Difluoromethylornithine Decreases Postischemic Brain Edema and Blood-Brain Barrier Breakdown

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Abstract

ABSTRACT

BRAIN POLYAMINES HAVE been associated with posttraumatic vasogenic edema and blood-brain barrier (BBB) breakdown seen in some models of brain injury. We hypothesized that the inhibition of the enzyme responsible for polyamine production with the decarboxylase difluoromethylornithine (DFMO) may decrease BBB breakdown after a focal brain ischemic stroke. Thirty-two cats underwent 8 hours of middle cerebral artery occlusion and one of four treatments: sham operation (Sham), ischemia (Isc), ischemia/DFMO (Isc/DF), and ischemia/DFMO/putrescine (Isc/DF/PU). The regional brain specific gravity and the volume of Evans blue (EB) extravasation were measured at the time of death. The groups were monitored for temperature, heart rate, blood pressure, and arterial blood gases, and the values did not differ outside normal physiological ranges. EB results were expressed as the percentage of the hemisphere stained and showed the following: Sham, 2.23%; Isc, 32.8%; Isc/DF, 5.6%; Isc/DF/PU, 36.3%. As a measure of BBB, ischemia increased EB staining; DFMO pretreatment decreased the amount of EB staining to control levels; and the polyamine putrescine abolished the protective effect of DFMO (all significant at P = 0.05). DFMO pretreatment also resulted in a significant (P = 0.05) return to control values for specific gravity in the EB-stained regions (1.0328) of ischemic animals. This effect was present primarily in the white matter. Treatment with DFMO, an ornithine decarboxylase inhibitor, significantly decreased postischemic BBB breakdown and vasogenic edema in this model.

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