Characterization of the pharmacokinetics of human recombinant erythropoietin in blood and brain when administered immediately after lateral fluid percussion brain injury and its pharmacodynamic effects on IL-1beta and MIP-2 in rats.
This study sought to determine the bio-availability of recombinant human erythropoietin (EPO) in the brain and blood and its effects on the cerebral concentrations of the inflammatory mediators interleukin-1beta (IL-1beta) and macrophage-inflammation protein-2 (MIP-2) following lateral fluid percussion brain injury (FPI) in the rat. After induction of moderate FPI (1.6-1.8 atm), EPO was injected intraperitoneally (IP) or intravenously (IV) at doses of 1000-5000 U/kg in a randomized and blinded manner. Animals were then sacrificed at time points (4, 8, 12, 24 h) post-trauma, and the brain concentrations of EPO, IL-1beta, and MIP-2 were determined. EPO administration leads to a dose-dependent increase in the brain concentration of the drug; however, this could only be detected at doses of 3000 and 5000 U/kg. The cerebral concentration peaked in the first 4 h following trauma. EPO concentrations were significantly higher and decreased more slowly in the traumatized cortex compared to the contralateral side (p<0.0125). IV EPO (5000 U/kg) produced slightly higher concentrations of EPO than same doses injected IP; however, this was not significant. At a dose of 5000 U/kg, EPO significantly reduced the increase in IL-1beta at 8 and 12 h in both cortical sides. It also reduced the increase in MIP-2 but only after 8 h, on the contralateral side and after 12 h on the ipsilateral side. Our results suggest that EPO crosses the blood-brain barrier (BBB) by 4 h after trauma and is localized primarily in the traumatized cortex. Further, it has biological efficacy at 8 h on several inflammatory proteins, yet must be employed at high doses to cross the BBB.
Department Reanimation et Anesthesiologie, Hôpital Neurologique, Hospices Civils de Lyon, Lyon, France.
Thomas
T
Lieutaud
Peter J D
PJ
Andrews
Jonathan K J
JK
Rhodes
Robert
R
Williamson
D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D001921:Brain / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D001930:Brain Injuries / Q000188:drug therapy* / Q000276:immunology* / Q000503:physiopathology; D054426:Chemokine CXCL2 / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D004334:Drug Administration Schedule; D004660:Encephalitis / Q000188:drug therapy / Q000276:immunology / Q000503:physiopathology; D004921:Erythropoietin / Q000097:blood / Q000493:pharmacokinetics*; D007839:Functional Laterality / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D053583:Interleukin-1beta / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins; D013997:Time Factors
D054426:Chemokine CXCL2; C513296:Cxcl2 protein, rat; D053583:Interleukin-1beta; D011994:Recombinant Proteins; D004921:Erythropoietin