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

Abstract

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 Ca2+ 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 Ca2+‐stimulated neutral protease calpain. NS‐7 (1–30 µM) 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.

Cleavage of the Vesicular GABA Transporter under Excitotoxic Conditions Is Followed by Accumulation of the Truncated Transporter in Nonsynaptic Sites

“…Calpains are also activated in the striatum and in the cerebral cortex after MCAO, contributing to neuronal death (Takagaki et al, 1997;Bevers and Neumar, 2008), and may mediate the observed cleavage of VGAT in mice exposed to this model of transient focal brain ischemia. VGAT cleavage in the hippocampus of rats following systemic injection of kainate may also arise from calpain activation.…”

Effect of TTC-909 on Cerebral Infarction Following Permanent Occlusion of the Middle Cerebral Artery in Stroke Prone Spontaneously Hypertensive Rats

“…Takagaki et al (18) showed that infarction in the striatum developed during the early stage (within 6 h) after MCA occlusion and that development of cortical infarction was slower than that seen in the striatum after permanent occlusion of MCA according to the method of Tamura et al (3). On the other hand, it was reported that the ischemic region in the MRI analysis increased progressively over a few days after the occlusion of MCA in rats (19,20).…”

Effect of fentanyl on ischemic depolarization and ischemic neuronal damage of hippocampal CA1 in the gerbil

“…Accumulation of intracellular calcium inhibits mitochondrial adenosine diphosphate phosphorylation [12] and protein synthesis as a result of the disaggregation of ribosomes [13], and further activates many enzymes, including phospholipase, protease, and protein kinase, leading to accumulation of arachidonic acid [14], collapse of cytoskeletal elements [15], and release of neurotransmitters [12]. As already mentioned, because ischemic depolarization triggers a cascade of neuronal damage following the loss of neuronal ion homeostasis, the onset time and the duration of ischemic depolarization have strong correlations with the degree of subsequent neuronal damage [4,5].…”