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.
Earley
B
B
Department of Pharmacology, University College, Galway, Ireland.
Canney
M
M
Clune
B
B
Caldwell
M
M
Leonard
B E
BE
Junien
J L
JL
D000818:Animals; D002544:Cerebral Infarction / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D002934:Cinnamates / Q000494:pharmacology; D003521:Cyclopropanes / Q000494:pharmacology; D016291:Dizocilpine Maleate / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D002546:Ischemic Attack, Transient / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D007546:Isoquinolines / Q000378:metabolism; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D018696:Neuroprotective Agents / Q000494:pharmacology*; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D009930:Organic Chemicals; D010880:Piperidines / Q000494:pharmacology; D011869:Radioligand Assay; D017480:Receptors, sigma / Q000187:drug effects*
D002934:Cinnamates; D003521:Cyclopropanes; D018691:Excitatory Amino Acid Antagonists; D007546:Isoquinolines; D018696:Neuroprotective Agents; D009930:Organic Chemicals; D010880:Piperidines; D017480:Receptors, sigma; C102336:JO 1994; C102337:JO 1997; D016291:Dizocilpine Maleate; D019001:Nitric Oxide Synthase; C010739:ifenprodil; C065310:igmesine; C037850:PK 11195