Permeability of a neuroprotective compound NS-7 into brain: Comparison between normal and middle cerebral artery-occluded rats

Short‐ and long‐term differential effects of neuroprotective drug NS‐7 on voltage‐dependent sodium channels in adrenal chromaffin cells

“…In brain Na + channels reconstituted into phospholipid vesicles, however, removal of β 1 ‐ (but not β 2 ‐) subunit reduced the abilities of Na + channels to bind to [ 3 H]‐STX and to increase 22 Na + influx in response to veratridine ( Messner & Catterall, 1986 ; Messner et al ., 1986 ). Although the precise molecular mechanisms of Na + channel gating remain largely unknown ( Catterall, 1992 ), most straightforward interpretation of our present results may be that although chronic treatment with NS‐7 causes up‐regulation of cell surface Na + channels, NS‐7, a highly lipophilic drug ( Itoh et al ., 1997 ), binds tightly to the membrane lipids, thus producing the long‐lived inhibition of toxin‐induced gating of Na + channels.…”

“…However, rinsing the NS‐7‐pretreated cells with the calf serum‐containing culture medium for 15 and 30 min gradually restored veratridine‐induced 22 Na + influx to 63 and 97% of the control values, respectively (Figure 1c, closed columns). Our present result may raise the question of whether the highly lipophilic NS‐7 ( Itoh et al ., 1997 ) was bound to the hydrophobic regions of plasma proteins contained in the calf serum, and was progressively removed from the NS‐7‐pretreated cells during the 30 min washing. As shown in Figure 1c (shaded columns), when the NS‐7‐pretreated cells were washed with the calf serum‐free culture medium for 15 and 30 min, veratridine‐induced 22 Na + influx was recovered to 37.8 and 62.0% of the nontreated cells.…”

“…Previous studies showed that the partition coefficient of NS‐7 between octanol and phosphate buffer (pH 6.8) was 81.3 ( Itoh et al ., 1997 ); because of the lipophilic property of NS‐7, about 50% of total amount (8 mg kg −1 ) of NS‐7 administered intravenously in rat was highly concentrated at 5 min in brain P 2 fraction, where Na channels were located ( Shimidzu et al ., 1997 ). They also found that during 2 h after the intravenous injection of NS‐7 (10 mg kg −1 ) into the rat, the striatal extracellular concentrations of NS‐7 were maintained at 1.1–1.4 μ M , the concentrations being comparable with those of NS‐7 in the extracellular milieu in our present study that caused up‐regulation of Na + channels.…”

Neuroprotective Effect of the Novel Na+/Ca2+ Channel Blocker NS-7 on Rat Retinal Ganglion Cells

“…Furthermore, a pharmacokinetic study showed that a substantial amount of NS-7 can penetrate ischemic brain regions when injected intravenously after middle cerebral artery occlusion in rats. 3 The voltage-sensitive Na + /Ca 2+ channel blocking property of NS-7, therefore, is also expected to show a favorable effect on RGCs in the ischemia-reperfusion model. The neural cell death from retinal ischemia-reperfusion is by apoptosis and necrosis.…”

“…[1][2][3][4][5][6][7][8][9][10][11] In the ERG experiment, NS-7 reduced the reduction of B-wave amplitudes in a dose-dependent manner, and significant effect was observed at doses of 0.1 (P < 0.05) and 0.3 mg/kg (P < 0.01). The histopathologic experiment showed a dosedependent tendency at 0.25 (P < 0.05) and 1.0 mg/kg (P < 0.10).…”