EFFECTS OF CA2-VITRO AND IN GLOBAL CEREBRAL-ISCHEMIA IN-VIVO( AND NA+CHANNEL INHIBITORS IN)

In the present study we have examined the effects of the small organic molecules: NNC 09-0026 aminophenyl)-3-[(4-trifluoromethyl-phenoxy)met hyl] piperidine dihydrochloride); SB 201823-A (4-[2-(3,4-dichloropheno xy)ethyl]-1-pentyl piperidine hydrochloride); NS 649 (2-amino-1-(2,5-d imethoxyphenyl)-5-trifluoromethyl benzimidazole); CNS 1237 (N-acenapht hyl-N'-4-methoxynaphth-1-yl guanidine) and riluzole on human omega-con otoxin sensitive N-type voltage-dependent Ca2+ channel currents (I-Ca) expressed in HEK293 cells, on Na+ channel currents (I-Na) in acutely isolated cerebellar Purkinje neurones in vitro and in the gerbil model of global cerebral ischaemia in vivo. Estimated IC50 values for stead y-state inhibition of I-Ca were as follows; NNC 09-0026, 1.1 mu M; CNS 1237, 4.2 mu M; SB 201823-A, 11.2 mu M; NS 649, 45.7 mu M and riluzol e, 233 mu M Estimated IC50 values for steady-state inhibition of Na+ c hannel currents were as follows: NNC 09-0026, 9.8 mu M; CNS 1237, 2.5 mu M; SB 201823-A, 4.6 mu M; NS 649, 36.7 mu M and riluzole, 9.4 mu M. In the gerbil model of global cerebral ischaemia the number of viable cells (mean +/- S.E.M.) per 1 mm of the CA1 was 215 +/- 7 (sham opera ted), 10 +/- 2 (ischaemic control), 44 +/- 15 (NNC 09-0026 30 mg/kg i. p.), 49 +/- 19 (CNS 1237 30 mg/kg i.p.), 11 +/- 2 (SB 201823-A IO mg/k g i.p.), 17 +/- 4 (NS 649 50 mg/kg i.p.) and 48 +/- 18 (riluzole IO mg /kg i.p.). Thus NNC 09-0026, CNS 1237 and riluzole provided significan t neuroprotection when administered prior to occlusion while SB 201823 -A and NS 649 failed to protect. These results indicate that the Ca2channel antagonists studied not only inhibited human N-type voltage-de pendent Ca2+ channels but were also effective blockers of rat Na+ chan nels. Both NNC 09-0026 and CNS 1237 showed good activity at bath Ca2and Na+ channels and this may contribute to the observed neuroprotecti on. (C) 1997 Elsevier Science B.V.