NA-VOLTAGE-ACTIVATED CA2+ CHANNEL BLOCKING ACTIONS OF NS-7, A NOVEL NEUROPROTECTIVE AGENT, IN NG108-15 CELLS( AND HIGH)

The actions of a novel neuroprotective compound, enyl)-2-methyl-6-(5-p iperidinopentyloxy)pyrimidine hydrochloride (NS-7), on voltage-gated N a+, Ca2+ and K+ channels were investigated in a mouse neuroblastoma an d rat,glioma hybrid cell line, NG108-15, using a whole-cell voltage cl amp technique. NG108-15 cells have a tetrodotoxin sensitive Na+ channe l, three types of Ca2+ channel (L, N and T) and voltage-gated K+ chann els, all of which were inhibited by NS-7 in a concentration-dependent manner. However, there was a considerable difference in its potency: t he IC50 values for the tetrodotoxin-sensitive Na+ channel, L-type Ca2 channel and N-type Ca2+ channel were similar (7.8, 4.5 and 7.3 mu M, respectively), lower than the IC,, value for the T-type Ca2+ channel ( 17.1 mu M), and much lower than the IC,, value for the voltage-gated K + channel (160.5 mu M). NS-7 altered neither the shape nor the reversa l potential of the current-voltage curves for Na+, L-type or N-type Ca 2+ channels, although the currents were reduced at every potential tes ted. These results indicate that NS-7 is a Na+ and high-voltage-activa ted (L-and N-type) Ca2+ channel blocker, and its channel-blocking prop erties may contribute to its neuroprotective action. (C) 1997 Elsevier Science B.V.