Post-ischemic treatment with erythropoietin or carbamylated erythropoietin reduces infarction and improves neurological outcome in a rat model of focal cerebral ischemia.
OBJECTIVE
Recombinant human erythropoietin (rhEPO; Epoetin-alpha; PROCRITtrade mark) has been shown to exert neuroprotective and restorative effects in a variety of CNS injury models. However, limited information is available regarding the dose levels required for these beneficial effects or the neuronal responses that may underlie them. Here we have investigated the dose-response to rhEPO and compared the effects of rhEPO with those of carbamylated rhEPO (CEPO) in a model of cerebral stroke in rats.


METHODS
Rats subjected to embolic middle cerebral artery occlusion (MCAo) were treated with rhEPO or CEPO, starting at 6 h and repeated at 24 and 48 h, after MCAo. Cerebral infarct volumes were assessed at 28 days and neurological impairment at 7, 14, 21 and 28 days, post-MCAo.


RESULTS
rhEPO at dose levels of 500, 1150 or 5000 IU kg(-1) or CEPO at a dose level of 50 microg kg(-1) significantly reduced cortical infarct volume and reduced neurologic impairment. All doses of rhEPO, but not CEPO, produced a transient increase in haematocrit, while rhEPO and CEPO substantially reduced the number of apoptotic cells and activated microglia in the ischemic boundary region.


CONCLUSIONS
These data indicate that rhEPO and CEPO have anti-inflammatory and anti-apoptotic effects, even with administration at 6 h following embolic MCAo in rats. Taken together, these actions of rhEPO and CEPO are likely to contribute to their reduction of neurologic impairment following cerebral ischemia.
Wang
Y
Y
Department of Neurology, Henry Ford Health Science Center, 2799 West Grand Boulevard, Detroit, MI 48202, USA.
Zhang
Z G
ZG
Rhodes
K
K
Renzi
M
M
Zhang
R L
RL
Kapke
A
A
Lu
M
M
Pool
C
C
Heavner
G
G
Chopp
M
M
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001812:Blood-Brain Barrier; D002545:Brain Ischemia / Q000188:drug therapy*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D000068817:Epoetin Alfa; D004921:Erythropoietin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology*; D006397:Hematinics / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D006400:Hematocrit; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy / Q000503:physiopathology; D008297:Male; D017628:Microglia / Q000187:drug effects; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins; D020521:Stroke / Q000188:drug therapy*
D006397:Hematinics; D018696:Neuroprotective Agents; D011994:Recombinant Proteins; C488171:carbamylated erythropoietin; D004921:Erythropoietin; D000068817:Epoetin Alfa