-20 weeks) were obtained from the Experimental Animal Centre of Chongqing Medical University (Chongqing, China). The experimental animals were housed in cages under a 12 h light/12 h dark cycle (lights on at 8:00 a.m.), 60 ± 5% humidity, and a temperature of 23 ± 1 with access to water and food freely. All experimental procedures were conducted in accordance with the Ethics Committee of Chongqing Medical University. EDA was purchased from Sigma-Aldrich (St. Louis, USA) and was dissolved in Vehicle (NaCl, 0.9%) at a dosage of 10 mg/kg. EX527 (a Sirt1 inhibitor) and ML385 (a Nrf2 inhibitor) were obtained from MedChemExpress (New Jersey, USA).

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Response regulation The inflammation and oxidative stress (OS) have been considered crucial components of the pathogenesis of depression. Edaravone possesses potent antidepressant and anxiolytic properties through Sirt1/Nrf2/HO-1/Gpx4 axis and Gpx4-mediated ferroptosis may play a key role in this effect.
Experiment 2 Reporting the Ferroptosis-centered Drug Act on This Target [3]
Target for Ferroptosis Marker/Suppressor
Responsed Disease Cerebral ischemia ICD-11: 8B10
 Disease Info 
Pathway Response Glutathione metabolism hsa00480
Ferroptosis hsa04216
Cell Process Cell ferroptosis
In Vivo Model
Seventy-three specific-pathogen-free (SPF)grade healthy male Sprague Dawley (SD) rats, weighing 240 ± 20 g, were purchased from Hunan Slake Jingda Experimental Animal Co., Ltd., China (animal certificate number SCXK (Xiang) 2013-0004). The animals were reared in an SPF animal laboratory, and the ambient temperature was maintained at 23 ± 1 . All protocols followed the ARRIVE guidelines in terms of study design, sample size, randomization, outcome measures, data analysis, experimental procedures, and reporting of results. This study was approved by the Animal Ethics Committee of the Hunan University of Chinese Medicine.

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Response regulation Edaravone inhibits ferroptosis to attenuate cerebral ischemia-reperfusion injury, probably through the activation of the Nrf2/FPN pathway.
Unspecific Target
In total 1 item(s) under this Target
Experiment 1 Reporting the Ferroptosis-centered Drug Act on This Target [2]
Responsed Disease Neuroinflammation ICD-11: 8C1Z
 Disease Info 
Responsed Regulator Toll-like receptor 4 (TLR4) Driver
 Regulator Info 
Pathway Response Ferroptosis hsa04216
Fatty acid metabolism hsa01212
Cell Process Cell ferroptosis
Cell apoptosis
In Vitro Model HT22 cells Normal Mus musculus CVCL_0321
Response regulation Edaravone could significantly reduce A1-42-induced apoptosis of HT22 cells and formation of pro-inflammatory factors TNF-, IL-1 and IL-6, prevent the activation of TLR4/NF-kB /NLRP3 signaling pathway, and inhibit ferroptosis and lipid peroxidation. Taken together, EDA contributes to inhibiting neuroinflammatory injury and ferroptosis in A 1-42-induced HT22 cells, and thus may be a potential candidate for the treatment of AD.
Solute carrier family 40 member 1 (SLC40A1)
 Target Info 
In total 1 item(s) under this Target
Experiment 1 Reporting the Ferroptosis-centered Drug Act on This Target [3]
Target for Ferroptosis Suppressor
Responsed Disease Cerebral ischemia ICD-11: 8B10
 Disease Info 
Pathway Response Glutathione metabolism hsa00480
Ferroptosis hsa04216
Cell Process Cell ferroptosis
In Vivo Model
Seventy-three specific-pathogen-free (SPF)grade healthy male Sprague Dawley (SD) rats, weighing 240 ± 20 g, were purchased from Hunan Slake Jingda Experimental Animal Co., Ltd., China (animal certificate number SCXK (Xiang) 2013-0004). The animals were reared in an SPF animal laboratory, and the ambient temperature was maintained at 23 ± 1 . All protocols followed the ARRIVE guidelines in terms of study design, sample size, randomization, outcome measures, data analysis, experimental procedures, and reporting of results. This study was approved by the Animal Ethics Committee of the Hunan University of Chinese Medicine.

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Response regulation Edaravone inhibits ferroptosis to attenuate cerebral ischemia-reperfusion injury, probably through the activation of the Nrf2/FPN pathway.
Polyunsaturated fatty acid 5-lipoxygenase (ALOX5)
 Target Info 
In total 1 item(s) under this Target
Experiment 1 Reporting the Ferroptosis-centered Drug Act on This Target [4]
Target for Ferroptosis Driver
Responsed Disease Spinal cord injury ICD-11: ND51
 Disease Info 
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
In Vitro Model rSCTs (Rat spinal cord tissues)
In Vivo Model
The rats were initially anesthetized with 5% isoflurane (RWD life science, Shenzhen, China) and then maintained with 22.5% isoflurane. A 1-cm midline incision was made over the thoracic vertebrae, and laminectomy on T10 and the caudal half of T9 vertebrae was performed. Spinal cord contusion injury was conducted by NYU Impactor Model III (W.M. Keck Center for Collaborative Neuroscience Rutgers, The State University of New Jersey, United States) using a 10-g node dropping freely from a height of 2.5 cm and muscles and skin sutured in layers. Sham controls underwent laminectomy without the contusion. To prevent infection at the incision, cefuroxime sodium was applied for 3 days after injury. The bladders were emptied manually twice daily in the first week after injury.

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Response regulation Edaravone not only rescues the ferroptosis negative regulators, xCT and GPX4, but also downregulates those pro-ferroptosis factors, ACSL4 and 5-LOX. Therefore, secondary injury below the lesion site is reversed by edaravone via ferroptosis inhibition. And in the acute phase of spinal cord injury (SCI), edaravone reduced neuronal cell death and neuroinflammation.
Phospholipid hydroperoxide glutathione peroxidase (GPX4)
 Target Info 
In total 1 item(s) under this Target
Experiment 1 Reporting the Ferroptosis-centered Drug Act on This Target [4]
Target for Ferroptosis Suppressor
Responsed Disease Spinal cord injury ICD-11: ND51
 Disease Info 
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
In Vitro Model rSCTs (Rat spinal cord tissues)
In Vivo Model
The rats were initially anesthetized with 5% isoflurane (RWD life science, Shenzhen, China) and then maintained with 22.5% isoflurane. A 1-cm midline incision was made over the thoracic vertebrae, and laminectomy on T10 and the caudal half of T9 vertebrae was performed. Spinal cord contusion injury was conducted by NYU Impactor Model III (W.M. Keck Center for Collaborative Neuroscience Rutgers, The State University of New Jersey, United States) using a 10-g node dropping freely from a height of 2.5 cm and muscles and skin sutured in layers. Sham controls underwent laminectomy without the contusion. To prevent infection at the incision, cefuroxime sodium was applied for 3 days after injury. The bladders were emptied manually twice daily in the first week after injury.

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Response regulation Edaravone not only rescues the ferroptosis negative regulators, xCT and GPX4, but also downregulates those pro-ferroptosis factors, ACSL4 and 5-LOX. Therefore, secondary injury below the lesion site is reversed by edaravone via ferroptosis inhibition. And in the acute phase of spinal cord injury (SCI), edaravone reduced neuronal cell death and neuroinflammation.
Long-chain-fatty-acid--CoA ligase 4 (ACSL4)
 Target Info 
In total 1 item(s) under this Target
Experiment 1 Reporting the Ferroptosis-centered Drug Act on This Target [4]
Target for Ferroptosis Driver
Responsed Disease Spinal cord injury ICD-11: ND51
 Disease Info 
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
In Vitro Model rSCTs (Rat spinal cord tissues)
In Vivo Model
The rats were initially anesthetized with 5% isoflurane (RWD life science, Shenzhen, China) and then maintained with 22.5% isoflurane. A 1-cm midline incision was made over the thoracic vertebrae, and laminectomy on T10 and the caudal half of T9 vertebrae was performed. Spinal cord contusion injury was conducted by NYU Impactor Model III (W.M. Keck Center for Collaborative Neuroscience Rutgers, The State University of New Jersey, United States) using a 10-g node dropping freely from a height of 2.5 cm and muscles and skin sutured in layers. Sham controls underwent laminectomy without the contusion. To prevent infection at the incision, cefuroxime sodium was applied for 3 days after injury. The bladders were emptied manually twice daily in the first week after injury.

    Click to Show/Hide
Response regulation Edaravone not only rescues the ferroptosis negative regulators, xCT and GPX4, but also downregulates those pro-ferroptosis factors, ACSL4 and 5-LOX. Therefore, secondary injury below the lesion site is reversed by edaravone via ferroptosis inhibition. And in the acute phase of spinal cord injury (SCI), edaravone reduced neuronal cell death and neuroinflammation.
References
Ref 1 Edaravone ameliorates depressive and anxiety-like behaviors via Sirt1/Nrf2/HO-1/Gpx4 pathway. J Neuroinflammation. 2022 Feb 7;19(1):41. doi: 10.1186/s12974-022-02400-6.
Ref 2 Edaravone Attenuates A 1-42-Induced Inflammatory Damage and Ferroptosis in HT22 Cells. Neurochem Res. 2023 Feb;48(2):570-578. doi: 10.1007/s11064-022-03782-y. Epub 2022 Nov 4.
Ref 3 Edaravone Ameliorates Cerebral Ischemia-Reperfusion Injury by Downregulating Ferroptosis via the Nrf2/FPN Pathway in Rats. Biol Pharm Bull. 2022;45(9):1269-1275. doi: 10.1248/bpb.b22-00186.
Ref 4 Edaravone Modulates Neuronal GPX4/ACSL4/5-LOX to Promote Recovery After Spinal Cord Injury. Front Cell Dev Biol. 2022 May 18;10:849854. doi: 10.3389/fcell.2022.849854. eCollection 2022.