Dizocilpine

We assessed the effect of a novel calmodulin antagonist, DY-9760e (3-[2-[4-(3-chloro-2-methylphenyl)-1piperazinyl]ethyl]-5,6-dimethoxy-1-(4-imidazolylmethyl)- 1 H-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^sup -1^ h^sup -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 125.7 +/- 31.8 mm^sup 3^ (DY-9760e; n = 9). Administration with a 30 min delay resulted in a mean infarct volume of 173.2 +/- 32.4mm^sup 3^ (vehicle; n = 12) and 143.3 +/- 35.3 mm^sup 3^ (DY-9760e; n = 11). Dy-9760e significantly reduced the infarct under these conditions (p

Keywords: Focal cerebral ischemia; spontaneously hypertensive rats; calcium; calmodulin antagonist, DY-9760e

CONCLUSION

The present study showed that a novel potent CaM antagonist, DY-9760e, reduced the cerebral infarct volume in a chronic hypertensive animal permanent focal cerebral ischemia model without affecting the local CBF. The results also demonstrate that the protective effect was noted even when DY-9760e was administered 30 min after the MCAO. To our knowledge, this therapeutic time window is the widest for permanent proximal MCAO in SHRs.

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Kiyoshi Takagi, Toshiyuki Sato*, Yasufumi Shirasaki*, Koji Narita, Akira Tamura and Keiji Sano

Department of Neurosurgery, Teikyo University School of Medicine, Tokyo *New Product Research Laboratories Ill, Daiichi Pharmaceutical Co. Ltd, Tokyo, Japan

Correspondence and reprint requests to: Kiyoshi Takagi, MD, Department of Neurosurgery, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi-ko, Tokyo, 173-8605, Japan. Accepted for publication December 2000.

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