title: Post-acute delivery of erythropoietin induces stroke recovery by promoting perilesional tissue remodelling and contralesional pyramidal tract plasticity.
abstract: The promotion of post-ischaemic motor recovery remains a major challenge in clinical neurology. Recently, plasticity-promoting effects have been described for the growth factor erythropoietin in animal models of neurodegenerative diseases. To elucidate erythropoietin's effects in the post-acute ischaemic brain, we examined how this growth factor influences functional neurological recovery, perilesional tissue remodelling and axonal sprouting of the corticorubral and corticobulbar tracts, when administered intra-cerebroventricularly starting 3 days after 30 min of middle cerebral artery occlusion. Erythropoietin administered at 10 IU/day (but not at 1 IU/day), increased grip strength of the contralesional paretic forelimb and improved motor coordination without influencing spontaneous locomotor activity and exploration behaviour. Neurological recovery by erythropoietin was associated with structural remodelling of ischaemic brain tissue, reflected by enhanced neuronal survival, increased angiogenesis and decreased reactive astrogliosis that resulted in reduced scar formation. Enhanced axonal sprouting from the ipsilesional pyramidal tract into the brainstem was observed in vehicle-treated ischaemic compared with non-ischaemic animals, as shown by injection of dextran amines into both motor cortices. Despite successful remodelling of the perilesional tissue, erythropoietin enhanced axonal sprouting of the contralesional, but not ipsilesional pyramidal tract at the level of the red and facial nuclei. Moreover, molecular biological and histochemical studies revealed broad anti-inflammatory effects of erythropoietin in both hemispheres together with expression changes of plasticity-related molecules that facilitated contralesional axonal growth. Our study establishes a plasticity-promoting effect of erythropoietin after stroke, indicating that erythropoietin acts via recruitment of contralesional rather than of ipsilesional pyramidal tract projections.
authors.affiliation: Dementia and Ageing Disorders, Department of Neurology, University Hospital Essen, Hufelandstr 55, D-45122 Essen, Germany. dirk.hermann@uk-essen.de
authors.forename: Raluca
authors.initials: R
authors.lastname: Reitmeir
authors.forename: Ertugrul
authors.initials: E
authors.lastname: Kilic
authors.forename: Ulkan
authors.initials: U
authors.lastname: Kilic
authors.forename: Marco
authors.initials: M
authors.lastname: Bacigaluppi
authors.forename: Ayman
authors.initials: A
authors.lastname: ElAli
authors.forename: Giuliana
authors.initials: G
authors.lastname: Salani
authors.forename: Stefano
authors.initials: S
authors.lastname: Pluchino
authors.forename: Max
authors.initials: M
authors.lastname: Gassmann
authors.forename: Dirk M
authors.initials: DM
authors.lastname: Hermann
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D002545:Brain Ischemia / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D004921:Erythropoietin / Q000627:therapeutic use*; D005106:Exploratory Behavior / Q000187:drug effects; D018737:Hand Strength / Q000502:physiology; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D009473:Neuronal Plasticity / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D020127:Recovery of Function / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction; D045442:Rotarod Performance Test; D020521:Stroke / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology
chemical_list: D004921:Erythropoietin