Inhibition of neuronal nitric oxide synthase activity by 3-[2-[4-(3-chloro-2-methylphenyl)- 1-piperazinyl]ethyl]-5,6-dimethoxy-1-(4-imidazolylmethyl)-1H-indazole dihydrochloride 3.5 hydrate (DY-9760e), a novel neuroprotective agent, in vitro and in cultured neuroblastoma cells in situ

Fukunaga, Kohji; Ohmitsu, Masao; Miyamoto, Eishichi; Sato, Toshiyuki; Sugimura, Masunobu; Uchida, Toshihiro; Shirasaki, Yasufumi

doi:10.1016/s0006-2952(00)00370-1

Cited by 30 publications

(16 citation statements)

References 32 publications

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“…These in vitro models allowed us to test the effects of novel cardioprotective drugs on caveolin-3/dystrophin breakdown in humoral factor-induced cardiac injury. We showed previously that DY-9760e, a novel calmodulin antagonist, inhibited nNOS and eNOS and reduced NO production in N1E-115 cells (Fukunaga et al, 2000). However, DY-9760e also inhibits cytochrome P450 enzymes in the liver.…”

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confidence: 91%

Phenylephrine-Induced Cardiomyocyte Injury Is Triggered by Superoxide Generation through Uncoupled Endothelial Nitric-Oxide Synthase and Ameliorated by 3-[2-[4-(3-Chloro-2-methylphenyl)-1-piperazinyl]ethyl]-5,6-dimethoxyindazole (DY-9836), a Novel Calmodulin Antagonist

Han

Shioda³

et al. 2008

Mol Pharmacol

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confidence: 91%

Phenylephrine-Induced Cardiomyocyte Injury Is Triggered by Superoxide Generation through Uncoupled Endothelial Nitric-Oxide Synthase and Ameliorated by 3-[2-[4-(3-Chloro-2-methylphenyl)-1-piperazinyl]ethyl]-5,6-dimethoxyindazole (DY-9836), a Novel Calmodulin Antagonist

Han

Shioda³

et al. 2008

Mol Pharmacol

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“…Effect of DY-9760e on NO Production after ME We have previously demonstrated that DY-9760e inhibited Ca 2ϩ /calmodulin-dependent NOS activity in vitro 18) and NO production during ischemia/reperfusion in gerbil ischemic model. 19) To address whether NO production is implicated in ME-induced ischemic cell death, we investigated changes in NO levels after ME induction using in vivo brain microdialysis and evaluated effect of DY-9760e on the NO production.…”

Section: Effect Of Dy-9760e On Infarct Areamentioning

confidence: 95%

“…18) Briefly, rats were anesthetized as above, and the head was placed in a stereotaxic apparatus (David Kopf Instruments, Tujunga, CA, U.S.A.). A microdialysis probe (Eicom, Kyoto, Japan) was perpendicularly implanted into the left striatum (5 mm posterior and 2.5 mm lateral to the bregma, 6 mm below the brain surface) and secured with Ringer's solution at a constant rate of 1 ml/min with the microsyringe pump (ESP-64; Eicom, Kyoto, Japan).…”

Section: Determination Of Infarct Areamentioning

confidence: 99%

“…17) We recently introduced a novel calmodulin antagonist, DY9760e, having a potent inhibitory effect on Ca 2ϩ /calmodulindependent nNOS. 18,19) DY-9760e rescues neurons from the ischemia/reperfusion-induced neuronal death with concomitant inhibition of NO production during ischemia/reperfusion in the gerbil hippocampus. 20) Ischemia/reperfusion-induced neuronal injury is also triggered by peroxynitrite (ONOO Ϫ ), which is formed by the rapid reaction of NO with superoxide (O 2 Ϫ ).…”

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confidence: 99%

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Inhibition of Nitric Oxide Production and Protein Tyrosine Nitration Contribute to Neuroprotection by a Novel Calmodulin Antagonist, DY-9760e, in the Rat Microsphere Embolism

Saito

Han

Shiota

et al. 2005

Biological & Pharmaceutical Bulletin

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Human multiple small cerebral infarcts are implicated in induction of stroke attacks and dementia associated with multiple brain embolism. These disorders were caused by permanent or prolonged occlusion of multiple microvascular in the brain. Unfortunately, few animal models can mimic clinical features in human multiple brain embolism. Recent evidences, however, suggest that microsphere embolism (ME)-induced ischemia model in rat resembles to multiple embolism or multi-infarct dementia in human with the clinical features.2,3) The cerebral multiple embolism is performed by injection of non-radioactive microsphere with a diameter ranging from 15 to 50 mm into the unilateral internal carotid artery in the rat. The light microscopic analysis or 2,3,5-triphenyltetrazolium chloride (TTC) staining shows widespread scattered infarct in the cerebral cortex, striatum and hippocampus of the ipsilateral hemisphere injected microsphere. The intra-arterial infusion of microsphere also leads blood-brain barrier disruption and cerebral vascular injury, thereby inducing severe brain edema. 4,5) Furthermore, during and after ME-induced ischemia, abnormal intracellular signal transduction underlying detrimental metabolic and morphologic neuronal damages was observed.6) However, little neurochemical events through nitric oxide (NO) production are known in the rodent multiple embolism model.During cerebral ischemia, an abnormal elevation of intracellular Ca 2ϩ triggers activation of various Ca 2ϩ -dependent enzymes including endonucleases, proteases and phospholipases, thereby leading neuronal cell death.7-10) Among Ca 2ϩ -mediated cell death pathways, calmodulin (CaM) is partly involved in the detrimental events leading neuronal injury. [11][12][13] In fact, CaM antagonists such as W-7 and calmidazolium have neuroprotective effects on NMDA-induced neuronal cell death 14) and trifluoperazine reduced infarct volume in transient focal cerebral ischemia.15) Similarly, FK-506, an immunosuppressant inhibiting calcineurin, exerts neuroprotective actions in glutamate neurotoxity.16) Since neuronal nitric oxide synthase (nNOS) knockout mice showed a reduced infarct size following brain ischemia, nNOS underlies detrimental events in the brain ischemia. 17)We recently introduced a novel calmodulin antagonist, DY9760e, having a potent inhibitory effect on Ca 2ϩ /calmodulindependent nNOS.18,19) DY-9760e rescues neurons from the ischemia/reperfusion-induced neuronal death with concomitant inhibition of NO production during ischemia/reperfusion in the gerbil hippocampus.20) Ischemia/reperfusion-induced neuronal injury is also triggered by peroxynitrite (ONOO Ϫ ), which is formed by the rapid reaction of NO with superoxide (O 2 Ϫ ).21) The protein tyrosine nitration during ischemia/ reperfusion was also prevented by DY-9760e treatment in the gerbil ischemic brain. 20) Thus, the detrimental effects of NO and protein tyrosine nitration were defined in the ischemia/ reperfusion-induced neuronal injury. However, the detrimental effects of NO productio...

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“…/ CaM-dependent NOS in vitro and in vivo (17,28), thereby inhibiting NO production and protein tyrosine nitration following brain I / R (17). DY-9760e also inhibited fodrin breakdown (15).…”

Section: +mentioning

confidence: 99%

Cytoprotective Effect of 3-[2-[4-(3-Chloro-2-methylphenyl)-1-piperazinyl]ethyl]-5,6-dimethoxy-1-(4-imidazolylmethyl)-1H-indazole Dihydrochloride 3.5 Hydrate (DY-9760e) Against Ischemia/Reperfusion-Induced Injury in Rat Heart Involves Inhibition of Fodrin Breakdown and Protein Tyrosine Nitration

et al. 2005

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Abstract. We here assessed the effects of 3-[2-[4-(3-chloro-2-methylphenyl)-1-piperazinyl] ethyl]-5,6-dimethoxy-1-(4-imidazolylmethyl)-1H-indazole dihydrochloride 3.5 hydrate (DY9760e), a novel calmodulin antagonist, on infarct size in the rat heart subjected to ischemia / reperfusion. Rats were subjected to a 30-min coronary occlusion followed by a 24-h reperfusion. DY-9760e was intravenously infused for 20 min, starting at 20 min after coronary occlusion. Treatment with DY-9760e (10 mg / kg) significantly reduced the infarct size in the risk area assessed by Evans Blue / TTC (triphenyltetrazolium chloride) staining. DY-9760e treatment also ameliorated contractile dysfunction of the left ventricle 72 h after reperfusion. DY-9760e significantly inhibited fodrin breakdown and caspase-3 activation. The inhibitory effect of DY9760e on the fodrin breakdown was prominent in the rim rather than in the center of the risk area. DY-9760e also blocked protein tyrosine nitration associated with infarction. These results suggest that the cardioprotective effect of DY-9760e involved inhibition of calpain / caspase activation and protein tyrosine nitration.

show abstract

Inhibition of neuronal nitric oxide synthase activity by 3-[2-[4-(3-chloro-2-methylphenyl)- 1-piperazinyl]ethyl]-5,6-dimethoxy-1-(4-imidazolylmethyl)-1H-indazole dihydrochloride 3.5 hydrate (DY-9760e), a novel neuroprotective agent, in vitro and in cultured neuroblastoma cells in situ

Cited by 30 publications

References 32 publications

Phenylephrine-Induced Cardiomyocyte Injury Is Triggered by Superoxide Generation through Uncoupled Endothelial Nitric-Oxide Synthase and Ameliorated by 3-[2-[4-(3-Chloro-2-methylphenyl)-1-piperazinyl]ethyl]-5,6-dimethoxyindazole (DY-9836), a Novel Calmodulin Antagonist

Phenylephrine-Induced Cardiomyocyte Injury Is Triggered by Superoxide Generation through Uncoupled Endothelial Nitric-Oxide Synthase and Ameliorated by 3-[2-[4-(3-Chloro-2-methylphenyl)-1-piperazinyl]ethyl]-5,6-dimethoxyindazole (DY-9836), a Novel Calmodulin Antagonist

Inhibition of Nitric Oxide Production and Protein Tyrosine Nitration Contribute to Neuroprotection by a Novel Calmodulin Antagonist, DY-9760e, in the Rat Microsphere Embolism

Cytoprotective Effect of 3-[2-[4-(3-Chloro-2-methylphenyl)-1-piperazinyl]ethyl]-5,6-dimethoxy-1-(4-imidazolylmethyl)-1H-indazole Dihydrochloride 3.5 Hydrate (DY-9760e) Against Ischemia/Reperfusion-Induced Injury in Rat Heart Involves Inhibition of Fodrin Breakdown and Protein Tyrosine Nitration

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