Intracerebroventricularly delivered VEGF promotes contralesional corticorubral plasticity after focal cerebral ischemia via mechanisms involving anti-inflammatory actions

Josephine Herz, Raluca Reitmeir, Sabine I. Hagen, Barbara S. Reinboth, Zeyun Guo, Anil Zechariah, Ayman ElAli, Thorsten R. Doeppner, Marco Bacigaluppi, Stefano Pluchino, Ülkan Kilic, Ertugrul Kilic, Dirk M. Hermann

Research output: Contribution to journalArticlepeer-review

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 3days after stroke, on functional neurological recovery, corticorubral plasticity and inflammatory brain responses in mice submitted to 30min 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 30days 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.

Original languageEnglish
Pages (from-to)1077-1085
Number of pages9
JournalNeurobiology of Disease
Volume45
Issue number3
DOIs
Publication statusPublished - Mar 2012

Keywords

  • Axonal sprouting
  • Brain plasticity
  • Ischemic stroke
  • Neuroinflammation
  • Neuroprotection

ASJC Scopus subject areas

  • Neurology

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