title: A glycine site antagonist ZD9379 reduces number of spreading depressions and infarct size in rats with permanent middle cerebral artery occlusion.
abstract: Spreading depressions (SDs) occur in experimental focal ischemia and contribute to lesion evolution. N-methyl-D-aspartate (NMDA) antagonists inhibit SDs and reduce infarct size. The glycine site on the NMDA receptor complex offers a therapeutic target for acute focal ischemia, potentially devoid of many side effects associated with competitive and non-competitive NMDA antagonists. We evaluated the effect of the glycine antagonist, ZD9379, on SDs and brain infarction. Male Sprague-Dawley rats (n = 18) weighing 290 to 340 g undergoing permanent middle cerebral artery occlusion (MCAO) were randomly and blindly assigned to receive drug or placebo: Group 1 (pre-MCAO treatment group, n = 5) a 5 mg/kg bolus of ZD9379 over 5 minutes followed by 5 mg/kg/hour drug infusion for 4 hours beginning 30 minutes before MCAO; Group 2 (post-MCAO treatment group, n = 7) a 5 mg/kg bolus of ZD9379 30 minutes after MCAO followed by 5 mg/kg/hour drug infusion for 4 hours; and Group 3 (control group, n = 6) vehicle for 5 hours beginning 30 minutes before MCAO. SDs were monitored electrophysiologically for 4.5 hours following MCAO by continuous recording of cortical direct current (DC) potentials and electrocorticogram (ECoG). Infarct volume was measured 24 hours after MCAO by 2,3,5 triphenyltetrazolium chloride (TTC) staining. Corrected infarct volume was 90 +/- 72 mm3 (mean +/- standard deviation) in Group 1, 105 +/- 46 mm3 in Group 2, and 226 +/- 41 mm3 in Group 3 (P < .001). The corresponding numbers of SDs in the 3 groups were 8.2 +/- 5.8, 8.1 +/- 2.5, and 16.0 +/- 5.1, respectively (P < .01). When all animals (n = 18) were analyzed, infarct volumes and the number of SDs were significantly correlated (r = .68, P = .002). This study demonstrated that ZD9379 initiated before or after MCAO significantly reduced the number of SDs and infarct volume in a permanent focal ischemia model, implying that ZD9379 is neuroprotective and its neuroprotective effect may be related to inhibiting ischemia-related SDs.
authors.affiliation: Department of Neurology, Helsinki University Central Hospital, Helsinki, Finland.
authors.forename: T
authors.initials: T
authors.lastname: Tatlisumak
authors.forename: K
authors.initials: K
authors.lastname: Takano
authors.forename: M R
authors.initials: MR
authors.lastname: Meiler
authors.forename: M
authors.initials: M
authors.lastname: Fisher
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000503:physiopathology; D001929:Brain Edema / Q000503:physiopathology*; D013181:Cortical Spreading Depression / Q000187:drug effects*; D020244:Infarction, Middle Cerebral Artery / Q000503:physiopathology*; D007262:Infusions, Intravenous; D008297:Male; D018696:Neuroprotective Agents / Q000494:pharmacology*; D011724:Pyridazines / Q000494:pharmacology*; D011804:Quinolines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018009:Receptors, Glycine / Q000037:antagonists & inhibitors*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*
chemical_list: D018696:Neuroprotective Agents; D011724:Pyridazines; D011804:Quinolines; D018009:Receptors, Glycine; D016194:Receptors, N-Methyl-D-Aspartate; C106383:ZD 9379