The influence of repeated doses, route and time of administration on the neuroprotective effects of BIII 277 CL in a rat model of focal cerebral ischemia.

OBJECTIVE

We investigated the influence of dose, route and time of administration on the neuroprotective effects of the noncompetitive N-methyl-D-aspartic acid antagonist BIII 277 CL ([2R-[2alpha, 3(R*), 6alpha]]-1,2,3,4,5,6-hexahydro-3-(2-methoxy-propyl)-6,11,11-trimethyl-2,6-methao-3-benzazocin-9-ol hydrochloride).

METHODS

Focal cerebral ischemia was induced in isoflurane-anaesthetized Fischer rats by permanent occlusion of the left middle cerebral artery. Rats were treated with BIII 277 CL three times at doses of 1 and 3 mg/kg intraperitoneally (IP) (5 to 10 minutes and 4 and 24 hours after occlusion) or twice with 0.1, 0.3, and 1.0 mg/kg subcutaneously (SC) (5 to 10 minutes and 3 hours after occlusion) or twice with 1 mg/kg SC (30 minutes and 3 hours 30 minutes; 1 and 4 hours; 2 and 5 hours; or 4 and 7 hours after occlusion). Other rats received (+)MK-801 (dizocilpine) three times at doses of 0.3, 1.0, and 3.0 mg/kg IP (5 to 10 minutes and 4 and 24 hours after occlusion). Control rats received an equal volume of saline. Infarct volume was determined 48 hours after occlusion by standard histological techniques.

RESULTS

IP administration of BIII 277 CL caused a dose-dependent reduction of infarct volume (1 mg/kg, 13%; 3 mg/kg, 25%). (+)MK-801 had similar effects (0.3 mg/kg, 13%; 1.0 mg/kg, 21%; 3 mg/kg, 27%). BIII 277 CL also dose-dependently reduced the infarct volume after SC administration (0.1 mg/kg, 14%; 0.3 mg/kg, 30%; 1.0 mg/kg, 28%). Furthermore, significant neuroprotective effects of BIII 277 CL were observed even when initial treatment was delayed up to 1 hour after occlusion (30 minutes, 28%; 1 hour, 23%; 2 hours, 5%; 4 hours, 4%).

CONCLUSIONS

These results indicate that BIII 277 CL shows significant neuroprotective effects at doses as low as 0.1 mg/kg SC. The effects after IP administration are comparable with those of (+)MK-801, and significant effects were observed even when the BIII 277 CL was first administered up to 1 hour after the beginning of ischemia.