Vascular Iron Deposits Associate With Oxidative Injury in a Model of Multiple Sclerosis

Background: Elevated levels of iron deposits occur in both white and gray matter structures in the cerebrum of multiple sclerosis patients; however, it is not known whether this iron contributes to the pathogenesis of disease.  In white matter, iron deposits are often associated with vessels.

Objectives: To explore the hypothesis that abnormal perivascular iron deposits promote oxidative tissue damage.

Methods: We utilized a cerebral model of experimental autoimmune encephalomyelitis (cEAE) that previously has been shown to develop perivascular iron deposits in the cerebrum, and has many pathological features that are also observed in multiple sclerosis.  Brain tissue sections were stained by immunohistochemistry against albumin, which can be used to assess damage to the blood-brain barrier (BBB).  Additional sections were stained by iron histochemistry in combination with immunohistochemistry against nitrotyrosine, which is a tissue marker of oxidative tissue damage.

Results: There was evidence suggesting increased extravasation of albumin in the cerebrum of cEAE mice compared to controls indicating damage to the BBB in cEAE mice.  Vessels that displayed co-localization of nitrotyrosine plus iron deposition were greater in cEAE mice compared to control animals at multiple time points.  Vessels with co-localization often displayed extravasated red blood cells that were labeled by iron histochemistry.  Vessels that displayed nitrotyrosine without co-labeling of iron were less prevalent than co-labeled vessels in cEAE mice and these single labeled vessels were not increased in cEAE mice compared to controls.  

Conclusions: Since other studies have shown that heme containing proteins (i.e., hemoglobin) can catalyze the nitration of proteins, it is likely that this is at least one mechanism accounting for oxidative tissue injury.  These results provide evidence supporting the notion that perivascular iron deposition promotes tissue injury in multiple sclerosis.