Inhibition of nitric oxide production and protein tyrosine nitration contribute to neuroprotection by a novel calmodulin antagonist, DY-9760e, in the rat microsphere embolism.
Microsphere embolism (ME)-induced ischemia model in rat resembles to multiple brain embolism in human with several clinical features. We here tested whether nitric oxide (NO) production contributes to the neuronal injury in the ME model. A novel calmodulin antagonist, DY-9760e, having a potent inhibitory effect on neuronal nitric oxide synthase (nNOS), reduced brain infarct size in the ME-induced brain ischemia. Consistent with our previous observation with gerbil ischemia/reperfusion model, DY-9760e completely inhibited NO production immediately after and 24 or 48 h after ME. Unlike the gerbil ischemia/reperfusion model, protein tyrosine nitration markedly increased 6-48 h after ME. DY-9760e treatment completely inhibited the marked increase in the protein tyrosine nitration at 24 h after ME. These results suggest that the inhibition of NO production and protein tyrosine nitration by DY-9760e contribute to its neuroprotective action in the ME-induced brain damage.
Shirakura
Takashi
T
Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.
Han
Feng
F
Shiota
Norifumi
N
Moriguchi
Shigeki
S
Kasahara
Jiro
J
Sato
Toshiyuki
T
Shirasaki
Yasufumi
Y
Fukunaga
Kohji
K
D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000473:pathology; D002147:Calmodulin / Q000037:antagonists & inhibitors*; D002544:Cerebral Infarction / Q000473:pathology; D007191:Indazoles / Q000494:pharmacology*; D007274:Injections, Intraperitoneal; D020766:Intracranial Embolism / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D017551:Microdialysis; D008863:Microspheres; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents; D009566:Nitrates / Q000378:metabolism*; D009569:Nitric Oxide / Q000096:biosynthesis*; D051381:Rats; D014443:Tyrosine / Q000378:metabolism*
C109602:3-(2-(4-(3-chloro-2-methylphenyl)1-piperazinyl)ethyl)5,6-dimethoxy-1-(4-imidazolylmethyl)-1H-indazol dihydrochloride 3.5 hydrate; D002147:Calmodulin; D007191:Indazoles; D018696:Neuroprotective Agents; D009566:Nitrates; D009569:Nitric Oxide; D014443:Tyrosine