DY-9760e, a novel calmodulin antagonist, reduces brain damage induced by transient focal cerebral ischemia.

Abstract

Perturbations in Ca2+ homeostasis have been proposed to lead to neuronal damage after cerebral ischemia. DY-9760e (3-[2-[4-(3-chloro-2-methylphenyl)-1-piperazinyl]ethyl]-5,6-dimethoxy-1- (4-imidazolylethyl)-1H-indazole dihydrochloride 3.5 hydrate) is a novel calmodulin antagonist. In this study, we examined the effects of DY-9760e on brain damage in rats subjected to transient (1 h) focal cerebral ischemia. DY-9760e (0.25-1.00 mg kg(-1) h(-1)) was intravenously infused for 6 h, starting 1 h after middle cerebral artery occlusion. Treatment with DY-9760e 0.25, 0.50 and 1.00 mg kg(-1) h(-1) reduced infarct volume by 30, 42 (P < 0.05), and 60% (P < 0.05), respectively. Furthermore, the effect of DY-9760e on ischemia-induced fodrin breakdown was examined in the same model. Pronounced fodrin breakdown was observed in the cerebral cortex and striatum at 24 h after ischemia. DY-9760e caused potent suppression of fodrin breakdown in the cerebral cortex at the same doses as those that had a protective action against cerebral infarction. From these results DY-9760e may have a therapeutic effect against cerebral ischemic damage in the acute stage.

• Authors: T Sato, Y Morishima, M Sugimura, T Uchida, Y Shirasaki
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 370 Issue 2 Pg. 117-23 (Apr 09 1999) ISSN: 0014-2999 [Print] Netherlands
• PMID: 10323259 (Publication Type: Journal Article)

Chemical References

• 3-(2-(4-(3-chloro-2-methylphenyl)1-piperazinyl)ethyl)5,6-dimethoxy-1-(4-imidazolylmethyl)-1H-indazol dihydrochloride 3.5 hydrate
• Calmodulin
• Carrier Proteins
• Indazoles
• Microfilament Proteins
• Nerve Tissue Proteins
• fodrin

Topics

• Animals
• Blood Pressure (drug effects)
• Brain Ischemia (drug therapy, metabolism)
• Calmodulin (antagonists & inhibitors)
• Carrier Proteins (metabolism)
• Cerebral Arteries (drug effects)
• Cerebral Cortex (drug effects, metabolism, pathology)
• Constriction, Pathologic
• Corpus Striatum (drug effects, metabolism, pathology)
• Indazoles (pharmacology, therapeutic use)
• Infusions, Intravenous
• Male
• Microfilament Proteins (metabolism)
• Nerve Tissue Proteins (metabolism)
• Rats
• Rats, Wistar