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  • 1
    ISSN: 1432-1912
    Keywords: Key words Neuroprotectant ; Voltage-sensitive sodium channel ; Batrachotoxin ; Saxitoxin ; Glutamate release ; Cerebral cortex ; Cardiac myocyte
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The effects of 4-(4-fluorophenyl)-2-methyl-6-(5-piperidinopentyloxy) pyrimidine hydrochloride (NS-7), a novel neuroprotective compound, on the voltage-sensitive sodium channels (VSSC) were examined in the rat brain and cardiac myocytes. NS-7 inhibited [3H]batrachotoxinin A 20α-benzoate (BTX) binding (neurotoxin receptor site 2) in brain membranes with a Ki value of 1 μM , while the compound was less effective in the cardiac myocytes (Ki = 13 μM). Aconitine, on the other hand, inhibited [3H]BTX binding to brain membranes and cardiac myocytes with the same potency. In contrast, NS-7 had no affinity for [3H]saxitoxin binding in brain (neurotoxin receptor site 1). In superfused slices of the rat cerebral cortex, NS-7 inhibited the veratridine (5 μM)-evoked glutamate release in a concentration-dependent manner, the IC50 value of which was 7.7 μM, whereas the compound showed a weak and not significant suppression of KCl-evoked glutamate release. The tissue concentrations of NS-7 in the rat cerebral cortex and heart were 89 and 28 nmole/g tissue, respectively, 5 min after its intravenous injection (8 mg/kg). Furthermore, in the cerebral cortex, NS-7 distributed preferentially to the membrane-enriched synaptosomal fraction. Since neurotoxin receptor site 2 is located in the transmembrane region of the VSSC moiety, the channel function may be substantially inhibited by a peripheral administration of NS-7. These results suggest that the blockade of neurotoxin receptor site 2 of VSSC in the brain contributes to the neuroprotective action of NS-7.
    Type of Medium: Electronic Resource
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  • 2
    Electronic Resource
    Electronic Resource
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 358 (1998), S. 191-196 
    ISSN: 1432-1912
    Keywords: Key words Neuroprotectant ; Calcium channel blocker ; Sodium channel blocker ; Hypoxic injury ; ATP ; Cerebral cortex
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The substance 4-(4-fluorophenyl)-2-methyl-6-(5-piperidinopentyloxy) pyrimidine hydrochloride (NS-7) has been developed recently as a cerebroprotective compound with Na+ and Ca2+ channel blocking action. In the present study, the effect of NS-7 in an in vitro model of hypoxic injury was examined and the possible involvement of Na+ and Ca2+ channels in the hypoxic injury subsequently determined. When slices of rat cerebral cortex were exposed to hypoxia/glucose deprivation followed by reoxygenation and restoration of the glucose supply, marked leakage of lactate dehydrogenase (LDH) occurred 3–6 h after reoxygenation. This hypoxia/reoxygenation-induced injury was blocked almost completely by the removal of extracellular Ca2+ or by chelating intracellular Ca2+ with 1,2-bis(o-aminophenoxy)ethane-N,N,N’,N’-tetraacetic acid tetra(acetoxymethyl)ester (BAPTA/AM). In addition, combined treatment with the N-type Ca2+ channel blocker ω-conotoxin GVIA and the P/Q-type Ca2+ channel blocker ω-agatoxin IVA significantly reduced LDH leakage, although neither of these Ca2+ channel blockers alone, nor nimodipine, an L-type Ca2+ channel blocker, was effective. On the other hand, several Na+ channel blockers, including tetrodotoxin, local anaesthetics and antiepileptics, significantly reduced the hypoxic injury. NS-7 (3–30 µM) concentration-dependently inhibited LDH leakage caused by hypoxia/reoxygenation, but had no influence on the reduction of tissue ATP content and energy charge during hypoxia and glucose deprivation. It is suggested that blockade of Na+ and Ca2+ channels is implicated in the cerebroprotective action of NS-7.
    Type of Medium: Electronic Resource
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