Erythropoietin promotes neurological recovery after intracerebral haemorrhage in rats.
BACKGROUND
Attention has turned to neurorestorative therapies, including erythropoietin, for experimental ischaemic stroke and head injury. Treatments for intracerebral haemorrhage need to be developed, as this represents a particularly devastating and common form of neurological injury. Aim The aim of this study is to investigate the therapeutic potential of erythropoietin after intracerebral haemorrhage in rats and to measure its effects on mechanisms of recovery and neurogenesis.


METHODS
Intracerebral haemorrhage was induced in 24 Wistar male rats by intrastriatal infusion of autologous blood. Recombinant human erythropoietin (5000 or 10,000 U/kg BW/day) or saline was administered starting 1 day after intracerebral haemorrhage and continued daily for 1 week (n=8 for each group). To label proliferating cells, 5'-bromo-2' deoxyuridine was injected daily for 13 days after intracerebral haemorrhage. All animals survived for 2 weeks after intracerebral haemorrhage. Functional outcome, area of tissue loss and immunohistochemical staining were measured at 14 days after intracerebral haemorrhage. Global test or anova was used to test the erythropoietin dose effect.


RESULTS
Rats receiving recombinant human erythropoietin after intracerebral haemorrhage exhibited significant improvement in modified neurological severity score and corner test at 14 days (P<0.05). Increased expression of phenotypes of synaptogenesis and proliferating immature neurons were shown by immunohistochemical staining. Only the group receiving a lower dose of recombinant human erythropoietin had significantly less tissue loss compared with the control group (P<0.05). In rats treated with recombinant human erythropoietin, double staining for 5'-bromo-2' deoxyuridine and TUJ1 revealed a subpopulation of cells that express an immature neuronal marker while still dividing.


CONCLUSIONS
Erythropoietin improves neurological outcome and increases histochemical parameters of neurogenesis when given after intracerebral haemorrhage in rats. Intriguingly, only the lower dose of recombinant human erythropoietin was effective in reducing tissue loss in the region of intracerebral haemorrhage.
Seyfried
D M
DM
Department of Neurosurgery, Henry Ford Health System, Detroit, MI 48202, USA. nsdos@neuro.hfh.edu
Han
Y
Y
Yang
D
D
Ding
J
J
Chopp
M
M
D000818:Animals; D000963:Antimetabolites; D001921:Brain / Q000473:pathology; D001973:Bromodeoxyuridine; D002543:Cerebral Hemorrhage / Q000188:drug therapy* / Q000473:pathology; D004396:Coloring Agents; D004921:Erythropoietin / Q000627:therapeutic use*; D006801:Humans; D007150:Immunohistochemistry; D007202:Indicators and Reagents; D016014:Linear Models; D008297:Male; D009419:Nerve Tissue Proteins / Q000378:metabolism; D011597:Psychomotor Performance / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins; D020127:Recovery of Function; D016707:Tissue Fixation
D000963:Antimetabolites; D004396:Coloring Agents; D007202:Indicators and Reagents; D009419:Nerve Tissue Proteins; D011994:Recombinant Proteins; D004921:Erythropoietin; D001973:Bromodeoxyuridine
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