Premium
Inhibition of Ischemia‐Induced Fodrin Breakdown by a Novel Phenylpyrimidine Derivative NS‐7: An Implication for Its Neuroprotective Action in Rats with Middle Cerebral Artery Occlusion
Author(s) -
Takagaki Yumiko,
Itoh Yoshinori,
Aoki Yasuaki,
Ukai Yojiro,
Yoshikuni Yoshiaki,
Kimura Kiyoshi
Publication year - 1997
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.1997.68062507.x
Subject(s) - calpain , neuroprotection , ischemia , in vivo , cerebral cortex , chemistry , extracellular , pharmacology , medicine , anesthesia , endocrinology , biology , biochemistry , microbiology and biotechnology , enzyme
The effect of a novel neuroprotective compound, NS‐7[4‐(4‐fluorophenyl)‐2‐methyl‐6‐(5‐piperidinopentyloxy)pyrimidine hydrochloride], on ischemia‐induced fodrin breakdown was examined both in vitro and in vivo. The fodrin breakdown was measured by western blot followed by a densitometric analysis. In slices of the rat cerebral cortex, a pronounced fodrin breakdown was observed under hypoxic and hypoglycemic conditions. The enhancement of fodrin breakdown was completely blocked by omission of extracellular Ca 2+ and significantly inhibited by calpain inhibitors such as E‐64 and calpain inhibitor‐I, thereby suggesting that the fodrin breakdown induced by hypoxia/hypoglycemia is due to the activation of Ca 2+ ‐stimulated neutral protease calpain. NS‐7 (1–30 µ M ) produced a concentration‐dependent inhibition of hypoxia/hypoglycemia‐induced fodrin breakdown. In rats with unilateral middle cerebral artery occlusion (MCAO), a pronounced fodrin breakdown was observed in the cerebral cortex and striatum, although the time course for the development of the fodrin breakdown was much slower in the cerebral cortex than in the striatum. NS‐7 (0.5 mg/kg i.v.), when injected immediately after MCAO, suppressed not only the fodrin breakdown but also the infarction in the cerebral cortex. From these results it is suggested that inhibition of calpain activation is implicated in the neuroprotective action of NS‐7.