title: Autoradiographic analysis of 3H-MK-801 (dizocilpine) in vivo uptake and in vitro binding after focal cerebral ischemia in the rat.
abstract: The clinical utility of N-methyl-D-aspartate (NMDA) receptor antagonists is now being assessed in ischemic brain injury in humans. The uptake and retention of NMDA receptor antagonists in ischemic tissue will influence the design of clinical trials. The effects of permanent occlusion of the middle cerebral artery, induced 15 minutes prior to isotope administration, on the uptake of 3H-MK-801 (dizocilpine) have been assessed in the rat with quantitative autoradiography. In a group of three rats at 15 minutes after the intravenous administration of 3H-MK-801, the level (mean +/- standard error of the mean) of isotopic tracer in the ischemic cortex and striatum was markedly less than that in the contralateral hemisphere (ipsilateral vs. contralateral caudate nucleus: 22 +/- 4 vs. 84 +/- 11 pmol/gm, p less than 0.01). In contrast, in a group of five rats at 60 minutes after the intravenous administration of 3H-MK-801, the level of isotopic tracer in the ischemic cortex and striatum was greater than that in the contralateral hemisphere (ipsilateral vs. contralateral caudate nucleus: 52 +/- 8 vs. 32 +/- 4 pmol/gm, p less than 0.05). There were no significant alterations in the specific binding of 3H-MK-801 in vitro in ischemic tissue at equivalent times. The early uptake of 3H-MK-801 into the central nervous system is dominated by the level of cerebral blood flow, whereas at later times after administration enhancement of MK-801 binding by elevated extracellular glutamate concentrations appears to be more important in determining the level of the drug in ischemic tissue.
authors.affiliation: Wellcome Surgical Institute, University of Glasgow, Scotland.
authors.forename: M C
authors.initials: MC
authors.lastname: Wallace
authors.forename: G M
authors.initials: GM
authors.lastname: Teasdale
authors.forename: J
authors.initials: J
authors.lastname: McCulloch
mesh_terms: D000818:Animals; D001345:Autoradiography; D016291:Dizocilpine Maleate / Q000378:metabolism* / Q000493:pharmacokinetics*; D066298:In Vitro Techniques; D002546:Ischemic Attack, Transient / Q000378:metabolism*; D008297:Male; D011869:Radioligand Assay; D051381:Rats; D011919:Rats, Inbred Strains; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D014316:Tritium
chemical_list: D016194:Receptors, N-Methyl-D-Aspartate; D014316:Tritium; D016291:Dizocilpine Maleate