Published Online
on January 6, 2005

A more recent version of this article appeared on February 1, 2005

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Submitted on October 8, 2004
Accepted on October 27, 2004

Holo-Transferrin and Thrombin Can Interact to Cause Brain Damage

Takehiro Nakamura MD; Guohua Xi MD; Jung-Weon Park MD; Ya Hua MD; Julian T. Hoff M.D; and Richard F. Keep PhD^*

From the Departments of Neurosurgery (T.N., G.X., J.-W.P., Y.H., J.T.H., R.F.K.), Toxicology (J.-W.P.), and Physiology (R.F.K.), University of Michigan, Ann Arbor.

^* To whom correspondence should be addressed. E-mail: rkeep{at}umich.edu.

Background and Purpose--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.

Key words: brain edema • iron • oxidative stress • thrombin • transferrin

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