Blockade of voltage-sensitive sodium channels by NS-7, a novel neuroprotective compound, in the rat brain
Shimidzu, T; Itoh, Y; Tatsumi, S; Hayashi, S; Ukai, Y; Yoshikuni, Y; Kimura, K
| HERO ID | 2796085 |
|---|---|
| In Press | No |
| Year | 1997 |
| Title | Blockade of voltage-sensitive sodium channels by NS-7, a novel neuroprotective compound, in the rat brain |
| Authors | Shimidzu, T; Itoh, Y; Tatsumi, S; Hayashi, S; Ukai, Y; Yoshikuni, Y; Kimura, K |
| Journal | Naunyn-Schmiedeberg's Archives of Pharmacology |
| Volume | 355 |
| Issue | 5 |
| Page Numbers | 601-608 |
| 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 20 alpha-benzoate (BTX) binding (neurotoxin receptor site 2) in brain membranes with a Ki value of 1 microM, while the compound was less effective in the cardiac myocytes (Ki = 13 microM). 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 microM)-evoked glutamate release in a concentration-dependent manner, the IC50 value of which was 7.7 microM, 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. |
| Doi | 10.1007/PL00004990 |
| Pmid | 9151299 |
| Wosid | WOS:A1997WW11200009 |
| Is Certified Translation | No |
| Dupe Override | No |
| Is Public | Yes |
| Language Text | English |
| Keyword | neuroprotectant; voltage-sensitive sodium channel; batrachotoxin; saxitoxin; glutamate release; cerebral cortex; cardiac myocyte |