Abstract TMP80: A Lipid-soluble Iron Chelator Protects Against Intracerebral Hemorrhage In Mice

Abstract

Background and purpose: Intracerebral hemorrhage (ICH) is a devastating form of stroke with no clinically proven treatment. Previous studies have indicated that 2,2’-dipyridyl, a lipid-soluble ferrous iron chelator, can reduce brain injury after cerebral ischemia and reduce cerebral vasospasm after subarachnoid hemorrhage. In this study, we examined the efficacy of 2,2’-dipyridyl after ICH in middle-aged mice (12 months old). Methods: ICH was modeled by intrastriatal injection of collagenase or autologous whole blood. 2,2’-Dipyridyl or vehicle was administered intraperitoneally 2 h before ICH (pretreatment) or 6 h after ICH (post-treatment) and then once daily for up to 3 days. Mice in the pretreatment group were sacrificed 1 or 3 days after ICH and examined for iron deposition, neuronal death, oxidative stress, microglial/astrocyte activation, neutrophil infiltration, and white matter damage. Mice in the post-treatment group were examined for brain lesion volume and edema on day 3 and for neurologic deficits on days 1, 3, and 28 after ICH. Results: Pretreatment with 2,2’-dipyridyl decreased iron accumulation and neuronal death, attenuated production of reactive oxygen species, reduced microglial activation without affecting astrocytes or neutrophil infiltration, and attenuated white matter damage (n=5 mice/group, all p <0.01). Post-treatment reduced brain lesion volume by 40.5%, lessened edema, and improved neurologic function (n=6-8 mice/group, all p <0.05) but did not affect body weight loss or mortality rate. Conclusions: The lipid-soluble ferrous iron chelator 2,2’-dipyridyl can reduce brain injury and improve functional recovery after ICH.