In vivo reduction of erythrocyte oxidant stress in a murine model of beta-thalassemia.
OBJECTIVE
Oxidant damage is an important contributor to the premature destruction of erythrocytes and anemia in thalassemias. To assess the extent of oxidant damage of circulating erythrocytes and the effects of antioxidant therapy on erythrocyte characteristics and anemia, we used a mouse model of human beta-thalassemia intermedia (b1/b2 deletion).


METHODS
Several parameters indicative of oxidant damage were measured at baseline and following administration of the semi-synthetic flavonoid antioxidant, 7-monohydroxyethylrutoside (monoHER), to beta-thalassemic mice at a dose of either 500 mg/kg i.p. once a day (n=6) or 250 mg/kg i.p. twice a day (n=6) for 21 days.


RESULTS
Significant erythrocyte oxidant damage at baseline was indicated by: (i) dehydration, reduced cell K content, and up-regulated K-Cl co-transport; (ii) marked membrane externalization of phosphatidylserine; (iii) reduced plasma and membrane content of vitamin E; and (iv) increased membrane bound IgG. MonoHER treatment increased erythrocyte K content, and markedly improved all cellular indicators of oxidant stress and of lipid membrane peroxidation. While anemia did not improve, monoHER therapy reduced reticulocyte counts, improved survival of a fraction of red cells, and reduced ineffective erythropoiesis with decreased total bilirubin, lactate dehydrogenase and plasma iron.


CONCLUSIONS
Antioxidant therapy reverses several indicators of oxidant damage in vivo. These promising antioxidant effects of monoHER should be investigated further.
de Franceschi
Lucia
L
Department of Clinical and Experimental Medicine, Section of Internal Medicine, University of Verona, Verona, Italy.
Turrini
Franco
F
Honczarenko
Marek
M
Ayi
Kojio
K
Rivera
Alicia
A
Fleming
Mark D
MD
Law
Terry
T
Mannu
Franca
F
Kuypers
Frans A
FA
Bast
Aalt
A
van der Vijgh
Wim J F
WJ
Brugnara
Carlo
C
D000818:Animals; D017302:Annexins / Q000097:blood; D000975:Antioxidants / Q000378:metabolism / Q000627:therapeutic use*; D002712:Chlorides / Q000097:blood; D004195:Disease Models, Animal; D004910:Erythrocyte Membrane / Q000378:metabolism; D004912:Erythrocytes / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D006896:Hydroxyethylrutoside / Q000031:analogs & derivatives / Q000097:blood / Q000627:therapeutic use; D007074:Immunoglobulin G / Q000097:blood; D017136:Ion Transport; D008297:Male; D051379:Mice; D018384:Oxidative Stress / Q000187:drug effects*; D011188:Potassium / Q000097:blood; D014810:Vitamin E / Q000097:blood; D017086:beta-Thalassemia / Q000097:blood* / Q000188:drug therapy* / Q000473:pathology
D017302:Annexins; D000975:Antioxidants; D002712:Chlorides; D006896:Hydroxyethylrutoside; D007074:Immunoglobulin G; D014810:Vitamin E; D011188:Potassium