From the Departments of Neurology and Radiology, Neuroprotection Research
Laboratory (T.K., E.H.L.); Departments of Neurosurgery and Neurology, Stroke
and Neurovascular Regulation Laboratory (M.S-S., M.A.M.); and Department of
Radiology, Center for Imaging and Pharmaceutical Research (J.R., G.L.W.),
Massachusetts General Hospital, Harvard Medical School, Charlestown, Mass.
Correspondence to Eng H. Lo, PhD, Departments of Neurology and Radiology, Neuroprotection Research Laboratory, Harvard Medical School, Massachusetts General Hospital, 149 13th St, Room 2322, Charlestown, MA 02129. E-mail eng{at}cipr.mgh.harvard.edu
Background and Purpose—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.
Laboratory
of Cerebrovascular Biology and Stroke,
Department of Neurology,
University of Minnesota,
Minneapolis, Minnesota
© 1998 American Heart Association, Inc.
Original Contributions
YM872, a Highly Water-Soluble AMPA Receptor Antagonist, Preserves the Hemodynamic Penumbra and Reduces Brain Injury After Permanent Focal Ischemia in Rats
Editorial Comment
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