Tumor necrosis factor-alpha increases cerebral blood flow and ultrastructural capillary damage through the release of nitric oxide in the rat brain

Tumor necrosis factor-alpha (TNF alpha) is a proinflammatory cytokine implicated in cerebrovascular pathology. The aim of the present study was to characterize the simultaneous effects of an intracarotid administration of TNFa on cerebral blood flow (CBF) and the ultrastructure of the blood-brain barrier (BBB) and to determine whether nitric oxide (NO) is a mediator of the TNF alpha-induced alterations in CBF and BBB. TNF alpha (2.5 mu g/ kg) or saline was infused into the right common carotid artery of male Wistar rats (n = 70). NO production was inhibited with L-NAME (20 mg/kg, i.v.). CBF was monitored for 2 h with laser-Doppler flowmetry. Tissue samples were taken from the unilateral frontoparietal cortex and prepared for electron microscopy. The proportion of capillaries with swollen astrocytic endfeet and the lumen diameter of the capillaries were measured. TNF alpha significantly increased CBF, which reached a maximum of 190% of the baseline 1 h after the cessation of TNF alpha infusion. L-NAME completely prevented the increase in CBF. TNF alpha elevated the swelling of the astrocytic endfeet from a baseline value of 22.4 +/- 9.35% to 64.9 +/- 3.16%. The administration of L-NAME before TNF alpha infusion prevented the astrocytic swelling. These results demonstrate that TNF alpha increases CBF and the swelling of astrocytes through the production of NO. Our data additionally demonstrate that the breakdown of the BBB by circulating TNF alpha may involve the astrocytic endfeet. (c) 2006 Elsevier Inc. All rights reserved.