Artikel
Neuroprotection by synthetic dendritic polyglycerol sulfates (dPGS) in focal cerebral ischemia in mice
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Veröffentlicht: | 28. April 2011 |
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Gliederung
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Objective: Inflammation is one of the main pathomechanisms in stroke that leads to an increase in infarct volume over time (for review see Dirnagl et al, 1999 [1]; Muir et al., 2007 [2]; Wang et al., 2007 [3]). Recruitment of leukocytes via activation of the vascular endothelium and activation of the parenchymal complement system are central mechanisms in ischemia-induced inflammation. Synthetic dendritic polyglycerol sulfates (dPGS) are macromolecules inhibiting leukocytic L-selectin and endothelial P-selectin and interacting with the complement factors C3 and C5 via a multivalent binding mechanism [4]. We therefore tested whether dPGS is neuroprotective in focal cerebral ischemia.
Methods: C57Bl6 mice were subjected to 60 min of filamentous middle cerebral artery occlusion (MCAo), followed by re.perfusion for 48 h. Starting at the time of re-perfusion, animals were treated daily with subcutaneous dPGS (10 mg/kg body weight, n = 13; 30 mg/kg body weight, n = 13) or saline as vehicle (n = 11). Infarct volume analysis was performed 48 h after ischemia. Additional animals (n = 2) received fluorescence-labelled dPGS (Cy3 wavelength) at the time of re-perfusion (10 mg dPGS /kg body weight) and were decapitated 4 h later for histological examination of dPGS binding at early time point of inflammation.
Results: dPGS given acutely after transient brain ischemia/re-perfusion significantly reduced lesion size compared to vehicle control (infarct volume in mm3: 10 mg/kg: 133 ± 34, 30 mg/kg: 149 ± 23; saline: 186 ± 44; p < 0.05). At an early time point, fluorescent dPGS accumulated mainly in vascular endothelium, as demonstrated by the co-localization with the von Willebrand factor.
Conclusions: Dendritic PGS acts as neuroprotectant in MCAo in mice when given at the time of re-perfusion. Before considering dPGS as possible new therapeutic in stroke, further studies have to be performed investigating long-term functional outcome and delayed start of application.
References
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