Holo-transferrin and thrombin can interact to cause brain damage.
OBJECTIVE
Previous studies have suggested that delayed release of hemoglobin degradation products, particularly iron, is involved in intracerebral hemorrhage (ICH)-induced brain injury. However, a recent study found evidence of iron-induced brain injury soon after ICH. This study, therefore, examined whether another iron-containing component of blood, holo-transferrin (holo-Tf), might also induce brain injury either alone or in combination with thrombin, another factor involved in early ICH-induced brain injury.


METHODS
Male Sprague-Dawley rats received an intracerebral infusion of holo-Tf, apo (noniron-loaded)-Tf, thrombin, or a combination of Tf with thrombin into the right basal ganglia. The rats were euthanized 24 hours later for measurement of brain edema and assessment of DNA damage (single- and double-strand breaks and 8-hydroxyl-2'-deoxyguanosine immunohistochemistry). Iron distribution was examined histochemically.


RESULTS
Holo-Tf, apo-Tf, and the dose of thrombin used (1 U) all failed to induce brain edema when administered alone. However, the combination of holo-Tf with thrombin (but not apo-Tf with thrombin) caused brain edema, DNA damage, and intracellular iron accumulation in the ipsilateral basal ganglia.


CONCLUSIONS
These results suggest that in addition to hemoglobin-bound iron, Tf-bound iron may contribute to ICH-induced brain injury and that thrombin may contribute to the latter by facilitating cellular iron uptake.
Nakamura
Takehiro
T
Department of Neurosurgery, University of Michigan, Ann Arbor, Michigan 48109-0532, USA.
Xi
Guohua
G
Park
Jung-Weon
JW
Hua
Ya
Y
Hoff
Julian T
JT
Keep
Richard F
RF
D000818:Animals; D034961:Antigens, Nuclear / Q000378:metabolism; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D001930:Brain Injuries / Q000378:metabolism / Q000473:pathology*; D002543:Cerebral Hemorrhage; D004249:DNA Damage; D053938:DNA Fragmentation; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000378:metabolism; D006454:Hemoglobins / Q000737:chemistry; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D007501:Iron / Q000493:pharmacokinetics; D000072200:Ku Autoantigen; D008297:Male; D018384:Oxidative Stress; D051381:Rats; D017207:Rats, Sprague-Dawley; D013917:Thrombin / Q000737:chemistry*; D014168:Transferrin / Q000737:chemistry*; D014867:Water / Q000378:metabolism
D034961:Antigens, Nuclear; D004268:DNA-Binding Proteins; D006454:Hemoglobins; D014168:Transferrin; C110714:holotransferrin; D014867:Water; D007501:Iron; D013917:Thrombin; C000606511:Xrcc6 protein, rat; D000072200:Ku Autoantigen