Research reportTumor necrosis factor alpha expression produces increased blood–brain barrier permeability following temporary focal cerebral ischemia in mice
Introduction
The blood–brain barrier (BBB) functions to eliminate the entry of macromolecules, microbial pathogens, and circulating leukocytes into the central nervous system (CNS). BBB breakdown occurs following postischemic reperfusion in the brain 8, 10, 26. The integrity of the BBB may play an important role in the subsequent pathophysiology since BBB disruption relates closely to brain edema formation and cerebral infarction following postischemic reperfusion [5]. However, the mechanism of BBB disruption during postischemic reperfusion is unclear.
Tumor necrosis factor-alpha (TNFα), a 17 kD pleiotropic cytokine, appears to be involved in BBB disruption in brain injury [11]. In patients with bacterial meningitis, intrathecal TNFα levels correlate with the albumin quotient (Qalb), which is the best chemical indicator of barrier damage 28, 32. In patients with active multiple sclerosis, only those with detectable TNFα showed signs of BBB damage [29]. Administration of TNFα into the cerebrospinal fluid (CSF) of newborn pigs induced an extravasation of sodium fluorescein in different regions of the brain parenchyma [22]. Using a similar method in rats, intracisternal administration of TNFα causes circulating albumin to enter into the CSF [17]. In vitro studies have shown that exposure of differentiated brain capillary endothelial cells co-cultured with astrocytes to high concentrations of TNFα leads to a delayed increase in sucrose permeability and a selective reorganization of F-actin filaments [9].
TNFα levels in brain tissue, plasma, and CSF are elevated in several CNS disorders including cerebral ischemia 20, 21, 23, 33. The expression of TNFα mRNA increases from 30 min to 5 days after focal cerebral ischemia in the rat [34]. Early TNFα mRNA and immunohistochemical expression have been identified in neurons, microglia, and astrocytes following cerebral ischemia in both rats and mice 6, 20, 33, 34. Recent studies demonstrate that TNFα exacerbates focal ischemic brain injury and blocking endogenous TNF seems neuroprotective [4].
TNFα may be an important mediator in altering BBB permeability during postischemic reperfusion, but how postischemic reperfusion induces BBB disruption is still unknown. The purposes of this study are (1) to find the cellular source of TNFα following mouse temporary middle cerebral artery occlusion (MCAO), and (2) to demonstrate the relationship between TNFα overexpression and BBB disruption.
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Materials and methods
Procedures using laboratory animals were approved by the institutional animal care and use committee. Eighty-eight mice (N=6 to 8 in each group) were subjected to three experiments. In the double labeling immunofluorescence experiment, five groups of mice (N=6) were subjected to 1 h MCAO followed by 2, 6, 12, 24 and 48 h reperfusion. A control group of mice (N=6) received the surgical procedure without MCAO. In the albumin immunostaining experiment, six groups (0, 2, 6, 12, 24 and 48 h) of mice
Results
Physiological parameters The physiological parameters including blood pressure, blood gases, and body temperature were in the normal range during ischemia in the experimental mice. There were no significant differences in the physiological parameters between neutralizing antibody treated and control groups and they are all in the normal ranges (p>0.05, data not shown here).
CBF at the ischemic core region was reduced to 14±2% and 12±3% of the baseline 5 min after occlusion in the control group
Discussion
An alteration of BBB permeability following cerebral ischemia and reperfusion may be an important factor in the evolution of ischemic and reperfusion brain damage, especially in secondary damage [2]. BBB disruption after postischemic reperfusion depends upon the degree and the duration of ischemia [12]. Using the rat four vessel occlusion model, several investigators reported that 30 min occlusion followed by 1 or 3 h reperfusion resulted in BBB disruption and brain edema formation 10, 26.
Acknowledgements
These studies were supported by grants NS35089 (GYY) and NS23870 (ALB) from the National Institutes of Health. The authors thank Dr. Richard F. Keep for helpful discussion and Ms. Kathleen Donahoe for editorial assistance.
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