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

Autor: Adrian Carter, Uwe Pschorn
Rok vydání: 1996
Předmět:
Zdroj: Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association. 6(2)
ISSN: 1052-3057
Popis: 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-[2α, 3(R*), 6α]]-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.
Databáze: OpenAIRE
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