title: Reduced functional deficits, neuroinflammation, and secondary tissue damage after treatment of stroke by nonerythropoietic erythropoietin derivatives.
abstract: Carbamylerythropoietin (CEPO) does not bind to the classical erythropoietin (EPO) receptor. Nevertheless, similarly to EPO, CEPO promotes neuroprotection on the histologic level in short-term stroke models. In the present study, we investigated whether CEPO and other nonerythropoietic EPO analogs could enhance functional recovery and promote long-term histologic protection after experimental focal cerebral ischemia. Rats were treated with the compounds after focal cerebral ischemia. Animals survived 1, 7, or 60 days and underwent behavioral testing (sensorimotor and foot-fault tests). Brain sections were stained and analyzed for Iba-1, myeloperoxidase, Tau-1, CD68 (ED1), glial fibrillary acidic protein (GFAP), Fluoro-Jade B staining, and overall infarct volumes. Treatment with CEPO reduced perifocal microglial activation (P<0.05), polymorphomonuclear cell infiltration (P<0.05), and white matter damage (P<0.01) at 1 day after occlusion. Carbamylerythropoietin-treated rats showed better functional recovery relative to vehicle-treated animals as assessed 1, 7, 14, 28, and 50 days after stroke. Both GFAP and CD68 were decreased within the ipsilateral thalamus of CEPO-treated animals 60 days postoperatively (P<0.01 and P<0.05, respectively). Furthermore, behavioral analysis showed efficacy of CEPO treatment even if administered 24 h after the stroke. Other nonerythropoietic derivatives such as carbamylated darbepoetin alfa and the mutant EPO-S100E were also found to protect against ischemic damage and to improve postischemic neurologic function. In conclusion, these results show that postischemic intravenous treatment with nonerythropoietic EPO derivatives leads to improved functional recovery, which may be linked to their long-term effects against neuroinflammation and secondary tissue damage.
authors.affiliation: Mario Negri Institute of Pharmacological Research, Milan, Italy.
authors.forename: Pia
authors.initials: P
authors.lastname: Villa
authors.forename: Johan
authors.initials: J
authors.lastname: van Beek
authors.forename: Anna Kirstine
authors.initials: AK
authors.lastname: Larsen
authors.forename: Jens
authors.initials: J
authors.lastname: Gerwien
authors.forename: Søren
authors.initials: S
authors.lastname: Christensen
authors.forename: Anthony
authors.initials: A
authors.lastname: Cerami
authors.forename: Michael
authors.initials: M
authors.lastname: Brines
authors.forename: Marcel
authors.initials: M
authors.lastname: Leist
authors.forename: Pietro
authors.initials: P
authors.lastname: Ghezzi
authors.forename: Lars
authors.initials: L
authors.lastname: Torup
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000473:pathology; D002545:Brain Ischemia / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D004921:Erythropoietin / Q000031:analogs & derivatives* / Q000627:therapeutic use; D006801:Humans; D007150:Immunohistochemistry; D007249:Inflammation / Q000188:drug therapy; D008297:Male; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D051381:Rats; D020127:Recovery of Function / Q000187:drug effects
chemical_list: D018696:Neuroprotective Agents; C488171:carbamylated erythropoietin; D004921:Erythropoietin