Post-ischemic administration of DY-9760e, a novel calmodulin antagonist, reduced infarct volume in the permanent focal ischemia model of spontaneously hypertensive rat.
We assessed the effect of a novel calmodulin 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) in a spontaneously hypertensive rat (SHR) permanent focal cerebral ischemia. In experiment I, the left middle cerebral artery was permanently occluded in 62 SHRs. DY-9760e (0.5 mg kg(-1) h(-1)) or vehicle alone were administered continuously i.v. for 6 h, beginning 0, 30, or 60 min after the arterial occlusion. The infarct volume was measured 24 h of ischemia. In experiment II, the effect of DY-9760e on CBF was assessed in 10 SHRs. Administration without a delay resulted in a mean infarct volume of 166.7 +/- 21.0 mm3 (vehicle; n = 10) and 125.1 +/- 31.8 mm3 (DY-9760e; n = 9). Administration with a 30 min delay resulted in a mean infarct volume of 173.2 +/- 32.4 mm3 (vehicle; n = 12) and 143.3 +/- 35.3 mm3 (DY-9760e; n = 11). Dy-9760e significantly reduced the infarct under these conditions (p < 0.05). The administration with a 60 min delay failed to reduce the infarct. DY-9760e had no effect on the CBF. Continuous i.v. administration of DY-9760e reduced infarct volume in a SHR permanent focal ischemia without affecting ischemic CBF.
Takagi
K
K
Department of Neurosurgery, Teikyo University School of Medicine, Tokyo, Japan.
Sato
T
T
Shirasaki
Y
Y
Narita
K
K
Tamura
A
A
Sano
K
K
D000818:Animals; D020520:Brain Infarction / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D002545:Brain Ischemia / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D002118:Calcium / Q000378:metabolism*; D002147:Calmodulin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D002560:Cerebrovascular Circulation / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D018698:Glutamic Acid / Q000378:metabolism; D007191:Indazoles / Q000494:pharmacology*; D008297:Male; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D009410:Nerve Degeneration / Q000188:drug therapy* / Q000503:physiopathology / Q000517:prevention & control; D018696:Neuroprotective Agents / Q000494:pharmacology*; D051381:Rats; D011918:Rats, Inbred SHR
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; D018698:Glutamic Acid; D002118:Calcium