Brain edema and tumor necrosis factor-like weak inducer of apoptosis in rats with cerebral ischemia

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Abstract

BACKGROUND:

Recent studies have demonstrated that tumor necrosis factor-like weak inducer of apoptosis (TWEAK) participates in brain edema. However, it is unclear whether blood-brain barrier (BBB) disruption is associated with TWEAK during the process of brain edema

OBJECTIVE:

To investigate the effects of TWEAK on BBB permeability in brain edema.

DESIGN, TIME AND SETTING:

An immunohistochemical observation, randomized, controlled animal experiment was performed at the Laboratory of Neurosurgical Anatomy, Xiangya Medical College, Central South University & Central Laboratory, Third Xiangya Hospital, Central South University between January 2006 and December 2007.

MATERIALS:

A total of 48 adult Wistar rats were randomly divided into three groups: normal control (n = 8), sham-operated (n = 8), and ischemia/reperfusion (n = 32). Rats from the ischemia/reperfusion group were randomly assigned to four subgroups according to different time points, i.e., 2 hours of ischemia followed by 6 hours (n = 8), 12 hours (n = 8), 1 day (n = 8), or 12 days (n = 8) of reperfusion.

METHODS:

Focal cerebral ischemia/reperfusion injury was induced by middle cerebral artery occlusion (MCAO) using the suture method in rats from the ischemia/reperfusion group. Thread was introduced at a depth of 17–19 mm. Rats in the sham-operated group were subjected to experimental procedures similar to the ischemia/reperfusion group; however, the introducing depth of thread was 10 mm. The normal control group was not given any intervention.

MAIN OUTCOME MEASURES:

TWEAK expression was examined by immunohistochemistry; brain water content on the ischemic side was calculated as the ratio of dry to wet tissue weight; BBB permeability was measured by Evans blue extravasation.

RESULTS:

A total of eight rats died prior to and after surgery and an additional eight rats were randomly entered into the study. Thus 48 rats were included in the final analysis. In the ischemia/reperfusion group, TWEAK-positive cells were present in the ischemic penumbra surrounding the lamellar necrotic region in the right cerebral hemisphere at 6 hours reperfusion and increased thereafter; by 2 days reperfusion they had reached a peak level, which was significantly higher than the sham-operated and normal control groups (P < 0.05). At 6 hours reperfusion, both brain water content and Evans blue extravasation showed the same tendency for change as TWEAK expression. Pearson correlation analysis results revealed that the degree of TWEAK expression was positively correlated with brain water content (r = 0.892, P < 0.05).

CONCLUSION:

The present results confirmed that TWEAK was involved in BBB disruption and participated in brain edema following cerebral ischemia.

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