Abstract TP342: Protective Effects of the Lipophilic Dadmdft Iron Chelator Against Brain Hemoglobin Toxicity

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Background and Purpose: Intracerebral hemorrhage (ICH) is a devastating form of stroke, and therapies are largely non-existent. Among the deleterious processes occurring after ICH, iron toxicity is suggested to contribute to secondary injury. There is a pressing need for the continued development of new iron-chelating agents that can selectively remove released iron after ICH from brain tissues especially vulnerable to iron-induced toxicity. The DADMDFT analogue [(S)-4,5-dihydro-2-(2-hydroxyphenyl)-4-thiazolecarboxylic acid] used here is a more lipophilic iron chelator that achieves higher concentrations in the plasma and has a longer half-life than most commonly used chelators.Methods: The DADMDFT-treated mice were subjected to intrastriatal injection of stroma-free hemoglobin. Infarct volume and ferric iron distribution were assessed by using Cresyl violet and Perls’ staining respectively. Knowing that hemoglobin can activate microglial cells, thus microglial activation was monitored by Iba1 immunohistochemistry. Behavioral functions were evaluated by rotarod and neurological deficit score at 24 and 72h after hemoglobin injection.Results: We found that DADMDFT treatment at 75 and 150μmol/kg both significantly reduced the lesion volume after hemoglobin intrastriatal injection. Moreover, around the lesion site, smaller accumulation of iron was observed after DADMDFT treatment in contrast to the vehicle group. Our quantitative analyses indicated that there were more activated microglial cells at peri-lesion area with DADMDFT treatment at the dose of 75 and 150μmol/kg, as compared to the vehicle-treated group. In behavioral tests, DADMDFT treatment significantly prolonged the latency to fall during the rotarod test at 150μmol/kg at 24h after injection. In addition, DADMDFT of 75 and 150μmol/kg significantly improved the neurological deficit score at 24 and 72h after injection.Conclusions: We found that the lipophilic DADMDFT can protect brain tissue from hemoglobin toxicity. The potential mechanism of its protective effects is that DADMDFT treatment could help maintaining the cell number and phagocytosis function of activated microglia around the lesion site, which could promote the clearance of toxic ferric iron.

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