Neuroprotective effect of erythropoietin and darbepoetin alfa after experimental intracerebral hemorrhage.
OBJECTIVE
Intracerebral hemorrhage (ICH) is a devastating clinical syndrome for which no truly efficacious therapy has yet been identified. In preclinical studies, erythropoietin (EPO) and its long-lasting analog, darbepoetin alfa, have been demonstrated to be neuroprotective in several models of neuronal insult. The objectives of this study were to analyze whether the systemic administration of recombinant human EPO (rHuEPO) and its long-lasting derivative darbepoetin alfa expedited functional recovery and brain damage in a rat model of ICH.


METHODS
Experimental ICH was induced in rats by injecting autologous blood into the right striatum under stereotactic guidance. Subsequently, animals underwent placebo treatment, daily injections of rHuEPO, or weekly injections of darbepoetin alfa. Animals were killed 14 days after injury.


RESULTS
Both rHuEPO and darbepoetin alfa were effective in reducing neurological impairment after injury, as assessed by the neurological tasks performed. rHuEPO- and darbepoetin alfa-treated animals exhibited a restricted brain injury with nearly normal parenchymal architecture. In contrast, the saline-treated group exhibited extensive cerebral cytoarchitectural disruption and edema. The number of surviving NeuN-positive neurons was significantly higher in the rats treated with rHuEPO and darbepoetin alfa compared with those that received saline (P < 0.05).


CONCLUSIONS
These results demonstrate that weekly administered darbepoetin alfa confers behavioral and histological neuroprotection after ICH in rats similar to that of daily EPO administration. Administration of EPO and its long-lasting recombinant forms affords significant neuroprotection in an ICH model and may hold promise for future clinical applications.
Grasso
Giovanni
G
Neurosurgical Clinic, Department of Clinical Neurosciences, University of Palermo, Palermo, Italy. ggrasso@unipa.it
Graziano
Francesca
F
Sfacteria
Alessandra
A
Carletti
Fabio
F
Meli
Francesco
F
Maugeri
Rosario
R
Passalacqua
Marcello
M
Certo
Francesco
F
Fazio
Marco
M
Buemi
Michele
M
Iacopino
Domenico Gerardo
DG
D000818:Animals; D020145:Basal Ganglia Hemorrhage / Q000150:complications / Q000188:drug therapy / Q000503:physiopathology; D001804:Blood Transfusion, Autologous / Q000009:adverse effects; D001921:Brain / Q000098:blood supply / Q000187:drug effects / Q000473:pathology; D001929:Brain Edema / Q000188:drug therapy / Q000209:etiology / Q000503:physiopathology; D020520:Brain Infarction / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D002543:Cerebral Hemorrhage / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D003342:Corpus Striatum / Q000098:blood supply / Q000187:drug effects / Q000473:pathology; D000068256:Darbepoetin alfa; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D004921:Erythropoietin / Q000031:analogs & derivatives* / Q000494:pharmacology* / Q000627:therapeutic use; D006397:Hematinics / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D008297:Male; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000494:pharmacology / Q000627:therapeutic use; D016896:Treatment Outcome
D006397:Hematinics; D018696:Neuroprotective Agents; D011994:Recombinant Proteins; D004921:Erythropoietin; D000068256:Darbepoetin alfa