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  1. Kentaro Deguchi, Kazunori Miyazaki, Fengfeng Tian, Ning Liu, Wentao Liu, Hiromi Kawai, Yosiho Omote, Syoichiro Kono, Taijun Yunoki, Shoko Deguchi and Koji Abe.
    Modifying neurorepair and neuroregenerative factors with tPA and edaravone after transient middle cerebral artery occlusion in rat brain.. Brain research 1436:168–77, February 2012.
    Abstract Changes in expression of neurorepair and neuroregenerative factors were examined after transient cerebral ischemia in relation to the effects of tissue plasminogen activator (tPA) and the free radical scavenger edaravone. Physiological saline or edaravone was injected twice during 90 min of transient middle cerebral artery occlusion (tMCAO) in rats, followed by the same saline or tPA at reperfusion. Sizes of the infarct and protein factors relating to neurorepair and neuroregeneration were examined at 4d after tMCAO. The protein factors examined were: a chondroitin sulfate proteoglycan neurocan, semaphorin type 3A (Sema3A), a myelin-associated glycoprotein receptor (Nogo receptor, Nogo-R), a synaptic regenerative factor (growth associated protein-43, GAP43), and a chemotropic factor netrin receptor (deleted in colorectal cancer, DCC). Two groups treated by edaravone only or edaravone plus tPA showed a reduction in infarct volume compared to the two groups treated by vehicle only or vehicle plus tPA. Immunohistochemistry and western blot analyses indicated that protein expression of neurocan, Sema3A, Nogo-R, GAP43, and DCC was decreased with tPA, but recovered with edaravone. Additive edaravone prevented the reductions of these five proteins induced by tPA. The present study demonstrates for the first time that exogenous tPA reduced protein factors involved in inhibiting and promoting axonal growth, but that edaravone ameliorated such damage in brain repair after acute ischemia.
    URL, DOI BibTeX

    @article{Deguchi2012,
    	abstract = "Changes in expression of neurorepair and neuroregenerative factors were examined after transient cerebral ischemia in relation to the effects of tissue plasminogen activator (tPA) and the free radical scavenger edaravone. Physiological saline or edaravone was injected twice during 90 min of transient middle cerebral artery occlusion (tMCAO) in rats, followed by the same saline or tPA at reperfusion. Sizes of the infarct and protein factors relating to neurorepair and neuroregeneration were examined at 4d after tMCAO. The protein factors examined were: a chondroitin sulfate proteoglycan neurocan, semaphorin type 3A (Sema3A), a myelin-associated glycoprotein receptor (Nogo receptor, Nogo-R), a synaptic regenerative factor (growth associated protein-43, GAP43), and a chemotropic factor netrin receptor (deleted in colorectal cancer, DCC). Two groups treated by edaravone only or edaravone plus tPA showed a reduction in infarct volume compared to the two groups treated by vehicle only or vehicle plus tPA. Immunohistochemistry and western blot analyses indicated that protein expression of neurocan, Sema3A, Nogo-R, GAP43, and DCC was decreased with tPA, but recovered with edaravone. Additive edaravone prevented the reductions of these five proteins induced by tPA. The present study demonstrates for the first time that exogenous tPA reduced protein factors involved in inhibiting and promoting axonal growth, but that edaravone ameliorated such damage in brain repair after acute ischemia.",
    	author = "Deguchi, Kentaro and Miyazaki, Kazunori and Tian, Fengfeng and Liu, Ning and Liu, Wentao and Kawai, Hiromi and Omote, Yosiho and Kono, Syoichiro and Yunoki, Taijun and Deguchi, Shoko and Abe, Koji",
    	doi = "10.1016/j.brainres.2011.12.016",
    	file = ":C$\backslash$:/Users/riku/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Deguchi et al. - 2012 - Modifying neurorepair and neuroregenerative factors with tPA and edaravone after transient middle cerebral arter.pdf:pdf",
    	issn = "1872-6240",
    	journal = "Brain research",
    	keywords = "Animals,Antipyrine,Antipyrine: administration \& dosage,Antipyrine: analogs \& derivatives,Brain,Brain: metabolism,Chondroitin Sulfate Proteoglycans,Chondroitin Sulfate Proteoglycans: analysis,Fibrinolytic Agents,Fibrinolytic Agents: administration \& dosage,Fibrinolytic Agents: adverse effects,Free Radical Scavengers,Free Radical Scavengers: administration \& dosage,GAP-43 Protein,GAP-43 Protein: metabolism,GPI-Linked Proteins,GPI-Linked Proteins: analysis,Infarction, Middle Cerebral Artery,Infarction, Middle Cerebral Artery: drug therapy,Male,Myelin Proteins,Myelin Proteins: analysis,Rats,Receptors, Cell Surface,Receptors, Cell Surface: analysis,Receptors, Cell Surface: metabolism,Reperfusion,Semaphorin-3A,Semaphorin-3A: analysis,Tissue Plasminogen Activator,Tissue Plasminogen Activator: administration \& dos,Tissue Plasminogen Activator: adverse effects",
    	month = "feb",
    	pages = "168--77",
    	pmid = 22221736,
    	title = "{Modifying neurorepair and neuroregenerative factors with tPA and edaravone after transient middle cerebral artery occlusion in rat brain.}",
    	url = "http://www.sciencedirect.com/science/article/pii/S0006899311022165",
    	volume = 1436,
    	year = 2012
    }
    
  2. Krishnamoorthy Srinivasan and Shyam S Sharma.
    Edaravone Offers Neuroprotection in a Diabetic Stroke Model via Inhibition of Endoplasmic Reticulum Stress.. Basic & clinical pharmacology & toxicology, July 2011.
    Abstract   Recent investigations have postulated a link between oxidative stress and endoplasmic reticulum (ER) dysfunction in cerebral ischaemic/reperfusion (I/R) injury. Diabetes is common amongst elderly patients with stroke and has been postulated to aggravate brain I/R damage by triggering oxidative as well as ER stress. We investigated whether treatment with edaravone (1-10 mg/kg), a potent free radical scavenger protects against cerebral I/R injury in rats associated with comorbid type 2 diabetes. Diabetic rats exposed to 2-hr middle cerebral artery occlusion (MCAO) and 22 hr of reperfusion significantly had increased infarct, oedema volume and functional neurological deficits as compared to sham-operated rats. Also, the massive DNA fragmentation accompanied by significant increase in terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling (TUNEL) positive cells was noticed in the ipsilateral penumbral brain region of diabetic I/R rats. The effects of I/R injury were associated with significant up-regulation of 78 kDa-glucose-regulated protein (GRP78), CCAAT/enhancer binding protein homologous protein or growth arrest DNA damage-inducible gene 153 (CHOP/GADD153) and activation of caspase-12, markers of ER stress/apoptosis. Treatment with edaravone (3 and 10 mg/kg) significantly diminished the cerebral infarct, oedema volume and improved functional recovery of neurological deficits. In addition, edaravone treatment ameliorated the DNA fragmentation concomitantly with a significant decrease in induction of GRP78, CHOP/GADD153 immunoreactivity/expression and activation of caspase-12 in the ischaemic brain hemispheres. Overall, the present data indicate that edaravone offers good neuroprotection against diabetic stroke by interrupting the ER stress-mediated apoptotic pathways involving CHOP/GADD153 and caspase-12.
    URL, DOI BibTeX

    @article{Srinivasan2011,
    	abstract = "  Recent investigations have postulated a link between oxidative stress and endoplasmic reticulum (ER) dysfunction in cerebral ischaemic/reperfusion (I/R) injury. Diabetes is common amongst elderly patients with stroke and has been postulated to aggravate brain I/R damage by triggering oxidative as well as ER stress. We investigated whether treatment with edaravone (1-10 mg/kg), a potent free radical scavenger protects against cerebral I/R injury in rats associated with comorbid type 2 diabetes. Diabetic rats exposed to 2-hr middle cerebral artery occlusion (MCAO) and 22 hr of reperfusion significantly had increased infarct, oedema volume and functional neurological deficits as compared to sham-operated rats. Also, the massive DNA fragmentation accompanied by significant increase in terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling (TUNEL) positive cells was noticed in the ipsilateral penumbral brain region of diabetic I/R rats. The effects of I/R injury were associated with significant up-regulation of 78 kDa-glucose-regulated protein (GRP78), CCAAT/enhancer binding protein homologous protein or growth arrest DNA damage-inducible gene 153 (CHOP/GADD153) and activation of caspase-12, markers of ER stress/apoptosis. Treatment with edaravone (3 and 10 mg/kg) significantly diminished the cerebral infarct, oedema volume and improved functional recovery of neurological deficits. In addition, edaravone treatment ameliorated the DNA fragmentation concomitantly with a significant decrease in induction of GRP78, CHOP/GADD153 immunoreactivity/expression and activation of caspase-12 in the ischaemic brain hemispheres. Overall, the present data indicate that edaravone offers good neuroprotection against diabetic stroke by interrupting the ER stress-mediated apoptotic pathways involving CHOP/GADD153 and caspase-12.",
    	author = "Srinivasan, Krishnamoorthy and Sharma, Shyam S",
    	doi = "10.1111/j.1742-7843.2011.00763.x",
    	issn = "1742-7843",
    	journal = "Basic \& clinical pharmacology \& toxicology",
    	month = "jul",
    	pmid = 21752197,
    	title = "{Edaravone Offers Neuroprotection in a Diabetic Stroke Model via Inhibition of Endoplasmic Reticulum Stress.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/21752197",
    	year = 2011
    }
    
  3. Hidemi Yoshida, Norifumi Metoki, Akira Ishikawa, Tadaatsu Imaizumi, Tomoh Matsumiya, Kunikazu Tanji, Ken Ota, Chikara Ohyama and Kei Satoh.
    Edaravone improves the expression of nerve growth factor in human astrocytes subjected to hypoxia/reoxygenation.. Neuroscience research 66(3):284–9, 2010.
    Abstract Edaravone (MCI-186, 3-methyl-1-phenyl-2-pyrazolin-5-one), a free radical scavenger, is known to ameliorate postischemic neuronal dysfunction. Nerve growth factor (NGF) is essential for neuronal growth and survival. We have addressed the effect of edaravone on the NGF expression in astrocytes exposed to hypoxia/reoxygenation. Normal human astrocytes in culture were incubated under hypoxia for 3h and then treated with edaravone under normal culture condition for up to 72h. The levels of NGF mRNA were analyzed by reverse transcription-polymerase chain reaction (RT-PCR) or real-time quantitative PCR and NGF protein levels were measured by enzyme-linked immunosorbent assay (ELISA). Edaravone enhanced, in time- and concentration-dependent manners, the expressions of NGF mRNA and protein in astrocytes under reoxygenation condition. After the treatment for 72h, 1mmol/L edaravone enhanced the levels of NGF protein in astrocyte-conditioned media by 1.7-fold of the control. An inhibitor of c-Jun N-terminal kinase (JNK) suppressed the effect of edaravone on the NGF expression, and cellular levels of phospho-JNK were increased in response to edaravone. We conclude that edaravone enhances, via the JNK pathway, NGF expression in astrocytes. This agent may exert a neurotrophic effect in the therapy of brain injury in ischemia/reperfusion.
    URL, DOI BibTeX

    @article{Yoshida2010,
    	abstract = "Edaravone (MCI-186, 3-methyl-1-phenyl-2-pyrazolin-5-one), a free radical scavenger, is known to ameliorate postischemic neuronal dysfunction. Nerve growth factor (NGF) is essential for neuronal growth and survival. We have addressed the effect of edaravone on the NGF expression in astrocytes exposed to hypoxia/reoxygenation. Normal human astrocytes in culture were incubated under hypoxia for 3h and then treated with edaravone under normal culture condition for up to 72h. The levels of NGF mRNA were analyzed by reverse transcription-polymerase chain reaction (RT-PCR) or real-time quantitative PCR and NGF protein levels were measured by enzyme-linked immunosorbent assay (ELISA). Edaravone enhanced, in time- and concentration-dependent manners, the expressions of NGF mRNA and protein in astrocytes under reoxygenation condition. After the treatment for 72h, 1mmol/L edaravone enhanced the levels of NGF protein in astrocyte-conditioned media by 1.7-fold of the control. An inhibitor of c-Jun N-terminal kinase (JNK) suppressed the effect of edaravone on the NGF expression, and cellular levels of phospho-JNK were increased in response to edaravone. We conclude that edaravone enhances, via the JNK pathway, NGF expression in astrocytes. This agent may exert a neurotrophic effect in the therapy of brain injury in ischemia/reperfusion.",
    	author = "Yoshida, Hidemi and Metoki, Norifumi and Ishikawa, Akira and Imaizumi, Tadaatsu and Matsumiya, Tomoh and Tanji, Kunikazu and Ota, Ken and Ohyama, Chikara and Satoh, Kei",
    	doi = "10.1016/j.neures.2009.11.011",
    	issn = "1872-8111",
    	journal = "Neuroscience research",
    	keywords = "Antipyrine,Antipyrine: administration \& dosage,Antipyrine: analogs \& derivatives,Antipyrine: pharmacology,Astrocytes,Astrocytes: drug effects,Astrocytes: metabolism,Blotting, Western,Cell Hypoxia,Cell Survival,Cell Survival: drug effects,Cells, Cultured,Dose-Response Relationship, Drug,Enzyme Inhibitors,Enzyme Inhibitors: pharmacology,Enzyme-Linked Immunosorbent Assay,Free Radical Scavengers,Free Radical Scavengers: administration \& dosage,Free Radical Scavengers: pharmacology,Humans,JNK Mitogen-Activated Protein Kinases,JNK Mitogen-Activated Protein Kinases: antagonists,JNK Mitogen-Activated Protein Kinases: metabolism,MAP Kinase Signaling System,MAP Kinase Signaling System: drug effects,Nerve Growth Factor,Nerve Growth Factor: metabolism,Oxygen,Oxygen: metabolism,Phosphorylation,Phosphorylation: drug effects,Polymerase Chain Reaction,RNA, Messenger,RNA, Messenger: metabolism,Reverse Transcriptase Polymerase Chain Reaction,Time Factors",
    	month = "",
    	number = 3,
    	pages = "284--9",
    	pmid = 19954754,
    	title = "{Edaravone improves the expression of nerve growth factor in human astrocytes subjected to hypoxia/reoxygenation.}",
    	url = "http://www.mendeley.com/research/edaravone-improves-expression-nerve-growth-factor-human-astrocytes-subjected-hypoxiareoxygenation/",
    	volume = 66,
    	year = 2010
    }
    
  4. Paul A Lapchak.
    A critical assessment of edaravone acute ischemic stroke efficacy trials: is edaravone an effective neuroprotective therapy?. Expert opinion on pharmacotherapy 11(10):1753–63, 2010.
    Abstract IMPORTANCE OF THE FIELD: Edaravone (Radicut) is a free radical scavenger marketed in Japan by Mitsubishi Tanabe Pharma Corp. to treat acute ischemic stroke (AIS) patients presenting within 24 h of the attack. Injectable edaravone ampoules (30 mg b.i.d., i.v., 14 days) were first approved on 23 May 2001. On 19 January 2010, as a new innovation, the Radicut BAG (Intravenous BAG) was approved by the Japanese Ministry of Health and Welfare. Efficacy of edaravone ranges from large significant clinical improvements to only modest improvements in clinical function measured using standard stroke scales when administered 6-72 h following an ischemic stroke. With almost 17 years of edaravone clinical experience, a few adverse events–including acute renal failure–have been noted. WHAT THE READER WILL GAIN: This is the only article to date to critically review available clinical efficacy and toxicology data published in the literature to ascertain whether edaravone should be further pursued as a candidate for development worldwide. AREAS COVERED IN THIS REVIEW: This review covers clinical studies carried out over the period 1993-2008. TAKE HOME MESSAGE: Edaravone may be a useful neuroprotective agent to treat the > 15 million victims worldwide who are devastated by stroke annually. Additional clinical studies are necessary to verify the efficacy of edaravone.
    URL, DOI BibTeX

    @article{Lapchak2010,
    	abstract = "IMPORTANCE OF THE FIELD: Edaravone (Radicut) is a free radical scavenger marketed in Japan by Mitsubishi Tanabe Pharma Corp. to treat acute ischemic stroke (AIS) patients presenting within 24 h of the attack. Injectable edaravone ampoules (30 mg b.i.d., i.v., 14 days) were first approved on 23 May 2001. On 19 January 2010, as a new innovation, the Radicut BAG (Intravenous BAG) was approved by the Japanese Ministry of Health and Welfare. Efficacy of edaravone ranges from large significant clinical improvements to only modest improvements in clinical function measured using standard stroke scales when administered 6-72 h following an ischemic stroke. With almost 17 years of edaravone clinical experience, a few adverse events--including acute renal failure--have been noted. WHAT THE READER WILL GAIN: This is the only article to date to critically review available clinical efficacy and toxicology data published in the literature to ascertain whether edaravone should be further pursued as a candidate for development worldwide. AREAS COVERED IN THIS REVIEW: This review covers clinical studies carried out over the period 1993-2008. TAKE HOME MESSAGE: Edaravone may be a useful neuroprotective agent to treat the > 15 million victims worldwide who are devastated by stroke annually. Additional clinical studies are necessary to verify the efficacy of edaravone.",
    	author = "Lapchak, Paul A",
    	doi = "10.1517/14656566.2010.493558",
    	file = ":C$\backslash$:/Users/riku/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Lapchak - 2010 - A critical assessment of edaravone acute ischemic stroke efficacy trials is edaravone an effective neuroprotective ther.pdf:pdf",
    	issn = "1744-7666",
    	journal = "Expert opinion on pharmacotherapy",
    	keywords = "Animals,Antipyrine,Antipyrine: adverse effects,Antipyrine: analogs \& derivatives,Antipyrine: pharmacokinetics,Antipyrine: therapeutic use,Brain Ischemia,Brain Ischemia: drug therapy,Drug Evaluation, Preclinical,Free Radical Scavengers,Free Radical Scavengers: therapeutic use,Humans,Neuroprotective Agents,Neuroprotective Agents: therapeutic use,Stroke,Stroke: drug therapy,Translational Medical Research",
    	language = "EN",
    	month = "",
    	number = 10,
    	pages = "1753--63",
    	pmid = 20491547,
    	publisher = "Informa UK Ltd London, UK",
    	title = "{A critical assessment of edaravone acute ischemic stroke efficacy trials: is edaravone an effective neuroprotective therapy?}",
    	url = "http://informahealthcare.com/doi/abs/10.1517/14656566.2010.493558",
    	volume = 11,
    	year = 2010
    }
    
  5. Kiyoshi Kikuchi, Salunya Tancharoen, Fumiyo Matsuda, Kamal Krishna Biswas, Takashi Ito, Yoko Morimoto, Yoko Oyama, Kazunori Takenouchi, Naoki Miura, Noboru Arimura, Yuko Nawa, Xiaojie Meng, Binita Shrestha, Shinichiro Arimura, Masahiro Iwata, Kentaro Mera, Hisayo Sameshima, Yoshiko Ohno, Ryuichi Maenosono, Yutaka Tajima, Hisaaki Uchikado, Terukazu Kuramoto, Kenji Nakayama, Minoru Shigemori, Yoshihiro Yoshida, Teruto Hashiguchi, Ikuro Maruyama and Ko-Ichi Kawahara.
    Edaravone attenuates cerebral ischemic injury by suppressing aquaporin-4.. Biochemical and biophysical research communications 390(4):1121–5, December 2009.
    Abstract Aquaporin-4 (AQP4) plays a role in the generation of post-ischemic edema. Pharmacological modulation of AQP4 function may thus provide a novel therapeutic strategy for the treatment of stroke, tumor-associated edema, epilepsy, traumatic brain injury, and other disorders of the central nervous system (CNS) associated with altered brain water balance. Edaravone, a free radical scavenger, is used for the treatment of acute ischemic stroke (AIS) in Japan. In this study, edaravone significantly reduced the infarct area and improved the neurological deficit scores at 24h after reperfusion in a rat transient focal ischemia model. Furthermore, edaravone markedly reduced AQP4 immunoreactivity and protein levels in the cerebral infarct area. In light of observations that edaravone specifically inhibited AQP4 in a rat transient focal ischemia model, we propose that edaravone might reduce cerebral edema through the inhibition of AQP4 expression following cerebral infarction.
    URL, DOI BibTeX

    @article{Kikuchi2009,
    	abstract = "Aquaporin-4 (AQP4) plays a role in the generation of post-ischemic edema. Pharmacological modulation of AQP4 function may thus provide a novel therapeutic strategy for the treatment of stroke, tumor-associated edema, epilepsy, traumatic brain injury, and other disorders of the central nervous system (CNS) associated with altered brain water balance. Edaravone, a free radical scavenger, is used for the treatment of acute ischemic stroke (AIS) in Japan. In this study, edaravone significantly reduced the infarct area and improved the neurological deficit scores at 24h after reperfusion in a rat transient focal ischemia model. Furthermore, edaravone markedly reduced AQP4 immunoreactivity and protein levels in the cerebral infarct area. In light of observations that edaravone specifically inhibited AQP4 in a rat transient focal ischemia model, we propose that edaravone might reduce cerebral edema through the inhibition of AQP4 expression following cerebral infarction.",
    	author = "Kikuchi, Kiyoshi and Tancharoen, Salunya and Matsuda, Fumiyo and Biswas, Kamal Krishna and Ito, Takashi and Morimoto, Yoko and Oyama, Yoko and Takenouchi, Kazunori and Miura, Naoki and Arimura, Noboru and Nawa, Yuko and Meng, Xiaojie and Shrestha, Binita and Arimura, Shinichiro and Iwata, Masahiro and Mera, Kentaro and Sameshima, Hisayo and Ohno, Yoshiko and Maenosono, Ryuichi and Tajima, Yutaka and Uchikado, Hisaaki and Kuramoto, Terukazu and Nakayama, Kenji and Shigemori, Minoru and Yoshida, Yoshihiro and Hashiguchi, Teruto and Maruyama, Ikuro and Kawahara, Ko-Ichi",
    	doi = "10.1016/j.bbrc.2009.09.015",
    	file = ":C$\backslash$:/Users/riku/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Kikuchi et al. - 2009 - Edaravone attenuates cerebral ischemic injury by suppressing aquaporin-4.pdf:pdf",
    	issn = "1090-2104",
    	journal = "Biochemical and biophysical research communications",
    	keywords = "Animals,Antipyrine,Antipyrine: analogs \& derivatives,Antipyrine: therapeutic use,Aquaporin 4,Aquaporin 4: antagonists \& inhibitors,Brain Edema,Brain Edema: drug therapy,Brain Edema: etiology,Brain Ischemia,Brain Ischemia: complications,Disease Models, Animal,Free Radical Scavengers,Free Radical Scavengers: therapeutic use,Male,Rats",
    	month = "dec",
    	number = 4,
    	pages = "1121--5",
    	pmid = 19737535,
    	title = "{Edaravone attenuates cerebral ischemic injury by suppressing aquaporin-4.}",
    	url = "http://www.sciencedirect.com/science/article/pii/S0006291X09017938",
    	volume = 390,
    	year = 2009
    }
    
  6. Kenji Yagi, Keiko T Kitazato, Masaaki Uno, Yoshiteru Tada, Tomoya Kinouchi, Kenji Shimada and Shinji Nagahiro.
    Edaravone, a free radical scavenger, inhibits MMP-9-related brain hemorrhage in rats treated with tissue plasminogen activator.. Stroke; a journal of cerebral circulation 40(2):626–31, February 2009.
    Abstract BACKGROUND AND PURPOSE: Intracerebral hemorrhage, induced by recombinant tissue plasminogen activator (rtPA) in ischemic stroke, is attributable to the increased activity of matrix metalloproteinase-9 (MMP-9). Patients with acute infarct benefit from the neuroprotective drug edaravone, a free radical scavenger. We examined the mechanisms by which edaravone may help to suppress rtPA-induced brain hemorrhage. METHODS: Male Wistar rats weighing 250 to 280 g were subjected to 3-hour transient middle cerebral artery occlusion (MCAO) and divided randomly into 3 groups. Immediately after reperfusion, 1 group was intravenously injected with 10 mg/kg rtPA, another with rtPA plus 3 mg/kg edaravone, and the 3rd group received no treatment. We assessed the hemorrhage volume and the activity of MMP-9 in the brain 24 hours postischemia. We also studied the activity of MMP-9, its mRNA expression, and nuclear factor-kappa B (NF-kappaB) activity in rtPA-stimulated human microvascular endothelial cells (HBECs). RESULTS: The degree of hemorrhage and the level of endothelial cell-derived MMP-9 were elevated in rats treated with rtPA alone and attenuated in rats treated with rtPA plus edaravone. In rtPA-stimulated HBECs, edaravone suppressed the activity and mRNA expression of MMP-9 in a dose-dependent manner. Edaravone also inhibited NF-kappaB activation. CONCLUSIONS: We demonstrate that edaravone inhibits rtPA-induced cerebral hemorrhage in the ischemic brain of rats via the inhibition of MMP-9 expression in vivo, which is substantiated by inhibition of MMP-9 expression and NF-kappaB activation in HBECs. Edaravone may render thrombolytic therapy safer for the administration of rtPA in patients with ischemic stroke.
    URL, DOI BibTeX

    @article{Yagi2009,
    	abstract = "BACKGROUND AND PURPOSE: Intracerebral hemorrhage, induced by recombinant tissue plasminogen activator (rtPA) in ischemic stroke, is attributable to the increased activity of matrix metalloproteinase-9 (MMP-9). Patients with acute infarct benefit from the neuroprotective drug edaravone, a free radical scavenger. We examined the mechanisms by which edaravone may help to suppress rtPA-induced brain hemorrhage. METHODS: Male Wistar rats weighing 250 to 280 g were subjected to 3-hour transient middle cerebral artery occlusion (MCAO) and divided randomly into 3 groups. Immediately after reperfusion, 1 group was intravenously injected with 10 mg/kg rtPA, another with rtPA plus 3 mg/kg edaravone, and the 3rd group received no treatment. We assessed the hemorrhage volume and the activity of MMP-9 in the brain 24 hours postischemia. We also studied the activity of MMP-9, its mRNA expression, and nuclear factor-kappa B (NF-kappaB) activity in rtPA-stimulated human microvascular endothelial cells (HBECs). RESULTS: The degree of hemorrhage and the level of endothelial cell-derived MMP-9 were elevated in rats treated with rtPA alone and attenuated in rats treated with rtPA plus edaravone. In rtPA-stimulated HBECs, edaravone suppressed the activity and mRNA expression of MMP-9 in a dose-dependent manner. Edaravone also inhibited NF-kappaB activation. CONCLUSIONS: We demonstrate that edaravone inhibits rtPA-induced cerebral hemorrhage in the ischemic brain of rats via the inhibition of MMP-9 expression in vivo, which is substantiated by inhibition of MMP-9 expression and NF-kappaB activation in HBECs. Edaravone may render thrombolytic therapy safer for the administration of rtPA in patients with ischemic stroke.",
    	author = "Yagi, Kenji and Kitazato, Keiko T and Uno, Masaaki and Tada, Yoshiteru and Kinouchi, Tomoya and Shimada, Kenji and Nagahiro, Shinji",
    	doi = "10.1161/STROKEAHA.108.520262",
    	issn = "1524-4628",
    	journal = "Stroke; a journal of cerebral circulation",
    	keywords = "Animals,Antipyrine,Antipyrine: analogs \& derivatives,Antipyrine: pharmacology,Blood Pressure,Blood Pressure: physiology,Blotting, Western,Brain Ischemia,Brain Ischemia: drug therapy,Brain Ischemia: pathology,Cells, Cultured,Cerebral Hemorrhage,Cerebral Hemorrhage: drug therapy,Cerebral Hemorrhage: enzymology,Dose-Response Relationship, Drug,Endothelial Cells,Endothelial Cells: drug effects,Endothelial Cells: metabolism,Free Radical Scavengers,Free Radical Scavengers: pharmacology,Immunohistochemistry,Infarction, Middle Cerebral Artery,Infarction, Middle Cerebral Artery: pathology,Male,Matrix Metalloproteinase Inhibitors,Middle Cerebral Artery,Middle Cerebral Artery: physiology,NF-kappa B,NF-kappa B: metabolism,RNA, Messenger,RNA, Messenger: biosynthesis,RNA, Messenger: genetics,Rats,Rats, Wistar,Reperfusion Injury,Reperfusion Injury: drug therapy,Reperfusion Injury: pathology,Reverse Transcriptase Polymerase Chain Reaction,Tissue Plasminogen Activator,Tissue Plasminogen Activator: pharmacology",
    	month = "feb",
    	number = 2,
    	pages = "626--31",
    	pmid = 19095969,
    	title = "{Edaravone, a free radical scavenger, inhibits MMP-9-related brain hemorrhage in rats treated with tissue plasminogen activator.}",
    	url = "http://stroke.ahajournals.org/content/40/2/626",
    	volume = 40,
    	year = 2009
    }
    
  7. Toshiaki Sato, Keizo Mizuno and Fumiyoshi Ishii.
    A novel administration route for edaravone: I. Effects of metabolic inhibitors on skin permeability of edaravone.. International journal of pharmaceutics 372(1-2):33–8, 2009.
    Abstract We examined the effects of metabolic inhibitors on skin permeation of edaravone. SKF-525A, diclofenac sodium (DIC) and indomethacin (IND) were added to supernatant fluid (SF) of hairless rat (HR) skin homogenate. L-Cysteine (L-Cys) and benzotriazole (BTA), as pharmaceutical additives, were added to HR skin homogenate SF, and incubated at 37 degrees C for 30 min. K(m) and V(max) values were calculated. For determination of edaravone skin permeation from edaravone/hydroxypropyl-beta-cyclodextrin (HPbetaCD) complex solution, HR skin was placed in a Franz diffusion cell, and kept at 37 degrees C. Edaravone/HPbetaCD solution that contained L-Cys was put into the donor side. The relative activity in skin homogenate SF after co-treatment with IND and SKF-525A decreased to 40.8% of the control. However, DIC and IND had a weak inhibitory effect. For inhibition of edaravone metabolism, L-Cys and BTA had no effect on K(m) value, but V(max) was significantly decreased compared with controls (*P<0.05, Tukey-Kramer test). The edaravone skin permeation rate and permeability coefficient from edaravone/HPbetaCD complex solution with inhibitor were significantly increased compared with those without inhibitor. We suggest that the metabolism inhibitor was useful for the transdermal delivery of edaravone.
    URL, DOI BibTeX

    @article{Sato2009,
    	abstract = "We examined the effects of metabolic inhibitors on skin permeation of edaravone. SKF-525A, diclofenac sodium (DIC) and indomethacin (IND) were added to supernatant fluid (SF) of hairless rat (HR) skin homogenate. L-Cysteine (L-Cys) and benzotriazole (BTA), as pharmaceutical additives, were added to HR skin homogenate SF, and incubated at 37 degrees C for 30 min. K(m) and V(max) values were calculated. For determination of edaravone skin permeation from edaravone/hydroxypropyl-beta-cyclodextrin (HPbetaCD) complex solution, HR skin was placed in a Franz diffusion cell, and kept at 37 degrees C. Edaravone/HPbetaCD solution that contained L-Cys was put into the donor side. The relative activity in skin homogenate SF after co-treatment with IND and SKF-525A decreased to 40.8\% of the control. However, DIC and IND had a weak inhibitory effect. For inhibition of edaravone metabolism, L-Cys and BTA had no effect on K(m) value, but V(max) was significantly decreased compared with controls (*P<0.05, Tukey-Kramer test). The edaravone skin permeation rate and permeability coefficient from edaravone/HPbetaCD complex solution with inhibitor were significantly increased compared with those without inhibitor. We suggest that the metabolism inhibitor was useful for the transdermal delivery of edaravone.",
    	author = "Sato, Toshiaki and Mizuno, Keizo and Ishii, Fumiyoshi",
    	doi = "10.1016/j.ijpharm.2008.12.038",
    	issn = "1873-3476",
    	journal = "International journal of pharmaceutics",
    	keywords = "Administration, Cutaneous,Animals,Antipyrine,Antipyrine: administration \& dosage,Antipyrine: analogs \& derivatives,Antipyrine: antagonists \& inhibitors,Antipyrine: metabolism,Male,Permeability,Permeability: drug effects,Proadifen,Proadifen: administration \& dosage,Rats,Rats, Hairless,Skin Absorption,Skin Absorption: drug effects,Skin Absorption: physiology",
    	month = "",
    	number = "1-2",
    	pages = "33--8",
    	pmid = 19166920,
    	title = "{A novel administration route for edaravone: I. Effects of metabolic inhibitors on skin permeability of edaravone.}",
    	url = "http://www.sciencedirect.com/science/article/pii/S0378517308008752",
    	volume = 372,
    	year = 2009
    }
    
  8. Wen Ji Yuan, Takao Yasuhara, Tetsuro Shingo, Kenichiro Muraoka, Takashi Agari, Masahiro Kameda, Takashi Uozumi, Naoki Tajiri, Takamasa Morimoto, Meng Jing, Tanefumi Baba, Feifei Wang, Hanbai Leung, Toshihiro Matsui, Yasuyuki Miyoshi and Isao Date.
    Neuroprotective effects of edaravone-administration on 6-OHDA-treated dopaminergic neurons.. BMC neuroscience 9(1):75, 2008.
    Abstract BACKGROUND: Parkinson's disease (PD) is a neurological disorder characterized by the degeneration of nigrostriatal dopaminergic systems. Free radicals induced by oxidative stress are involved in the mechanisms of cell death in PD. This study clarifies the neuroprotective effects of edaravone (MCI-186, 3-methyl-1-phenyl-2-pyrazolin-5-one), which has already been used for the treatment of cerebral ischemia in Japan, on TH-positive dopaminergic neurons using PD model both in vitro and in vivo. 6-hydroxydopamine (6-OHDA), a neurotoxin for dopaminergic neurons, was added to cultured dopaminergic neurons derived from murine embryonal ventral mesencephalon with subsequet administration of edaravone or saline. The number of surviving TH-positive neurons and the degree of cell damage induced by free radicals were analyzed. In parallel, edaravone or saline was intravenously administered for PD model of rats receiving intrastriatal 6-OHDA lesion with subsequent behavioral and histological analyses. RESULTS: In vitro study showed that edaravone significantly ameliorated the survival of TH-positive neurons in a dose-responsive manner. The number of apoptotic cells and HEt-positive cells significantly decreased, thus indicating that the neuroprotective effects of edaravone might be mediated by anti-apoptotic effects through the suppression of free radicals by edaravone. In vivo study demonstrated that edaravone-administration at 30 minutes after 6-OHDA lesion reduced the number of amphetamine-induced rotations significantly than edaravone-administration at 24 hours. Tyrosine hydroxylase (TH) staining of the striatum and substantia nigra pars compacta revealed that edaravone might exert neuroprotective effects on nigrostriatal dopaminergic systems. The neuroprotective effects were prominent when edaravone was administered early and in high concentration. TUNEL, HEt and Iba-1 staining in vivo might demonstrate the involvement of anti-apoptotic, anti-oxidative and anti-inflammatory effects of edaravone-administration. CONCLUSION: Edaravone exerts neuroprotective effects on PD model both in vitro and in vivo. The underlying mechanisms might be involved in the anti-apoptotic effects, anti-oxidative effects, and/or anti-inflammatory effects of edaravone. Edaravone might be a hopeful therapeutic option for PD, although the high therapeutic dosage remains to be solved for the clinical application.
    URL, DOI BibTeX

    @article{Yuan2008,
    	abstract = "BACKGROUND: Parkinson's disease (PD) is a neurological disorder characterized by the degeneration of nigrostriatal dopaminergic systems. Free radicals induced by oxidative stress are involved in the mechanisms of cell death in PD. This study clarifies the neuroprotective effects of edaravone (MCI-186, 3-methyl-1-phenyl-2-pyrazolin-5-one), which has already been used for the treatment of cerebral ischemia in Japan, on TH-positive dopaminergic neurons using PD model both in vitro and in vivo. 6-hydroxydopamine (6-OHDA), a neurotoxin for dopaminergic neurons, was added to cultured dopaminergic neurons derived from murine embryonal ventral mesencephalon with subsequet administration of edaravone or saline. The number of surviving TH-positive neurons and the degree of cell damage induced by free radicals were analyzed. In parallel, edaravone or saline was intravenously administered for PD model of rats receiving intrastriatal 6-OHDA lesion with subsequent behavioral and histological analyses. RESULTS: In vitro study showed that edaravone significantly ameliorated the survival of TH-positive neurons in a dose-responsive manner. The number of apoptotic cells and HEt-positive cells significantly decreased, thus indicating that the neuroprotective effects of edaravone might be mediated by anti-apoptotic effects through the suppression of free radicals by edaravone. In vivo study demonstrated that edaravone-administration at 30 minutes after 6-OHDA lesion reduced the number of amphetamine-induced rotations significantly than edaravone-administration at 24 hours. Tyrosine hydroxylase (TH) staining of the striatum and substantia nigra pars compacta revealed that edaravone might exert neuroprotective effects on nigrostriatal dopaminergic systems. The neuroprotective effects were prominent when edaravone was administered early and in high concentration. TUNEL, HEt and Iba-1 staining in vivo might demonstrate the involvement of anti-apoptotic, anti-oxidative and anti-inflammatory effects of edaravone-administration. CONCLUSION: Edaravone exerts neuroprotective effects on PD model both in vitro and in vivo. The underlying mechanisms might be involved in the anti-apoptotic effects, anti-oxidative effects, and/or anti-inflammatory effects of edaravone. Edaravone might be a hopeful therapeutic option for PD, although the high therapeutic dosage remains to be solved for the clinical application.",
    	author = "Yuan, Wen Ji and Yasuhara, Takao and Shingo, Tetsuro and Muraoka, Kenichiro and Agari, Takashi and Kameda, Masahiro and Uozumi, Takashi and Tajiri, Naoki and Morimoto, Takamasa and Jing, Meng and Baba, Tanefumi and Wang, Feifei and Leung, Hanbai and Matsui, Toshihiro and Miyoshi, Yasuyuki and Date, Isao",
    	doi = "10.1186/1471-2202-9-75",
    	file = ":C$\backslash$:/Users/riku/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Yuan et al. - 2008 - Neuroprotective effects of edaravone-administration on 6-OHDA-treated dopaminergic neurons.pdf:pdf",
    	issn = "1471-2202",
    	journal = "BMC neuroscience",
    	keywords = "Animals,Antipyrine,Antipyrine: analogs \& derivatives,Antipyrine: pharmacology,Antipyrine: therapeutic use,Cell Survival,Cell Survival: drug effects,Cell Survival: physiology,Cells, Cultured,Dopamine,Dopamine: physiology,Female,Mice,Mice, Inbred C57BL,Neurons,Neurons: drug effects,Neurons: pathology,Neurons: physiology,Neuroprotective Agents,Neuroprotective Agents: pharmacology,Neuroprotective Agents: therapeutic use,Oxidopamine,Oxidopamine: toxicity,Parkinson Disease,Parkinson Disease: drug therapy,Parkinson Disease: pathology,Rats,Rats, Sprague-Dawley,Substantia Nigra,Substantia Nigra: drug effects,Substantia Nigra: pathology,Substantia Nigra: physiology",
    	month = "",
    	number = 1,
    	pages = 75,
    	pmid = 18671880,
    	title = "{Neuroprotective effects of edaravone-administration on 6-OHDA-treated dopaminergic neurons.}",
    	url = "http://www.biomedcentral.com/1471-2202/9/75",
    	volume = 9,
    	year = 2008
    }
    
  9. Hidefumi Ito, Reika Wate, Jianhua Zhang, Shizuo Ohnishi, Satoshi Kaneko, Hisashi Ito, Satoshi Nakano and Hirofumi Kusaka.
    Treatment with edaravone, initiated at symptom onset, slows motor decline and decreases SOD1 deposition in ALS mice.. Experimental neurology 213(2):448–55, 2008.
    Abstract Edaravone is a free-radical scavenger, an agent being widely used for cerebral ischemia in Japan. To evaluate its efficacy for possible treatment of amyotrophic lateral sclerosis (ALS), we performed a randomized blind trial in ALS model mice. After identification of the clinical onset in each female G93A mutant SOD1 transgenic mouse, we intraperitoneally administered multiple doses of edaravone to the mice and observed their motor symptoms. We also counted the number of lumbar motoneurons, determined the 3-nitrotyrosine/tyrosine ratio, and evaluated the abnormal SOD1 aggregation in the spinal cord at the 10th day after the edaravone injection. Edaravone significantly slowed the motor decline of the transgenic mice. The remaining motoneurons were significantly preserved in the higher-dose edaravone-administered group, and the 3-nitrotyrosine/tyrosine ratios were reduced dose-dependently. Intriguingly, the area of abnormal SOD1 deposition in the spinal cord was significantly decreased in the higher-dose edaravone-administered group. Our results indicate that edaravone was effective to slow symptom progression and motor neuron degeneration in the ALS model mice. These favorable actions might be attributable to the yet unidentified mechanism responsible for reducing the deposition of mutant SOD1.
    URL, DOI BibTeX

    @article{Ito2008,
    	abstract = "Edaravone is a free-radical scavenger, an agent being widely used for cerebral ischemia in Japan. To evaluate its efficacy for possible treatment of amyotrophic lateral sclerosis (ALS), we performed a randomized blind trial in ALS model mice. After identification of the clinical onset in each female G93A mutant SOD1 transgenic mouse, we intraperitoneally administered multiple doses of edaravone to the mice and observed their motor symptoms. We also counted the number of lumbar motoneurons, determined the 3-nitrotyrosine/tyrosine ratio, and evaluated the abnormal SOD1 aggregation in the spinal cord at the 10th day after the edaravone injection. Edaravone significantly slowed the motor decline of the transgenic mice. The remaining motoneurons were significantly preserved in the higher-dose edaravone-administered group, and the 3-nitrotyrosine/tyrosine ratios were reduced dose-dependently. Intriguingly, the area of abnormal SOD1 deposition in the spinal cord was significantly decreased in the higher-dose edaravone-administered group. Our results indicate that edaravone was effective to slow symptom progression and motor neuron degeneration in the ALS model mice. These favorable actions might be attributable to the yet unidentified mechanism responsible for reducing the deposition of mutant SOD1.",
    	author = "Ito, Hidefumi and Wate, Reika and Zhang, Jianhua and Ohnishi, Shizuo and Kaneko, Satoshi and Ito, Hisashi and Nakano, Satoshi and Kusaka, Hirofumi",
    	doi = "10.1016/j.expneurol.2008.07.017",
    	issn = "1090-2430",
    	journal = "Experimental neurology",
    	keywords = "Amyotrophic Lateral Sclerosis,Amyotrophic Lateral Sclerosis: drug therapy,Amyotrophic Lateral Sclerosis: enzymology,Animals,Antipyrine,Antipyrine: administration \& dosage,Antipyrine: analogs \& derivatives,Female,Humans,Male,Mice,Mice, Transgenic,Motor Skills,Motor Skills Disorders,Motor Skills Disorders: drug therapy,Motor Skills Disorders: enzymology,Motor Skills: drug effects,Motor Skills: physiology,Superoxide Dismutase,Superoxide Dismutase: genetics,Superoxide Dismutase: metabolism,Time Factors",
    	month = "",
    	number = 2,
    	pages = "448--55",
    	pmid = 18718468,
    	title = "{Treatment with edaravone, initiated at symptom onset, slows motor decline and decreases SOD1 deposition in ALS mice.}",
    	url = "http://www.sciencedirect.com/science/article/pii/S001448860800294X",
    	volume = 213,
    	year = 2008
    }
    
  10. Toshiyuki Arai, Mitsuru Nonogawa, Keisuke Makino, Nobuyuki Endo, Hiroko Mori, Takashi Miyoshi, Kouhei Yamashita, Masataka Sasada, Masahiro Kakuyama and Kazuhiko Fukuda.
    The radical scavenger edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one) reacts with a pterin derivative and produces a cytotoxic substance that induces intracellular reactive oxygen species generation and cell death.. The Journal of pharmacology and experimental therapeutics 324(2):529–38, 2008.
    Abstract Cytotoxic effects of the combined use of edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one), a radical scavenger and an approved medicine for acute brain infarction in Japan, with a pterin derivative, were examined in vitro. When pancreatic cancer cell line Panc-1 cells were incubated with 50 to 400 microM of a pterin derivative, 2-(N,N-dimethylaminomethyleneamino)-6-formyl-3-pivaloylpteridine-4-one (DFP), and the equivalent dose of edaravone, reactive oxygen species (ROS), were generated, and cell death was induced. ROS generation and the loss of mitochondrial membrane potential (MMP) preceding cell death were simultaneously monitored using time-lapse microscopy with an ROS-sensitive dye and a probe to monitor MMP, respectively. Cell death was also estimated quantitatively by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. ROS generation and cell death were prominent when more than 100 microM of each agent was used in combination, whereas the sole use of each agent did not show any effects even at the highest dose, 400 microM. Chemical analysis revealed that DFP and edaravone react immediately in aqueous solution and produce a new compound named DFP-E. DFP-E chemically reacted with NADH much faster than DFP and generated ROS, and biologically, it was much more cell-permeable than DFP. These findings collectively indicated that the combined use of DFP with edaravone produced DFP-E, which caused intracellular ROS generation and cell death. Cell death was observed in normal cells, and edaravone reacted with another pterin derivative to yield an ROS-generating compound. As a result, care should be taken with the clinical use of edaravone when pterin derivatives stay in the body.
    URL, DOI BibTeX

    @article{Arai2008,
    	abstract = "Cytotoxic effects of the combined use of edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one), a radical scavenger and an approved medicine for acute brain infarction in Japan, with a pterin derivative, were examined in vitro. When pancreatic cancer cell line Panc-1 cells were incubated with 50 to 400 microM of a pterin derivative, 2-(N,N-dimethylaminomethyleneamino)-6-formyl-3-pivaloylpteridine-4-one (DFP), and the equivalent dose of edaravone, reactive oxygen species (ROS), were generated, and cell death was induced. ROS generation and the loss of mitochondrial membrane potential (MMP) preceding cell death were simultaneously monitored using time-lapse microscopy with an ROS-sensitive dye and a probe to monitor MMP, respectively. Cell death was also estimated quantitatively by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. ROS generation and cell death were prominent when more than 100 microM of each agent was used in combination, whereas the sole use of each agent did not show any effects even at the highest dose, 400 microM. Chemical analysis revealed that DFP and edaravone react immediately in aqueous solution and produce a new compound named DFP-E. DFP-E chemically reacted with NADH much faster than DFP and generated ROS, and biologically, it was much more cell-permeable than DFP. These findings collectively indicated that the combined use of DFP with edaravone produced DFP-E, which caused intracellular ROS generation and cell death. Cell death was observed in normal cells, and edaravone reacted with another pterin derivative to yield an ROS-generating compound. As a result, care should be taken with the clinical use of edaravone when pterin derivatives stay in the body.",
    	author = "Arai, Toshiyuki and Nonogawa, Mitsuru and Makino, Keisuke and Endo, Nobuyuki and Mori, Hiroko and Miyoshi, Takashi and Yamashita, Kouhei and Sasada, Masataka and Kakuyama, Masahiro and Fukuda, Kazuhiko",
    	doi = "10.1124/jpet.107.131391",
    	issn = "1521-0103",
    	journal = "The Journal of pharmacology and experimental therapeutics",
    	keywords = "Antipyrine,Antipyrine: analogs \& derivatives,Antipyrine: chemistry,Antipyrine: metabolism,Cell Death,Cell Death: physiology,Cell Survival,Cell Survival: drug effects,Cell Survival: physiology,Cells, Cultured,Cytotoxins,Cytotoxins: metabolism,Free Radical Scavengers,Free Radical Scavengers: chemistry,Free Radical Scavengers: metabolism,Humans,Intracellular Fluid,Intracellular Fluid: metabolism,Pterins,Pterins: chemistry,Pterins: metabolism,Reactive Oxygen Species,Reactive Oxygen Species: metabolism",
    	month = "",
    	number = 2,
    	pages = "529--38",
    	pmid = 18029546,
    	title = "{The radical scavenger edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one) reacts with a pterin derivative and produces a cytotoxic substance that induces intracellular reactive oxygen species generation and cell death.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/18029546",
    	volume = 324,
    	year = 2008
    }
    
  11. Cristina Zona, Massimo Pieri and Irene Carunchio.
    Voltage-dependent sodium channels in spinal cord motor neurons display rapid recovery from fast inactivation in a mouse model of amyotrophic lateral sclerosis.. Journal of neurophysiology 96(6):3314–22, December 2006.
    Abstract Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by a substantial loss of motor neurons in the spinal cord, brain stem, and motor cortex. Previous evidence showed that in a mouse model of a familial form of ALS expressing high levels of the human mutated protein Cu,Zn superoxide dismutase (Gly(93)–>Ala, G93A), the firing properties of single motor neurons are altered to induce neuronal hyperexcitability. To determine whether the functionality of the macroscopic voltage-dependent Na(+) currents is modified in G93A motor neurons, in the present work their physiological properties were examined. The voltage-dependent sodium channels were studied in dissociated motor neurons in culture from nontransgenic mice (Control), from transgenic mice expressing high levels of the human wild-type protein [superoxide dismutase 1 (SOD1)], and from G93A mice, using the whole cell configuration of the patch-clamp recording technique. The voltage dependency of activation and of steady-state inactivation, the kinetics of fast inactivation and slow inactivation of the voltage-dependent Na(+) channels were not modified in the mutated mice. Conversely, the recovery from fast inactivation was significantly faster in G93A motor neurons than that in Control and SOD1. The recovery from fast inactivation was still significantly faster in G93A motor neurons exposed for different times (3-48 h) and concentrations (5-500 microM) to edaravone, a free-radical scavenger. Clarification of the importance of these changes in membrane ion channel functionality may have diagnostic and therapeutic implications in the pathogenesis of ALS.
    URL, DOI BibTeX

    @article{Zona2006,
    	abstract = "Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by a substantial loss of motor neurons in the spinal cord, brain stem, and motor cortex. Previous evidence showed that in a mouse model of a familial form of ALS expressing high levels of the human mutated protein Cu,Zn superoxide dismutase (Gly(93)-->Ala, G93A), the firing properties of single motor neurons are altered to induce neuronal hyperexcitability. To determine whether the functionality of the macroscopic voltage-dependent Na(+) currents is modified in G93A motor neurons, in the present work their physiological properties were examined. The voltage-dependent sodium channels were studied in dissociated motor neurons in culture from nontransgenic mice (Control), from transgenic mice expressing high levels of the human wild-type protein [superoxide dismutase 1 (SOD1)], and from G93A mice, using the whole cell configuration of the patch-clamp recording technique. The voltage dependency of activation and of steady-state inactivation, the kinetics of fast inactivation and slow inactivation of the voltage-dependent Na(+) channels were not modified in the mutated mice. Conversely, the recovery from fast inactivation was significantly faster in G93A motor neurons than that in Control and SOD1. The recovery from fast inactivation was still significantly faster in G93A motor neurons exposed for different times (3-48 h) and concentrations (5-500 microM) to edaravone, a free-radical scavenger. Clarification of the importance of these changes in membrane ion channel functionality may have diagnostic and therapeutic implications in the pathogenesis of ALS.",
    	author = "Zona, Cristina and Pieri, Massimo and Carunchio, Irene",
    	doi = "10.1152/jn.00566.2006",
    	issn = "0022-3077",
    	journal = "Journal of neurophysiology",
    	keywords = "Algorithms,Amino Acid Substitution,Amyotrophic Lateral Sclerosis,Amyotrophic Lateral Sclerosis: physiopathology,Animals,Antipyrine,Antipyrine: analogs \& derivatives,Antipyrine: pharmacology,Cells, Cultured,Data Interpretation, Statistical,Electrophysiology,Free Radical Scavengers,Free Radical Scavengers: pharmacology,Immunohistochemistry,Kinetics,Mice,Mice, Transgenic,Motor Neurons,Motor Neurons: physiology,Mutation,Mutation: physiology,Patch-Clamp Techniques,Sodium Channels,Sodium Channels: physiology,Spinal Cord,Spinal Cord: cytology,Spinal Cord: physiopathology,Superoxide Dismutase,Superoxide Dismutase: genetics,Superoxide Dismutase: physiology",
    	month = "dec",
    	number = 6,
    	pages = "3314--22",
    	pmid = 16899637,
    	title = "{Voltage-dependent sodium channels in spinal cord motor neurons display rapid recovery from fast inactivation in a mouse model of amyotrophic lateral sclerosis.}",
    	url = "http://jn.physiology.org/content/96/6/3314",
    	volume = 96,
    	year = 2006
    }
    
  12. Hiide Yoshino and Akio Kimura.
    Investigation of the therapeutic effects of edaravone, a free radical scavenger, on amyotrophic lateral sclerosis (Phase II study).. Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases 7(4):241–5, December 2006.
    Abstract {Amyotrophic lateral sclerosis (ALS) is a rare disease involving selective and progressive degeneration and disappearance of motor neurons. Oxidative stress is believed to contribute to its pathogenesis. We have investigated the efficacy and safety of edaravone, a free radical scavenger previously approved for treatment of acute cerebral infarction, in ALS patients. Within an open trial design, 20 subjects with ALS received either 30 mg (5 subjects) or 60 mg (15 subjects) of edaravone via intravenous drip once per day. Two weeks of administration was followed by a two-week observation period. This four-week cycle was repeated six times. The primary endpoint was the change in the revised ALS functional rating scale (ALSFRS-R) score, while the secondary endpoint was 3-nitrotyrosine (3NT) level in cerebrospinal fluid (CSF). Efficacy was evaluated in the 60 mg group. During the six-month treatment period, the decline in the ALSFRS-R score (2.3+/-3.6 points) was significantly less than that in the six months prior to edaravone administration (4.7+/-2.1 points); the difference between the two was 2.4+/-3.5 points (Wilcoxon signed rank test
    URL, DOI BibTeX

    @article{Yoshino2006a,
    	abstract = "{Amyotrophic lateral sclerosis (ALS) is a rare disease involving selective and progressive degeneration and disappearance of motor neurons. Oxidative stress is believed to contribute to its pathogenesis. We have investigated the efficacy and safety of edaravone, a free radical scavenger previously approved for treatment of acute cerebral infarction, in ALS patients. Within an open trial design, 20 subjects with ALS received either 30 mg (5 subjects) or 60 mg (15 subjects) of edaravone via intravenous drip once per day. Two weeks of administration was followed by a two-week observation period. This four-week cycle was repeated six times. The primary endpoint was the change in the revised ALS functional rating scale (ALSFRS-R) score, while the secondary endpoint was 3-nitrotyrosine (3NT) level in cerebrospinal fluid (CSF). Efficacy was evaluated in the 60 mg group. During the six-month treatment period, the decline in the ALSFRS-R score (2.3+/-3.6 points) was significantly less than that in the six months prior to edaravone administration (4.7+/-2.1 points); the difference between the two was 2.4+/-3.5 points (Wilcoxon signed rank test",
    	p = "0.039). In almost all patients, CSF 3NT, a marker for oxidative stress, was markedly reduced to almost undetectable levels at the end of the six-month treatment period. Data from the present study suggest that edaravone is safe and may delay the progression of functional motor disturbances by reducing oxidative stress in ALS patients.}",
    	author = "Yoshino, Hiide and Kimura, Akio",
    	doi = "10.1080/17482960600881870",
    	issn = "1748-2968",
    	journal = "Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases",
    	keywords = "Amyotrophic Lateral Sclerosis,Amyotrophic Lateral Sclerosis: diagnosis,Amyotrophic Lateral Sclerosis: drug therapy,Antipyrine,Antipyrine: administration \& dosage,Antipyrine: adverse effects,Antipyrine: analogs \& derivatives,Dose-Response Relationship, Drug,Female,Free Radical Scavengers,Free Radical Scavengers: administration \& dosage,Free Radical Scavengers: adverse effects,Humans,Male,Middle Aged,Treatment Outcome",
    	language = "en",
    	month = "dec",
    	number = 4,
    	pages = "241--5",
    	pmid = 17127563,
    	publisher = "Informa UK Ltd UK",
    	title = "{Investigation of the therapeutic effects of edaravone, a free radical scavenger, on amyotrophic lateral sclerosis (Phase II study).}",
    	url = "http://informahealthcare.com/doi/abs/10.1080/17482960600881870",
    	volume = 7,
    	year = 2006
    }
    
  13. Hiide Yoshino and Akio Kimura.
    Investigation of the therapeutic effects of edaravone, a free radical scavenger, on amyotrophic lateral sclerosis (Phase II study).. Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases 7(4):241–5, 2006.
    Abstract {Amyotrophic lateral sclerosis (ALS) is a rare disease involving selective and progressive degeneration and disappearance of motor neurons. Oxidative stress is believed to contribute to its pathogenesis. We have investigated the efficacy and safety of edaravone, a free radical scavenger previously approved for treatment of acute cerebral infarction, in ALS patients. Within an open trial design, 20 subjects with ALS received either 30 mg (5 subjects) or 60 mg (15 subjects) of edaravone via intravenous drip once per day. Two weeks of administration was followed by a two-week observation period. This four-week cycle was repeated six times. The primary endpoint was the change in the revised ALS functional rating scale (ALSFRS-R) score, while the secondary endpoint was 3-nitrotyrosine (3NT) level in cerebrospinal fluid (CSF). Efficacy was evaluated in the 60 mg group. During the six-month treatment period, the decline in the ALSFRS-R score (2.3+/-3.6 points) was significantly less than that in the six months prior to edaravone administration (4.7+/-2.1 points); the difference between the two was 2.4+/-3.5 points (Wilcoxon signed rank test
    URL, DOI BibTeX

    @article{Yoshino2006,
    	abstract = "{Amyotrophic lateral sclerosis (ALS) is a rare disease involving selective and progressive degeneration and disappearance of motor neurons. Oxidative stress is believed to contribute to its pathogenesis. We have investigated the efficacy and safety of edaravone, a free radical scavenger previously approved for treatment of acute cerebral infarction, in ALS patients. Within an open trial design, 20 subjects with ALS received either 30 mg (5 subjects) or 60 mg (15 subjects) of edaravone via intravenous drip once per day. Two weeks of administration was followed by a two-week observation period. This four-week cycle was repeated six times. The primary endpoint was the change in the revised ALS functional rating scale (ALSFRS-R) score, while the secondary endpoint was 3-nitrotyrosine (3NT) level in cerebrospinal fluid (CSF). Efficacy was evaluated in the 60 mg group. During the six-month treatment period, the decline in the ALSFRS-R score (2.3+/-3.6 points) was significantly less than that in the six months prior to edaravone administration (4.7+/-2.1 points); the difference between the two was 2.4+/-3.5 points (Wilcoxon signed rank test",
    	p = "",
    	author = "Yoshino, Hiide and Kimura, Akio",
    	doi = "10.1080/17482960600881870",
    	issn = "1748-2968",
    	journal = "Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases",
    	keywords = "Amyotrophic Lateral Sclerosis,Amyotrophic Lateral Sclerosis: diagnosis,Amyotrophic Lateral Sclerosis: drug therapy,Antipyrine,Antipyrine: administration \& dosage,Antipyrine: adverse effects,Antipyrine: analogs \& derivatives,Dose-Response Relationship, Drug,Female,Free Radical Scavengers,Free Radical Scavengers: administration \& dosage,Free Radical Scavengers: adverse effects,Humans,Male,Middle Aged,Treatment Outcome",
    	month = "",
    	number = 4,
    	pages = "241--5",
    	pmid = 17127563,
    	title = "{Investigation of the therapeutic effects of edaravone, a free radical scavenger, on amyotrophic lateral sclerosis (Phase II study).}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/17127563",
    	volume = 7,
    	year = 2006
    }
    
  14. Hiroshi Yoshida, Kayoko Sasaki, Yoshihisa Namiki, Noriko Sato and Norio Tada.
    Edaravone, a novel radical scavenger, inhibits oxidative modification of low-density lipoprotein (LDL) and reverses oxidized LDL-mediated reduction in the expression of endothelial nitric oxide synthase.. Atherosclerosis 179(1):97–102, March 2005.
    Abstract Edaravone, a newly synthesized synthetic radical scavenger, has been identified and adopted as an anti-stroke agent. However, its mechanism and the effect of edaravone on lipoprotein oxidation are not fully understood. Therefore, whether edaravone could suppress oxidation of low-density lipoprotein (LDL) and be involved in the expression of endothelial nitric oxide synthase (eNOS) in relation to anti-atherogenesis by improving and conserving vascular circulation was investigated. We investigated the in vitro effects of edaravone on copper- and endothelial cell-mediated LDL oxidation, and the expression of eNOS in human umbilical vein endothelial cells (HUVEC) modulated by oxidized LDL. The in vivo effect of edaravone on antioxidative effect was also studied in male rats intravenously administered with edaravone. Edaravone apparently inhibited copper- and HUVEC-mediated LDL oxidation at the concentration equivalent to serum concentrations in clinical use. The intravenous administration of edaravone also enhanced serum radical-scavenging property in rats. We tested the effect of edaravone on protein and mRNA expression of eNOS in HUVEC. Edaravone enhanced eNOS expression in HUVEC, presumably because of increased stability of eNOS mRNA, and reversed eNOS expression reduced by oxidized LDL nearly to the control levels. The present study demonstrates for the first time that edaravone increases eNOS expression with the inhibition of LDL oxidation, and that edaravone can reverse oxidized LDL-mediated reduction in eNOS expression in endothelial cells. The preventive action of edaravone from ischemic disease consequence may be attributed to these eNOS up-regulation with decreased oxidation.
    URL, DOI BibTeX

    @article{Yoshida2005,
    	abstract = "Edaravone, a newly synthesized synthetic radical scavenger, has been identified and adopted as an anti-stroke agent. However, its mechanism and the effect of edaravone on lipoprotein oxidation are not fully understood. Therefore, whether edaravone could suppress oxidation of low-density lipoprotein (LDL) and be involved in the expression of endothelial nitric oxide synthase (eNOS) in relation to anti-atherogenesis by improving and conserving vascular circulation was investigated. We investigated the in vitro effects of edaravone on copper- and endothelial cell-mediated LDL oxidation, and the expression of eNOS in human umbilical vein endothelial cells (HUVEC) modulated by oxidized LDL. The in vivo effect of edaravone on antioxidative effect was also studied in male rats intravenously administered with edaravone. Edaravone apparently inhibited copper- and HUVEC-mediated LDL oxidation at the concentration equivalent to serum concentrations in clinical use. The intravenous administration of edaravone also enhanced serum radical-scavenging property in rats. We tested the effect of edaravone on protein and mRNA expression of eNOS in HUVEC. Edaravone enhanced eNOS expression in HUVEC, presumably because of increased stability of eNOS mRNA, and reversed eNOS expression reduced by oxidized LDL nearly to the control levels. The present study demonstrates for the first time that edaravone increases eNOS expression with the inhibition of LDL oxidation, and that edaravone can reverse oxidized LDL-mediated reduction in eNOS expression in endothelial cells. The preventive action of edaravone from ischemic disease consequence may be attributed to these eNOS up-regulation with decreased oxidation.",
    	author = "Yoshida, Hiroshi and Sasaki, Kayoko and Namiki, Yoshihisa and Sato, Noriko and Tada, Norio",
    	doi = "10.1016/j.atherosclerosis.2004.10.037",
    	issn = "0021-9150",
    	journal = "Atherosclerosis",
    	keywords = "Animals,Antioxidants,Antioxidants: pharmacology,Antipyrine,Antipyrine: analogs \& derivatives,Antipyrine: blood,Antipyrine: pharmacology,Blood Proteins,Blood Proteins: metabolism,Copper,Copper: metabolism,Free Radical Scavengers,Free Radical Scavengers: blood,Free Radical Scavengers: pharmacology,Injections, Intravenous,Lipoproteins, LDL,Lipoproteins, LDL: metabolism,Male,Nitric Oxide Synthase,Nitric Oxide Synthase Type III,Nitric Oxide Synthase: genetics,Nitric Oxide Synthase: metabolism,Oxidation-Reduction,RNA Stability,RNA Stability: drug effects,RNA, Messenger,RNA, Messenger: metabolism,Rats,Rats, Wistar",
    	month = "mar",
    	number = 1,
    	pages = "97--102",
    	pmid = 15721014,
    	publisher = "Elsevier",
    	title = "{Edaravone, a novel radical scavenger, inhibits oxidative modification of low-density lipoprotein (LDL) and reverses oxidized LDL-mediated reduction in the expression of endothelial nitric oxide synthase.}",
    	url = "http://www.atherosclerosis-journal.com/article/S0021-9150(04)00577-5/abstract",
    	volume = 179,
    	year = 2005
    }
    
  15. Masahiro Banno, Tetsuya Mizuno, Hideki Kato, Guiqin Zhang, Jun Kawanokuchi, Jinyan Wang, Reiko Kuno, Shijie Jin, Hideyuki Takeuchi and Akio Suzumura.
    The radical scavenger edaravone prevents oxidative neurotoxicity induced by peroxynitrite and activated microglia.. Neuropharmacology 48(2):283–90, February 2005.
    Abstract The free radical scavenger edaravone has been used as an anti-oxidative agent in acute ischemic brain disorders. We examined the effect of edaravone on the production of nitric oxide (NO), reactive oxygen species (ROS) and proinflammatory cytokines by activated microglia, and we also examined its neuroprotective role in cortical neuronal cultures oxidatively stressed by the peroxynitrite donor N-morpholinosydnonimine (SIN-1) or activated microglia. Edaravone significantly suppressed the production of NO and ROS by activated microglia, though it did not suppress production of inflammatory cytokines. In addition, edaravone significantly suppressed neuronal cell death and dendrotoxicity induced by either SIN-1 or activated microglia in a dose-dependent manner. These results suggest that edaravone may function as a neuroprotective agent counteracting oxidative neurotoxicity arising from activated microglia, as occurs in either inflammatory or neurodegenerative disorders of the central nervous system.
    URL, DOI BibTeX

    @article{Banno2005,
    	abstract = "The free radical scavenger edaravone has been used as an anti-oxidative agent in acute ischemic brain disorders. We examined the effect of edaravone on the production of nitric oxide (NO), reactive oxygen species (ROS) and proinflammatory cytokines by activated microglia, and we also examined its neuroprotective role in cortical neuronal cultures oxidatively stressed by the peroxynitrite donor N-morpholinosydnonimine (SIN-1) or activated microglia. Edaravone significantly suppressed the production of NO and ROS by activated microglia, though it did not suppress production of inflammatory cytokines. In addition, edaravone significantly suppressed neuronal cell death and dendrotoxicity induced by either SIN-1 or activated microglia in a dose-dependent manner. These results suggest that edaravone may function as a neuroprotective agent counteracting oxidative neurotoxicity arising from activated microglia, as occurs in either inflammatory or neurodegenerative disorders of the central nervous system.",
    	author = "Banno, Masahiro and Mizuno, Tetsuya and Kato, Hideki and Zhang, Guiqin and Kawanokuchi, Jun and Wang, Jinyan and Kuno, Reiko and Jin, Shijie and Takeuchi, Hideyuki and Suzumura, Akio",
    	doi = "10.1016/j.neuropharm.2004.10.002",
    	file = ":C$\backslash$:/Users/riku/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Banno et al. - 2005 - The radical scavenger edaravone prevents oxidative neurotoxicity induced by peroxynitrite and activated microglia.pdf:pdf",
    	issn = "0028-3908",
    	journal = "Neuropharmacology",
    	keywords = "Animals,Antipyrine,Antipyrine: analogs \& derivatives,Antipyrine: pharmacology,Cells, Cultured,Dose-Response Relationship, Drug,Free Radical Scavengers,Free Radical Scavengers: pharmacology,Mice,Mice, Inbred C57BL,Microglia,Microglia: drug effects,Microglia: metabolism,Neuroprotective Agents,Neuroprotective Agents: pharmacology,Oxidative Stress,Oxidative Stress: drug effects,Oxidative Stress: physiology,Peroxynitrous Acid,Peroxynitrous Acid: antagonists \& inhibitors,Peroxynitrous Acid: toxicity",
    	month = "feb",
    	number = 2,
    	pages = "283--90",
    	pmid = 15695167,
    	title = "{The radical scavenger edaravone prevents oxidative neurotoxicity induced by peroxynitrite and activated microglia.}",
    	url = "http://www.sciencedirect.com/science/article/pii/S0028390804003491",
    	volume = 48,
    	year = 2005
    }