title: Cytotoxic edema is independent of NMDA ion channel activation following middle cerebral artery occlusion (MCAO). An in vivo autoradiographic and MRI study.
abstract: Massive glutamate release is an important factor leading to ionic imbalance after occlusive stroke, which in turn contributes to cytotoxic edema formation. Currently, measurements of cytotoxic edema using 'diffusion weighted' MRI, is being used in human stroke studies, as a 'surrogate' end point for neuroprotective drug trials, including studies with glutamate antagonists. However, it is not fully understood to what extent glutamate-mediated N-methyl-D-aspartate (NMDA) receptor activation is related to 'cytotoxic' edema formation, and thus, to what degree apparent diffusion coefficient (ADC) changes, assessed by magnetic resonance imaging with 'ACD mapping', represent NMDA receptor activation. To study this relationship, four cats underwent permanent middle cerebral artery occlusion (MCAO). Edema formation was investigated using MRI with 'ACD mapping', while NMDA receptor activation was simultaneously detected in the same animals, using radio labeled 125IodoMK-801, which binds only in activated and open NMDA channels. At 5 h post-occlusion, a large area of edema could be found with significantly lower ADC values in the core and penumbral area of the ischemic lesion when compared to contralateral values. On corresponding sections of the feline brains, increased 125I-MK-801 binding was found in the infarct penumbra. However, there was no significant topographical correlation between ADC values and measured radioactivity. The results indicate that there is not a significant linkage between NMDA receptor activation and 'cytotoxic' edema following permanent MCAO. The detection of a large area of NMDA channel activation within regions of low ADC does however indicate an area of 'penumbral' ischemia susceptible to treatment with NMDA channel blockers.
authors.affiliation: Division of Neurosurgery, Medical College of Virginia, Virginia Commonwealth University, PO Box 980631, 1200 E. Broad Street, Richmond, VA 23298-0631, USA.
authors.forename: Xiao
authors.initials: X
authors.lastname: Di
authors.forename: Oscar L
authors.initials: OL
authors.lastname: Alves
authors.forename: Ross
authors.initials: R
authors.lastname: Bullock
mesh_terms: D000818:Animals; D001345:Autoradiography; D001929:Brain Edema / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000473:pathology*; D002415:Cats; D038524:Diffusion Magnetic Resonance Imaging; D016291:Dizocilpine Maleate / Q000378:metabolism / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000378:metabolism / Q000494:pharmacology; D005260:Female; D020244:Infarction, Middle Cerebral Artery / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000473:pathology*; D007457:Iodine Radioisotopes; D008297:Male; D011877:Radionuclide Imaging; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*
chemical_list: D018691:Excitatory Amino Acid Antagonists; D007457:Iodine Radioisotopes; D016194:Receptors, N-Methyl-D-Aspartate; D016291:Dizocilpine Maleate