TY - JOUR
T1 - 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
AU - Fukunaga, Kohji
AU - Ohmitsu, Masao
AU - Miyamoto, Eishichi
AU - Sato, Toshiyuki
AU - Sugimura, Masunobu
AU - Uchida, Toshihiro
AU - Shirasaki, Yasufumi
PY - 2000/9/1
Y1 - 2000/9/1
N2 - DY-9760e, 3-[2-[4-(3-chloro-2-methylphenyl)-1-piperazinyl]ethyl]-5,6-dimethoxy-1-(4-imidazolylmethyl)-1H-indazole dihydrochloride 3.5 hydrate, a novel calmodulin (CaM) antagonist, possesses neuroprotective activity. In the current study, we examined the effects of DY-9760e on nitric oxide synthase (NOS) activities in vitro and on calcium ionophore-induced NO production in situ. DY-9760e inhibited both neuronal NOS and endothelial NOS activities without affecting inducible NOS activity. It also inhibited purified neuronal NOS activity with a potency similar to that seen for purified CaM kinase II activity in vitro. Furthermore, DY-9760e significantly inhibited Ca2+ ionophore (A23187)-induced NO production in mouse N1E-115 neuroblastoma cells, at a concentration of less than 1 μM. In contrast, no apparent inhibitory effect on Ca2+/CaM-dependent protein kinase II activity was observed in cultured hippocampal neurons up to 5 μM. These results suggest that the inhibitory effect of DY-9760e on CaM-dependent NOS activities underlies neuroprotective effects of the agent. Copyright (C) 2000 Elsevier Science Inc.
AB - DY-9760e, 3-[2-[4-(3-chloro-2-methylphenyl)-1-piperazinyl]ethyl]-5,6-dimethoxy-1-(4-imidazolylmethyl)-1H-indazole dihydrochloride 3.5 hydrate, a novel calmodulin (CaM) antagonist, possesses neuroprotective activity. In the current study, we examined the effects of DY-9760e on nitric oxide synthase (NOS) activities in vitro and on calcium ionophore-induced NO production in situ. DY-9760e inhibited both neuronal NOS and endothelial NOS activities without affecting inducible NOS activity. It also inhibited purified neuronal NOS activity with a potency similar to that seen for purified CaM kinase II activity in vitro. Furthermore, DY-9760e significantly inhibited Ca2+ ionophore (A23187)-induced NO production in mouse N1E-115 neuroblastoma cells, at a concentration of less than 1 μM. In contrast, no apparent inhibitory effect on Ca2+/CaM-dependent protein kinase II activity was observed in cultured hippocampal neurons up to 5 μM. These results suggest that the inhibitory effect of DY-9760e on CaM-dependent NOS activities underlies neuroprotective effects of the agent. Copyright (C) 2000 Elsevier Science Inc.
KW - Brain ischemia
KW - CaM kinase II
KW - Calmodulin antagonist
KW - Neuroprotection
KW - Nitric oxide synthase
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U2 - 10.1016/S0006-2952(00)00370-1
DO - 10.1016/S0006-2952(00)00370-1
M3 - Article
C2 - 10927028
AN - SCOPUS:0034285059
VL - 60
SP - 693
EP - 699
JO - Biochemical Pharmacology
JF - Biochemical Pharmacology
SN - 0006-2952
IS - 5
ER -