YM872, a highly water-soluble AMPA receptor antagonist, preserves the hemodynamic penumbra and reduces brain injury after permanent focal ischemia in rats.
OBJECTIVE
We recently described an image analysis technique based on the temporal correlation mapping (TCM) of injected contrast agents that can be used to distinguish the hemodynamic core and hemodynamic penumbra after focal ischemia. In this study we used this technique for the first time to investigate the effects of the water-soluble AMPA receptor antagonist YM872 in permanent focal ischemia.


METHODS
Fischer 344 rats were subjected to permanent occlusion of the middle cerebral artery. Approximately 30 minutes after ischemia, functional CT images were collected with the use of a dynamic scanning protocol with bolus injections of nonionic contrast agent iohexol (1 mL/kg). TCM analysis defined the distributions of hemodynamic core and hemodynamic penumbra. Cerebral perfusion indices were calculated on the basis of the area under the first-pass transit curves. One hour after ischemia, animals were randomly treated with YM872 (n=8, 20 mg/kg per hour over 4 hours) or normal saline (n=10). Twenty-four hours later, neurological deficits were evaluated, and conventional CT and triphenyltetrazolium chloride staining were used to define volumes of ischemic damage.


RESULTS
At 24 hours after ischemia, hypodense lesions were visible on conventional CT scans that were highly correlated with triphenyltetrazolium chloride lesion volumes. YM872 improved neurological deficits and reduced volumes of ischemic damage in cortex (90+/-14 versus 170+/-16 mm3 in controls) but not striatum (57+/-14 versus 79+/-6 mm3 in controls). Comparison of early TCM images with conventional CT scans of ischemic injury showed that the hemodynamic core was always damaged in all rats. In controls, 54% of the tissue within the hemodynamic penumbra evolved into ischemic damage compared with 24% in YM872-treated rats. Furthermore, the perfusion index corresponding to the ischemic damage threshold was significantly reduced by YM872 (28+/-2% versus 37+/-2% in controls).


CONCLUSIONS
These results indicate that YM872 is a neuroprotective compound that ameliorates the deterioration of the hemodynamic penumbra after focal ischemia.
Shimizu-Sasamata
M
M
Departments of Neurosurgery and Neurology, Stroke and Neurovascular Regulation Laboratory, Harvard Medical School, Charlestown, MA.
Kano
T
T
Rogowska
J
J
Wolf
G L
GL
Moskowitz
M A
MA
Lo
E H
EH
D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000473:pathology*; D002545:Brain Ischemia / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology*; D002560:Cerebrovascular Circulation / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D007093:Imidazoles / Q000627:therapeutic use*; D008297:Male; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D011810:Quinoxalines / Q000627:therapeutic use*; D051381:Rats; D011916:Rats, Inbred F344; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors*; D012995:Solubility; D013997:Time Factors; D014057:Tomography, X-Ray Computed; D014867:Water
D007093:Imidazoles; D018696:Neuroprotective Agents; D011810:Quinoxalines; D018091:Receptors, AMPA; D014867:Water; C110629:YM 872