Erythropoietin reduces perihematomal inflammation and cell death with eNOS and STAT3 activations in experimental intracerebral hemorrhage.
Erythropoietin (EPO), a pleiotropic cytokine involved in erythropoiesis, is tissue-protective in ischemic, traumatic, toxic and inflammatory injuries. In this study, we investigated the effect of EPO in experimental intracerebral hemorrhage (ICH). Two hours after inducing ICH via the stereotaxic infusion of collagenase, recombinant human EPO (500 or 5000 IU/kg, ICH + EPO group) or PBS (ICH + vehicle group) was administered intraperitoneally, then once daily afterwards for 1 or 3 days. ICH + EPO showed the better functional recovery in both rotarod and modified limb placing tests. The brain water content was decreased in ICH + EPO dose-dependently, as compared with ICH + vehicle. The effect of EPO on the brain water content was inhibited by N(omega)-Nitro-L-arginine methyl ester hydrochloride (L-NAME, 10 mg/kg). Mean hemorrhage volume was also decreased in ICH + EPO. EPO reduced the numbers of TUNEL +, myeloperoxidase + or OX-42 + cells in the perihematomal area. In addition, EPO reduced the mRNA level of TNF-alpha, Fas and Fas-L, as well as the activities of caspase-8, 9 and 3. EPO treatment showed up-regulations of endothelial nitric oxide synthase (eNOS) and p-eNOS, pAkt, pSTAT3 and pERK levels. These data suggests that EPO treatment in ICH induces better functional recovery with reducing perihematomal inflammation and apoptosis, coupled with activations of eNOS, STAT3 and ERK.
Stroke and Neural Stem Cell Laboratory in Clinical Research Institute, Stem Cell Research Center, Department of Neurology, Seoul National University Hospital, Seoul, South Korea.
Soon-Tae
ST
Lee
Kon
K
Chu
Dong-In
DI
Sinn
Keun-Hwa
KH
Jung
Eun-Hee
EH
Kim
Se-Jeong
SJ
Kim
Jeong-Min
JM
Kim
Song-Yi
SY
Ko
Manho
M
Kim
Jae-Kyu
JK
Roh
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D015415:Biomarkers / Q000378:metabolism; D001834:Body Water / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D001929:Brain Edema / Q000188:drug therapy / Q000209:etiology / Q000503:physiopathology; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002543:Cerebral Hemorrhage / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004660:Encephalitis / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004921:Erythropoietin / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009410:Nerve Degeneration / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D052250:Nitric Oxide Synthase Type III / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function / Q000187:drug effects / Q000502:physiology; D050796:STAT3 Transcription Factor / Q000187:drug effects* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D016896:Treatment Outcome
D015415:Biomarkers; D004791:Enzyme Inhibitors; D050796:STAT3 Transcription Factor; C494088:Stat3 protein, rat; D004921:Erythropoietin; D052250:Nitric Oxide Synthase Type III; D019331:NG-Nitroarginine Methyl Ester