title: Intracerebroventricularly delivered VEGF promotes contralesional corticorubral plasticity after focal cerebral ischemia via mechanisms involving anti-inflammatory actions.
abstract: Vascular endothelial growth factor (VEGF) has potent angiogenic and neuroprotective effects in the ischemic brain. Its effect on axonal plasticity and neurological recovery in the post-acute stroke phase was unknown. Using behavioral tests combined with anterograde tract tracing studies and with immunohistochemical and molecular biological experiments, we examined effects of a delayed i.c.v. delivery of recombinant human VEGF(165), starting 3 days after stroke, on functional neurological recovery, corticorubral plasticity and inflammatory brain responses in mice submitted to 30 min of middle cerebral artery occlusion. We herein show that the slowly progressive functional improvements of motor grip strength and coordination, which are induced by VEGF, are accompanied by enhanced sprouting of contralesional corticorubral fibres that branched off the pyramidal tract in order to cross the midline and innervate the ipsilesional parvocellular red nucleus. Infiltrates of CD45+ leukocytes were noticed in the ischemic striatum of vehicle-treated mice that closely corresponded to areas exhibiting Iba-1+ activated microglia. VEGF attenuated the CD45+ leukocyte infiltrates at 14 but not 30 days post ischemia and diminished the microglial activation. Notably, the VEGF-induced anti-inflammatory effect of VEGF was associated with a downregulation of a broad set of inflammatory cytokines and chemokines in both brain hemispheres. These data suggest a link between VEGF's immunosuppressive and plasticity-promoting actions that may be important for successful brain remodeling. Accordingly, growth factors with anti-inflammatory action may be promising therapeutics in the post-acute stroke phase.
authors.affiliation: Department of Neurology, University Hospital, Essen, Germany.
authors.forename: Josephine
authors.initials: J
authors.lastname: Herz
authors.forename: Raluca
authors.initials: R
authors.lastname: Reitmeir
authors.forename: Sabine I
authors.initials: SI
authors.lastname: Hagen
authors.forename: Barbara S
authors.initials: BS
authors.lastname: Reinboth
authors.forename: Zeyun
authors.initials: Z
authors.lastname: Guo
authors.forename: Anil
authors.initials: A
authors.lastname: Zechariah
authors.forename: Ayman
authors.initials: A
authors.lastname: ElAli
authors.forename: Thorsten R
authors.initials: TR
authors.lastname: Doeppner
authors.forename: Marco
authors.initials: M
authors.lastname: Bacigaluppi
authors.forename: Stefano
authors.initials: S
authors.lastname: Pluchino
authors.forename: Ulkan
authors.initials: U
authors.lastname: Kilic
authors.forename: Ertugrul
authors.initials: E
authors.lastname: Kilic
authors.forename: Dirk M
authors.initials: DM
authors.lastname: Hermann
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage*; D001710:Biotin / Q000031:analogs & derivatives; D001929:Brain Edema / Q000209:etiology / Q000517:prevention & control; D002540:Cerebral Cortex / Q000187:drug effects* / Q000473:pathology; D002544:Cerebral Infarction / Q000209:etiology / Q000517:prevention & control; D016207:Cytokines / Q000378:metabolism; D003911:Dextrans; D004195:Disease Models, Animal; D007839:Functional Laterality / Q000187:drug effects*; D005786:Gene Expression Regulation / Q000187:drug effects; D018737:Hand Strength / Q000502:physiology; D020244:Infarction, Middle Cerebral Artery / Q000150:complications* / Q000188:drug therapy / Q000473:pathology; D007276:Injections, Intraventricular / Q000379:methods; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D009410:Nerve Degeneration / Q000209:etiology / Q000517:prevention & control; D009434:Neural Pathways / Q000187:drug effects; D009473:Neuronal Plasticity / Q000187:drug effects*; D009942:Organometallic Compounds; D009943:Organophosphorus Compounds; D012012:Red Nucleus / Q000187:drug effects* / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A / Q000008:administration & dosage*
chemical_list: D000893:Anti-Inflammatory Agents; D016207:Cytokines; D003911:Dextrans; D009942:Organometallic Compounds; D009943:Organophosphorus Compounds; D042461:Vascular Endothelial Growth Factor A; C076397:biotinylated dextran amine; C066850:Cascade Blue; D001710:Biotin