Article
Effect of leukotriene inhibitors in a brain contusion model
Effekt von Leukotrien-Synthese-Inhibitioren im Hirnkontusionsmodell
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Published: | April 11, 2007 |
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Objective: Previous research showed an increase of leukotriene levels in CSF following cortical contusion injury preceding the peak of contusion growth and brain edema. To test the hypothesis that leukotrienes are involved in the process of increasing contusion size and brain edema development, we investigated the effect of MK-886, an inhibitor of 5-lipoxygenase (5-LO) synthesis and of Boscari, a competitive non-redox 5-LO inhibitor.
Methods: 92 SD rats were investigated at 24h and 72h after Controlled Cortical Impact injury. Controls received vehicle (Group C, n=32), treated animals MK-886 5mg/kg, (Group M, n=28) or Boscari 100 mg/kg, (Group B, n=28) 1h before trauma and every 8h thereafter. MRI scans (Philips Intera, 1mm slice, T2, DWI, n=42) or ICP determination (n=50) was done. Fluorescence staining with Fluoro-Jade B was carried out. Triple immunofluorescence labelling enabled simultaneous visualization of neurones, astrocytes, microglia, macrophages and vessels. Lesion size was determined in T2 MRI scans and Fluoro-Jade stained brain sections.
Results: Lesion volume in T2 images decreased in both treatment groups (B and M) at 24h already, with significant differences found after 72h (74.6±17.1 mm3 and 72.8±18.3 mm3 vs. 93.4±11.9 mm3, p<0.02). The mean ADC in the contusion area increased by 26% (830.0±187.3 vs. 658.1±139.9 contralateral, p<0.001). At 72h there was a strong trend for lower ADCs in treatment groups (768±140 and 774±186, respectively, vs. 937±168 in controls p=0.054).Triple immunfluorescence staining allowed clear delineation of the contusion. At 72h the contusion core, depleted of neurons, showed a rarefication of vasculature and increased presence of macrophages. The bordering penumbra showed an up-regulation of glial and microglial cells. Lesions size in Fluoro-Jade stains was smaller in treatment groups (8.9±1.9 mm2 and 9.8±1.0 mm2 versus 11.2±0.9 mm2). ICP values were not raised in any group.
Conclusions: Inhibition of leukotriene synthesis, irrespective of the mode of action, leads to an attenuation of contusion growth as measured 72h after trauma. The trend towards a decrease in ADC in the contused area following treatment is compatible with a smaller area of contusion. First immunohistochemical analysis seems to confirm the MRI results. Thus, further research into leukotriene inhibition as a possible way to interfere with an increase in the contusion seems justified.