Protection by NMDA Antagonists against Selective Cell Loss following Transient Ischaemia

Abstract

We have administered antagonists acting competitively or noncompetitively at the N-methyl-D-aspartate receptor after a short period of incomplete ischaemia and evaluated selective neuronal loss in the CA₁ region of the rat hippocampus. The competitive antagonists D-(–)-2-amino-7-phosphonoheptanoate (2APH); 100 or 330 mg/kg; 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonate (CPP); 3.3 or 10 mg/kg; and CGS 19755 ( cis-4-phosphonomethyl-2-piperidine carboxylate) 3.3 or 10 mg/kg; and the noncompetitive antagonists MK801 {(+)5-methyl-10, 11-dihydro-5H-dibenzo[ a,d]cyclohepten-5,10-imine maleate}, 0.3, 1, or 3 mg/kg, and dextrorphan, 2, 6, 18, or 54 mg/kg, were administered intraperitoneally 15 min and 5 h after a 10-min incomplete ischaemia period; additionally MK801 (1 or 3 mg/kg) and CGS 19755 (10 or 30 mg/kg) were administered 5 and 10 h postischaemia. Seven days after ischaemia, the brains were fixed by perfusion. CA₁ pyramidal cell counts were performed on Nissl-stained sections using an ocular grid piece. Ventilated (no ischaemia) control animals had a mean of 406 ± 13 CA₁ neurones/3 grid lengths. Ischaemia reduced this mean to 157 ± 23. A significant protective effect against this cell loss was seen after two injections (at 15 min and 5 h postischaemia) of 2APH, CPP (10 mg/kg), CGS 19755 (10 mg/kg), MK801 (1 mg/kg), and dextrorphan (54 mg/kg). Delayed injection (5 and 10 h postischaemia) of CGS 19755 (10 and 30 mg/kg) and MK801 (1 and 3 mg/kg) did not provide any protection against pyramidal cell loss.