The neuroprotective effect of a novel calmodulin antagonist, 3-[2-[4-(3-chloro-2-methylphenyl)-1-piperazinyl]ethyl]-5,6-dimethoxy-1-(4-imidazolylmethyl)-1h-indazole dihydrochloride 3.5 hydrate, in transient forebrain ischemia
Section snippets
Surgical preparation
All experiments were performed on male Mongolian gerbils (SLC, Shizuoka, Japan) weighing 60–70 g. All experimental procedures were approved by the Committee of Animal Experiments at Kumamoto University School of Medicine. All efforts were made to minimize the number of animals used and their suffering.
Gerbils were administered 50 mg/kg DY-9760e i.p. (Daiichi Pharmaceutical Co., Tokyo, Japan) dissolved in 10% dimethyl sulfoxide (DMSO; Sigma, St. Louis, MO, USA) in saline (10 mg/ml) or 50 mg/kg NG
Inhibitory effect of DY-9760e on NO production after 10-min forebrain ischemia
The basal level of NOx− in 10-minute dialysate samples from the hippocampal CA1 region were 1.29±0.36, 1.08±0.22 and 1.21±0.18 μM (sham, vehicle and DY-9760e, respectively), and were not significantly different. Under freely moving condition without halothane anesthesia, which may affect NOS activity (Zuo et al., 1999), we successfully performed brain microdialysis to monitor NO production beyond 24 h after transient forebrain ischemia (Fig. 1). First, the levels of NOx− in the sham-operated
Discussion
Accumulating evidence suggests that both nNOS and inducible NOS (iNOS) have detrimental effects on neurons in the ischemic brain, whereas endothelial NOS (eNOS) activity has protective effects Huang et al., 1994, Huang et al., 1996, Iadecola et al., 1997, Samdani et al., 1997. Targeted disruption of the nNOS gene also attenuates hippocampal injury after transient global ischemia (Panahian et al., 1996). In the present study, the newly developed CaM antagonist, DY-9760e, showed a powerful
Acknowledgements
This study was supported in part by Grants-in Aid for Scientific Research (14370035) from the ministry of Education, Science, Sports and Culture of Japan (K.F.).
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