title: Combination stroke therapy in the mouse with blood-brain barrier penetrating IgG-GDNF and IgG-TNF decoy receptor fusion proteins.
abstract: 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.
authors: Department of Medicine, UCLA, Los Angeles, CA 90024, USA.
authors: Rachita K
authors: RK
authors: Sumbria
authors: Ruben J
authors: RJ
authors: Boado
authors: William M
authors: WM
authors: Pardridge
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier; D004359:Drug Therapy, Combination; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000235:genetics / Q000627:therapeutic use*; D007074:Immunoglobulin G / Q000235:genetics; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000627:therapeutic use*; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use; D020521:Stroke / Q000188:drug therapy* / Q000473:pathology
chemical_list: D051100:Glial Cell Line-Derived Neurotrophic Factor; D007074:Immunoglobulin G; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D011993:Recombinant Fusion Proteins