Effects of IV iron isomaltoside-1000 treatment on regional brain iron status in an iron-deficient animal

Background: Iron deficiency has been documented to affect human cognitive function and conditions with brain iron compromise such as the restless legs syndrome (RLS). Intravenous (IV) iron treatment is used to reduce iron deficiency but its effects on brain iron are not known. It is not known if IV iron is effective in correcting regional brain iron deficiencies nor if it poses a risk of producing iron overload in some brain regions. Preclinical study of IV iron in the iron-deficient (ID) murine model is needed to evaluate and develop IV iron treatments for brain iron deficiency. Methods: Response to tail vein injections of iron (iron isomaltoside-1000, dose equivalent to 1000. mg for 75. kg adult) or vehicle were evaluated for ID mice by microdialysis assessing non-transferrin bound (NTB) iron in the ventral midbrain (VMB) and autopsy at 3 and 10. days post-injection assessing iron content in critical brain regions. Results: The ID mice showed marked circadian variation in NTB extracellular iron. After iron injection, NTB iron was rapidly increased in the VMB and then decreased over 12. h to the levels observed for vehicle. Regional brain iron content at 3 and 10. days post-injection in the iron- compared to vehicle-treated group showed significantly more iron for the VMB and nucleus accumbens but not for the other regions (i.e. prefrontal cortex, caudate-putamen, cerebellum, and pons), which also did not show decreased iron content with the ID diet. Conclusion: Iron isomaltoside-1000 given IV corrects the regional brain iron deficiency in these ID mice without producing iron overload in any of the brain regions studied. This is the first demonstration of effects of IV iron in the brain and it provides a useful preclinical model for this assessment, particularly relevant for developing iron treatments for conditions with problematic iron deficiency, e.g. RLS.