Protective Effect of DY-9760e, a Calmodulin Antagonist, against Neuronal Cell Death

Takano, Haruo; Sugimura, Masunobu; Kanazawa, Yoshito; Uchida, Toshihiro; Morishima, Yasuo; Shirasaki, Yasufumi

doi:10.1248/bpb.27.1788

Cited by 9 publications

(7 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Treatment with DY-9760e, a calmodulin antagonist, resulted in a dosedependent prevention of neuronal cell death elicited by excitotoxicity, voltage-gated channel opening, and inhibition of ER Ca 2? ATPase [173]. Although the mode of cell death and underlying mechanisms are not yet clear, CaMK-II that is regulated by calcium has been shown to induce ERK activation in neurons and vascular smooth muscle cells [174,175].…”

Section: Protein Kinasesmentioning

confidence: 99%

Molecular and cellular mechanisms of excitotoxic neuronal death

2010

View full text Add to dashboard Cite

Glutamate receptor-mediated excitatory neurotransmission plays a key role in neural development, differentiation and synaptic plasticity. However, excessive stimulation of glutamate receptors induces neurotoxicity, a process that has been defined as excitotoxicity. Excitotoxicity is considered to be a major mechanism of cell death in a number of central nervous system diseases including stroke, brain trauma, epilepsy and chronic neurodegenerative disorders. Unfortunately clinical trials with glutamate receptor antagonists, that would logically prevent the effects of excessive receptor activation, have been associated with untoward side effects or little clinical benefit. Therefore, uncovering molecular pathways involved in excitotoxic neuronal death is of critical importance to future development of clinical treatment of many neurodegenerative disorders where excitotoxicity has been implicated. This review discusses the current understanding of the molecular and cellular mechanisms of excitotoxicity and their roles in the pathogenesis of diseases of the central nervous system.

show abstract

Section: Protein Kinasesmentioning

confidence: 99%

Molecular and cellular mechanisms of excitotoxic neuronal death

2010

View full text Add to dashboard Cite

show abstract

“…30) Therefore, there are strong clinical demands for neuroprotective agents that can block neuronal death associated with stroke. 31) We have developed DY-9760e, a calmodulin antagonist, which exerts neuroprotective action against cell death induced by Ca 2ϩ overload 15,17) and ameliorates brain injury that occurs after cerebral ischemia in rodents. [18][19][20][21][22]32,33) The present study demonstrates that DY9760e reduces the infarct volume in cats with permanent MCA occlusion, and this finding is consistent with previous studies in rats with permanent MCA occlusion, extending the observation into a gyrencephalic species.…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, DY-9760e can rescue neurons from cell death elicited by cell-toxic stimuli that mimic cellular events observed in cerebral ischemia. 15,17) In addition, it has been shown that trifluoperazine, a calmodulin antagonist that is structurally different from DY-9760e, attenuates brain injury after transient MCA occlusion without improving CBF. 43) Taken together, these results indicate that the neuroprotection demonstrated in animal models may be due to a direct action of DY-9760e in the brain parenchyma.…”

Section: Discussionmentioning

confidence: 99%

“…45,46) DY-9760e rescues cultured neurons from a wide variety of cell-toxic stimuli that increase intracellular Ca 2ϩ , including excitotoxicity, voltage-gated channel opening, Ca 2ϩ ionophore, and inhibition of endoplasmic reticulum Ca 2ϩ -ATPase. 15,17) DY-9760e is also capable of reducing the ischemic infarct volume when given up to 3 h after the onset of permanent MCA occlusion in rats. 20) Given a previous report showing that the Ca 2ϩ -bound calmodulin complex reaches maximal levels 4 h following cerebral ischemia, it is feasible that the therapeutic time window for DY-9760e is 3 h. 12) Taken together, it is plausible that the amelioration of ischemic brain injury with this drug is mediated by a calmodulin antagonistic action in the brain.…”

Section: Discussionmentioning

confidence: 99%

“…13,14) DY-9760e (3-[2-[4-(3-chloro-2-methylphenyl)-1-piperazinyl]ethyl]-5,6-dimethoxy-1-(4-imidazolylmethyl)-1H-indazole dihydrochloride 3.5 hydrate) is a calmodulin antagonist that is 2 to 70 times more potent than W-7, a well-known calmodulin antagonist, and can protect neurons against neuronal cell death elicited by Ca 2ϩ overload. [15][16][17] This compound ameliorates brain injury that occurs after transient or permanent focal ischemia and microembolization in rats. [18][19][20][21][22] Although these studies in various rodent models show a hopeful characteristic of DY-9760e, it is subsequently important to assess if it exerts a protective effect in a large animal model of focal cerebral ischemia.…”

Section: -9)mentioning

confidence: 99%

See 2 more Smart Citations

DY-9760e, a Calmodulin Antagonist, Reduces Brain Damage after Permanent Focal Cerebral Ischemia in Cats

Sugimura

Takamori

Fukushi

et al. 2005

Biological & Pharmaceutical Bulletin

Self Cite

View full text Add to dashboard Cite

Although the cellular pathophysiological mechanisms underlying ischemic brain damage remain to be fully clarified, accumulating evidence suggests that an excessive elevation of intracellular Ca 2ϩ in neurons is a primary mechanism by which cells become injured following cerebral ischemia. 1-3)An overload of Ca 2ϩ in neurons disrupts the ionic balance and activates various Ca 2ϩ -dependent enzymes. Treatment of ischemic animals with compounds that block Ca 2ϩ entry through Ca 2ϩ -permeable channels has been shown to provide protection against the consequences of ischemia in laboratory animals, 4-6) but these treatments have not been found suitable for use in humans. 7-9)Calmodulin is a major Ca 2ϩ -binding protein found mainly in the central nervous system. 10,11) Since many of the pathways through which Ca 2ϩ acts involve Ca 2ϩ /calmodulin signaling systems, including calmodulin-dependent enzymes, inhibition of calmodulin may be a possible alternative approach towards the treatment and prevention of post-ischemic injury. In fact, it has been reported that Ca 2ϩ -bound calmodulin, which is an active form, is increased following ischemia and regional changes correlate with regions of ischemic neuronal damage.12) Furthermore, calmodulin antagonists protect cultured neurons from cell death induced by glutamate, an excitatory amino acid, and protect hippocampal CA1 neurons against hypoxia/hypoglycemia in organotypic cultures. 13,14) DY-9760e (3-[2-[4-(3-chloro-2-methylphenyl)-1-piperazinyl]ethyl]-5,6-dimethoxy-1-(4-imidazolylmethyl)-1H-indazole dihydrochloride 3.5 hydrate) is a calmodulin antagonist that is 2 to 70 times more potent than W-7, a well-known calmodulin antagonist, and can protect neurons against neuronal cell death elicited by Ca 2ϩ overload. [15][16][17] This compound ameliorates brain injury that occurs after transient or permanent focal ischemia and microembolization in rats. [18][19][20][21][22] Although these studies in various rodent models show a hopeful characteristic of DY-9760e, it is subsequently important to assess if it exerts a protective effect in a large animal model of focal cerebral ischemia. Cats, a gyrencephalic species in common with humans, have long been used both in pathophysiological studies for cerebral ischemia and in investigations for the protective efficacy of agents. [23][24][25][26][27] Therefore, the present study was designed to evaluate the potential acute therapeutic effect of DY-9760e on ischemic injury resulting from permanent middle cerebral artery (MCA) occlusion in cats. MATERIALS AND METHODSAnimals Twenty-three male Ico: Fec Eur (Tif) cats (IFFA-CREDO, L'arbresle, France), weighing 2.7 to 3.3 kg, were used in this study. The animals were maintained on canned food (CK, Oriental Yeast, Tokyo, Japan), solid food (NK-C, Nihon Nosan, Yokohama, Japan) and tap water, which were given once a day under a constant 12-h dark-light cycle. All experimental procedures were performed in accordance with the in-house guidelines of the Institutional Animal Care and Use Committee ...

show abstract