Article
Reduced inflammation under candesartan treatment following transient focal ischemia in rats and in astrocyte primary culture
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Published: | August 8, 2006 |
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Outline
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In recent studies, the AT1 receptor blocker (ARB), candesartan, was shown to reduce infarct size and improve neurological outcome after stroke. Since candesartan also exerts anti-inflammatory actions and since stroke is associated with an inflammatory response, we hypothesized that candesartan ameliorates ischemia-induced brain injury by an anti-inflammatory action.
Normotensive wistar rats were pretreated (p.o.; twice daily) for 5 days with 0,1 mg/kg candesartan or vehicle (0,9% NaCl). Middle cerebral artery occlusion (MCAO) was performed for 90 min with reperfusion. Infarct volume was measured by MRI 48h after ischemia followed by tissue asservation.
Candesartan significantly (p<0.05) improved neurological outcome (Garcia-scale) 24 and 48 h after stroke and reduced infarct volume by about 40% (p<0.05) compared to vehicle. Quantitative real-time PCR showed significant (p<0.05-0.001) reduction of inflammatory marker genes in candesartan-treated vs. vehicle-treated rats: TNF-alpha: -75%; CXCL-1: -60%; NF-kappaB: -18%.
For in vitro studies, a primary cell culture of neonatal astrocytes were prepared from neonatal cortex of Wistar rats (1-3 days postpartum) and kept for 10-14 days in culture. Cells were pretreated with 10-6 M candesartan or with vehicle for 24 h, stimulated with 500 ng/ml LPS for 2 h and additionally for 0,5; 2 and 24 h with Angiotensin II 10-8M. Real-time PCR showed a significant (50%) reduction of the inflammatory marker gene CXCL-1 under candesartan pretreatment vs. vehicle.
The results of our in vivo and in vitro studies identify anti-inflammtory mechanisms of candesartan which may contribute to the known beneficial effects of this ARB in cerebral ischemia.