Stroke therapy may be optimized by combination therapy with both a neuroprotective neurotrophin and an anti-inflammatory agent. In the present work, the model neurotrophin is glial cell line-derived neurotrophic factor (GDNF), and the model anti-inflammatory agent is the type II tumor necrosis factor receptor (TNFR) decoy receptor. Both the GDNF and the TNFR are large molecules that do not cross the blood-brain barrier (BBB), which is intact in the early hours after stroke when neural rescue is still possible. The GDNF and the TNFR decoy receptor were re-engineered for BBB transport as IgG fusion proteins, wherein the GDNF or the TNFR are fused to the heavy chain of a chimeric monoclonal antibody (MAb) against the mouse transferrin receptor (TfR), and these fusion proteins are designated cTfRMAb-GDNF and cTfRMAb-TNFR, respectively. Mice were treated intravenously with (a) saline, (b) GDNF alone, (c) the cTfRMAb-GDNF fusion protein alone, or (d) the combined cTfRMAb-GDNF and cTfRMAb-TNFR fusion proteins, following a 1-h reversible middle cerebral artery occlusion (MCAO). The cTfRMAb-GDNF fusion protein alone caused a significant 25% and 30% reduction in hemispheric and cortical stroke volumes. Combined treatment with the cTfRMAb-GDNF and cTfRMAb-TNFR fusion proteins caused a significant 54%, 69% and 30% reduction in hemispheric, cortical and subcortical stroke volumes. Conversely, intravenous GDNF had no therapeutic effect. In conclusion, combination treatment with BBB penetrating IgG-GDNF and IgG-TNFR fusion proteins enhances the therapeutic effect of single treatment with the IgG-GDNF fusion protein following delayed intravenous administration in acute stroke.
Copyright © 2013 Elsevier B.V. All rights reserved.