Asialoerythropoietin attenuates neuronal cell death in the hippocampal CA1 region after transient forebrain ischemia in a gerbil model.
OBJECTIVE
Systemic administration of high-dose recombinant human erythropoietin (rhEPO) is known to attenuate ischemic injury. However, high-dose rhEPO might aggravate ischemic lesions by increasing blood viscosity because of its erythropoietic effects. Asialoerythropoietin (asialoEPO), an EPO derivative with an extremely short plasma half-life, has considerably lesser erythropoietic effect than that of naive EPO. We attempted to determine whether asialoEPO exerts the same neuroprotective effect as naive EPO in a gerbil transient forebrain ischemia model.


METHODS
Transient occlusion of both the common carotid arteries was performed in 23 adult gerbils. The drugs (asialoEPO or rhEPO, 10 U/g bodyweight) or phosphate-buffered saline (PBS) were injected intraperitoneally at three times (3 hours before, immediately after, and 24 hours after the ischemic insult). Learning and retention tests were performed on days 6 and 7, respectively, and histological analyses were performed on day 7.


RESULTS
Animals treated with asialoEPO and rhEPO showed significant neurological improvement compared to the PBS-treated animals. The number of viable neurons in the CA1 field of the rhEPO-treated (103.57 ± 27.90 cells/mm) and asialoEPO-treated (144.99 ± 34.87 cells/mm) animals was higher than that of the PBS-treated animals (19.53 ± 3.79 cells/mm). Terminal dinucleotidyltransferase-mediated UTP end labeling-positive cells were significantly lower in the rhEPO-treated (33.40 ± 8.13 cells/mm) and asialoEPO-treated (29.28 ± 14.91 cells/mm) animals than in the PBS-treated animals (76.67 ± 8.14 cells/mm). AsialoEPO treatment did not have any effect on erythropoiesis.


CONCLUSIONS
Multiple dosing of asialoEPO, like EPO, could protect the hippocampal CA1 neurons from ischemic damage without affecting erythropoiesis.
Yamashita
Taro
T
Department of Neurosurgery, Osaka Medical College, Japan. neu091@poh.osaka-med.ac.jp
Nonoguchi
Naosuke
N
Ikemoto
Toshiyuki
T
Miyatake
Shin-Ichi
S
Kuroiwa
Toshihiko
T
D000818:Animals; D001212:Asialoglycoproteins / Q000494:pharmacology*; D001362:Avoidance Learning / Q000187:drug effects; D056547:CA1 Region, Hippocampal / Q000473:pathology*; D002340:Carotid Artery Diseases / Q000150:complications; D002452:Cell Count / Q000379:methods; D016923:Cell Death / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004921:Erythropoietin / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D005849:Gerbillinae; D020287:In Situ Nick-End Labeling / Q000379:methods; D002546:Ischemic Attack, Transient / Q000188:drug therapy / Q000209:etiology / Q000473:pathology* / Q000503:physiopathology; D009474:Neurons / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D016548:Prosencephalon / Q000473:pathology*
D001212:Asialoglycoproteins; C554270:EPO protein, human; D018696:Neuroprotective Agents; C500605:asialoerythropoietin; D004921:Erythropoietin