DY-9760e, a novel calmodulin antagonist with cytoprotective action

Sugimura, Masunobu; Sato, Toshiyuki; Nakayama, Wakako; Morishima, Yasuo; Fukunaga, Kohji; Omitsu, Masao; Miyamoto, Eishichi; Shirasaki, Yasufumi

doi:10.1016/s0014-2999(97)01251-x

Cited by 35 publications

(22 citation statements)

References 34 publications

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“…Although inhibition of CaMKIIa and calcineurin activities by DY-9760e was evident in vitro (8), post-ischemic DY-9760e treatment had no apparent effects on these two enzymes at least at the dose of 5 mg / kg. The present study showed that inhibition of nitrotyrosine formation through nNOS inactivation by post-ischemic DY-9760e treatment, as well as in the pre-ischemic treatment (13), closely correlates with its neuroprotective effects.…”

Section: Discussionmentioning

confidence: 86%

“…One major target protein for calcineurin is DARPP-32, which is dephosphorylated at Thr-34 through activated calcineurin by NMDAreceptor stimulation (26). Although DY-9760e preferentially inhibits CaMKIIa and calcineurin in vitro in addition to nNOS (8,9), DY-9760e treatment altered neither the phosphorylation state or translocation of CaMKIIa nor the phosphorylation state of DARPP-32. Taken together, the post-ischemic treatment of DY9760e at least with the dose of 5 mg / kg inhibits neither CaMKIIa nor calcineurin in vivo.…”

Section: Discussionmentioning

confidence: 99%

“…We recently characterized a novel CaM antagonist, DY-9760e (3-[2-[4-(3-chloro-2-methylphenyl)-1-piperazinyl]ethyl]-5,6-dimethoxy-1-(4-imidazolylmethyl)-1H-indazole dihydrochloride 3.5 hydrate), which preferentially inhibits the indicated enzymes with the following order of potency: neuronal NOS (nNOS) > Ca 2+ / CaMdependent protein kinase II (CaMKII) > Ca 2+ / CaMdependent protein phosphatase 2B (calcineurin) (K i = 0.9, 1.4, and 2.0 m M, respectively) in vitro (8,9). DY9760e shows powerful neuroprotective effects in focal cerebral ischemia with moderately wide therapeutic time windows (10 -12).…”

Section: +mentioning

confidence: 99%

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The Post-ischemic Administration 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), a Novel Calmodulin Antagonist, Prevents Delayed Neuronal Death in Gerbil Hippocampus

et al. 2004

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Abstract. The novel calmodulin (CaM) antagonist DY-9760e (3-[2-[4-(3-chloro-2-methylphenyl)-1-piperazinyl]ethyl]-5,6-dimethoxy-1-(4-imidazolylmethyl)-1H-indazole dihydrochloride 3.5 hydrate) with an apparent neuroprotective effect in vivo preferentially inhibits neuronal nitric oxide synthase (nNOS), Ca 2+/ CaM-dependent protein kinase IIa (CaMKIIa ), and calcineurin in vitro. In the present study, we investigated the molecular mechanism underlying its neuroprotective effect with the gerbil transient forebrain ischemia model, by focusing on its inhibition of these Ca 2+ / CaM-dependent enzymes. Post-ischemic DY-9760e treatment (5 mg / kg, i.p.) immediately after 5-min ischemia significantly reduced the delayed neuronal death in the hippocampal CA1 region. CaMKIIa was transiently autophosphorylated immediately after reperfusion with concomitant sustained decrease in its total amounts in the Triton X-100-soluble fractions. Calcineurin activity, accessed by the phosphorylation state of dopamine-and cAMP-regulated phosphoprotein of Mr 32,000 (DARPP-32) at Thr34, was elevated at 6 h after reperfusion. Posttreatment of DY-9760e had no effects on both CaMKIIa and DARPP-32 phosphorylation at 6 h after reperfusion. However, DY-9760e significantly inhibited nitrotyrosine formation, as a biomarker of NO, and in turn, peroxynitrite (ONOO -) production. These results suggest that DY-9760e primarily inhibits Ca 2+ / CaM-dependent neuronal NOS, without any effects on CaMKII and calcineurin, and the inhibition of NO production possibly accounts for its neuroprotective action in brain ischemic injury.

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Section: Discussionmentioning

confidence: 86%

Section: Discussionmentioning

confidence: 99%

Section: +mentioning

confidence: 99%

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The Post-ischemic Administration 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), a Novel Calmodulin Antagonist, Prevents Delayed Neuronal Death in Gerbil Hippocampus

et al. 2004

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“…We have developed a competitive calmodulin antagonist, 3-[2-[4-(3-chloro-2-methylphenyl)-1-piperazinyl]ethyl]-5,6-dimethoxy-1-(4-imidazolylmethyl)-1H-indazole dihydrochloride 3.5 hydrate (DY-9760e), that exerts cytoprotective action (Sugimura et al, 1997) and reduces the cerebral infarct volume after transient and permanent focal ischemia in rats (Sato et al, 1999;Takagi et al, 2001). The purpose of this study was 1) to evaluate the effects of DY-9760e on brain edema formation and BBB integrity in rats subjected to transient focal ischemia; 2) to determine whether DY-9760e directly affects changes in the vascular barrier function of brain endothelial cells treated with TNF␣; and 3) to clarify the involvement of calmodulin in brain edema formation by using trifluoperazine, a calmodulin antagonist structurally unrelated to DY-9760e.…”

mentioning

confidence: 99%

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 Calmodulin Antagonist, Reduces Brain Edema through the Inhibition of Enhanced Blood-Brain Barrier Permeability after Transient Focal Ischemia

Sato¹,

Morishima²,

Shirasaki³

2002

J Pharmacol Exp Ther

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An alteration of the blood-brain barrier (BBB) permeability contributes to the development of brain edema after stroke. In this study, we evaluated 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 brain edema formation and BBB integrity in rats subjected to transient focal ischemia. DY-9760e (1 mg/kg/h) was intravenously infused for 6 h, starting immediately after reperfusion of a 1-h middle cerebral artery occlusion. Treatment with DY-9760e significantly suppressed the increase in water content and the extravasation of Evans blue dye after transient focal ischemia. Analysis of a magnetic resonance imaging method revealed that DY-9760e significantly prevented the development of brain edema in the cortical region of the ipsilateral hemisphere. Trifluoperazine, a calmodulin antagonist that is structurally different from DY-9760e, also attenuated brain edema elicited by transient focal ischemia. Furthermore, DY-9760e and trifluoperazine reduced tumor necrosis factor-␣-induced hyperpermeability of inulin through a cultured brain microvascular endothelial cell monolayer, suggesting an involvement of calmodulin in the regulation of brain microvascular barrier function. The present results demonstrate that DY-9760e ameliorates brain edema formation and suggest that this effect may be mediated in part by the inhibition of enhanced BBB permeability after ischemic insults. Thus, DY-9760e is expected to be a therapeutic drug for treatment of acute stroke patients.In acute-stage cerebral ischemia, the development of infarction is accompanied by the formation of severe edema. Brain edema produces increased intracranial pressure, leading to a compression of the microvasculature, which causes further cerebrocirculatory disorder followed by secondary expansion of the infarct volume and often leads to a fatal condition (Klatzo et al., 1986). Therefore, alleviation of brain edema may not only improve clinical symptoms by restricting subsequent infarction but also reduce mortality.The blood-brain barrier (BBB) functions to eliminate the free passage of hormones, drug, and other neuroactive and neurotoxic substances into the central nervous system. Ischemia and reperfusion injury causes BBB disruption, which accelerates the development of abnormal vascular permeability and exacerbates postischemic edema (Cole et al., 1991;Yang and Betz, 1994). Although the precise cellular mechanisms underlying changes in BBB permeability after cerebral ischemia are unclear, there are several lines of evidence that calcium and cytokines may play an important role in altering BBB permeability (Tschugguel et al., 1995;Merrill and Murphy, 1997;Abbruscato and Davis, 1999;Brown and Davis, 2002). Tumor necrosis factor-␣ (TNF␣) is an inflammatory cytokine that elicits enhanced vascular permeability (Deli et al., 1995;Mark and Miller, 1999). Increases in TNF␣ mRNA and protein expression occur in the rat and ...

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“…DY-9760e elicits a powerful neuroprotective effect against neuronal death induced by a Ca 2+ ionophore in neuroblastoma cells or brain I / R injury in vivo (15,16,27). We have also defined the molecular mechanisms underlying its neuroprotective action.…”

Section: Discussionmentioning

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.

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DY-9760e, a novel calmodulin antagonist with cytoprotective action

Cited by 35 publications

References 34 publications

The Post-ischemic Administration 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), a Novel Calmodulin Antagonist, Prevents Delayed Neuronal Death in Gerbil Hippocampus

The Post-ischemic Administration 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), a Novel Calmodulin Antagonist, Prevents Delayed Neuronal Death in Gerbil Hippocampus

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 Calmodulin Antagonist, Reduces Brain Edema through the Inhibition of Enhanced Blood-Brain Barrier Permeability after Transient Focal Ischemia

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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