The effects of MK-801, ifenprodil, JO 1784, JO 1994 and JO 1997 on PK 11195 receptor binding, nitric oxide synthase (NO synthase) activity and infarct volume in a mouse model of focal cerebral ischaemia.

Middle cerebral artery occlusion (MCAO) is a widely used surgical procedure for inducing focal cortical ischaemia in mice. In the present study, all experiments were performed on 4-week-old, male Swiss mice (OF-1 Iffa Credo, France), 20-25 g at the time of surgery. Sham-operated mice were subjected to simple exposure of the middle cerebral artery. Mice were injected with either MK-801, ifenprodil, JO 1784, JO 1994 or JO 1997 at the following time points after surgery; 5, 15, 45 min and 3, 6, 24, 30, 48 and 54 h. Mice were sacrificed 72 h after surgery and both ipsilateral and contralateral cortices were dissected in their entirety, weighed, and assayed for [3H]PK 11195 binding while the brain-stem and cerebellum were assayed for nitric oxide synthase (NO synthase) activity. In a separate experiment the area of ischaemic damage was determined planimetrically by means of an image analysis system. Coagulation of the middle cerebral artery induced a marked enhancement of the ipsilateral cortical omega 3 peripheral-type benzodiazepine binding site (PTBB'S) densities, an increase in NO synthase activity in the brain-stem and cerebellum, and an increase in the cortical infarct area. MK-801, ifenprodil, JO 1784, JO 1994 and JO 1997 demonstrated comparable neuroprotective effects on all three indices of cortical damage. A down-regulation of cortical omega 3 peripheral-type benzodiazepine binding site (PTBB'S) densities and a decrease in NOS activity occurred following pharmacological intervention. In contrast to JO 1784, JO 1994 and JO 1997 have a bimodal effect on omega 3 PTBB'S densities.