A glycine site antagonist, ZD9379, reduces number of spreading depressions and infarct size in rats with permanent middle cerebral artery occlusion.
OBJECTIVE
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 noncompetitive NMDA antagonists. We evaluated the effect of the glycine antagonist ZD9379 on SDs and brain infarction.


METHODS
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 per 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 per 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 after MCAO by continuous recording of cortical DC potentials and electrocorticogram. Infarct volume was measured 24 hours after MCAO by 2,3,5-triphenyltetrazolium chloride staining.


RESULTS
Corrected infarct volume was 90+/-72 mm3 (mean+/-standard deviation) in group 1, 105+/-46 mm3 in group 2, and 226+/-40 mm3 in group 3 (P<.001). The corresponding numbers of SDs in the three 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).


CONCLUSIONS
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.
Tatlisumak
T
T
Department of Neurology, Helsinki University Central Hospital, Finland. turgut.tatlisumak@helsinki.fi
Takano
K
K
Meiler
M R
MR
Fisher
M
M
D000704:Analysis of Variance; D000818:Animals; D002539:Cerebral Arterial Diseases / Q000150:complications / Q000473:pathology; D002540:Cerebral Cortex / Q000503:physiopathology; D002544:Cerebral Infarction / Q000188:drug therapy* / Q000473:pathology; D004396:Coloring Agents; D013181:Cortical Spreading Depression / Q000187:drug effects*; D004569:Electroencephalography; D005998:Glycine / Q000037:antagonists & inhibitors; D007262:Infusions, Intravenous; D007275:Injections, Intravenous; D002546:Ischemic Attack, Transient / Q000188:drug therapy / Q000473:pathology; D016014:Linear Models; D008297:Male; D016202:N-Methylaspartate / Q000037:antagonists & inhibitors; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D010919:Placebos; D011724:Pyridazines / Q000008:administration & dosage / Q000627:therapeutic use*; D011804:Quinolines / Q000008:administration & dosage / Q000627:therapeutic use*; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D018009:Receptors, Glycine / Q000037:antagonists & inhibitors*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D016037:Single-Blind Method; D013778:Tetrazolium Salts
D004396:Coloring Agents; D018696:Neuroprotective Agents; D010919:Placebos; D011724:Pyridazines; D011804:Quinolines; D018009:Receptors, Glycine; D016194:Receptors, N-Methyl-D-Aspartate; D013778:Tetrazolium Salts; C106383:ZD 9379; D016202:N-Methylaspartate; C009591:triphenyltetrazolium; D005998:Glycine