NMDA Receptors Mediate Activation of Polyamine Synthesis and Blood-Brain Barrier Breakdown after Cold Injury

Abstract

Cold injury (CI) of cerebral cortex is an extensively used model for focal bloodbrain barrier (BBB) breakdown and spreading vasogenic brain edema (Klatzo et al., 1981). CI also induces changes in neuronal function and metabolism, including epileptic discharges and slow (delta) wave activity (Pappius & McCann, 1969) and a depression of local cerebral glucose metabolism (Pappius, 1981). We found that focal CI of rat cerebral cortex induces a biphasic increase in polyamine (PA) levels and the activity of their regulatory synthetic enzyme ornithine decarboxylase (ODC), which converts ornithine to putrescine, in perilesional cortex involving both capillaries and brain cells (Koenig et al., 1989a). In the first phase, ODC activity and PA levels increase transiently between 1-5 min after CI. A secondary rise in ODC activity and PA levels occurs after a lag period of 4 h which lasts for more than 72 h. Agents which directly or indirectly inhibit CI-induced stimulation of ODC activity and PA accumulation also prevent BBB breakdown, monitored by fluorescein and horseradish peroxidase (HRP) leakage, while exogenous putrescine reverses the effects of ODC inhibition and restores BBB breakdown. These agents include the specific suicide ODC inhibitor a-difluoromethylornithine (DFMO), (Metcalf et al., 1978; Koenig et al., 1983, 1989a; Trout et al., 1986), verapamil, dexamethasone, and aspirin (Koenig et al., 1989a).