| Background and Purpose:Iron plays an important part in brain injury after intracerebral hemorrhage (ICH). The tetracycline derivative minocycline (MC) has been reported to provide neuroprotection by inhibiting microglia. Although minocycline also chelates iron, its effect on iron-induced brain injury has not been reported, and was examined in this study.Methods:Rats had intracaudate injection of 50?l of saline, FeC12 (0.5mM) or FeC13 (0.5mM); 50?l of FeC12+vehicle, FeC12+MC (0.5 or 1.5mM) or FeC12+MIF (microglia inhibitory factor,0.5mM); 50?l of FeC13 (0.5mM)+ vehicle, FeC13+MC (0.5mM). Rats were killed at 24 hours and the brains were used for brain water content determination, Fluoro-Jade C, PANT and TUNEL staining, immunohistochemistry, and western blotting assay.Results:Intracaudate iron injection, both ferrous and ferric iron, induced significantly upregulation of water content in ipsilateral basal ganglia, but ferrous iron induced higher water content than ferric iron. MC coinjection significantly attenuated both ferrous and ferric iron induced brain edema formation. MC, but not MIF, markedly reduced the ferrous induced brain edema, neuronal death, DNA damage, blood brain barrier (BBB) disruption and HO-1 expression. MC also attenuated the protein levels of transferring (Tf) and ceruloplasmin (CP).Conclusion:These results suggest that MC attenuates iron induced brain injury and the upregulation of iron-handling proteins. The protection effects of minocycline may be due at least in part to direct iron chelation rather than to a specific anti-inflammatory effect in intracerebral hemorrhage.Background and Purpose:Iron plays an important role after experimental intracerebral hemorrhage (ICH).Our previous study found minocycline (MC) might provide neuroprotection by chelating iron. The current study further examined the effect of MC on iron-induced brain injury.Methods:Rats had intracaudate injection of 50?l of saline, FeC12 (0.5mM) or FeC12+MC (0.5 mM). Rats were killed at 72 hours. The rat brains were used for HE staining, western blotting assay and immunohistochemistry.Results:Intracaudate ferrous injection induced brain swelling in ipsilateral basal ganglia. MC coinjection significantly attenuated the ferrous induced brain swelling and blood brain barrier (BBB) disruption. It also reduced the ferritin expression and the protein levels of HO-1, transferring (Tf), transferrin receptor (TfR), ceruloplasmin(CP).Conclusion:These results demonstrate that MC attenuates iron induced brain injury and the upregulation of iron-handling proteins. The iron chelation function may contribute to the beneficial effect of minocycline in intracerebral hemorrhage. Key Words:intracerebral hemorrhage, iron, minocycline, neuroprotectionBackground and Purpose:Iron plays a detrimental role in brain injury after intracerebral hemorrhage (ICH). The tetracycline derivative minocycline (MC) has been reported to provide neuroprotection by iron chelation in vitro. The present study investigated if the function of iron chelation contributed to the beneficial effect of MC after ICH.Methods:This study was divided into three parts. (1) Rats sustained an intracaudate injection of 10?L or 100?L autologous whole blood. Rats were killed for serum total iron and brain water content determination 3 days later. (2) Rats had an intracerebral injection of 100?l autologous whole blood, followed by minocycline or vehicle treatment. Rats were killed 1,3 and 7 days later for serum total iron determination, immunohistochemistry and Western blotting assay.Results—Serum total iron levels increased after ICH and were reduced by MC treatment at day 3 and 7. MC reduced the ICH inducedupregulation of brain nonheme iron and iron handling proteins. It also attenuated neuronal death after ICH.Conclusions—Minocycline treatment reduces ICH mediated serum and brain iron levels upregulation. It also attenuated ICH and iron induced brain injury. The therapeutic benefit of minocycline may be due to direct iron chelation rather than to a specific microglial inhibitor. (?)7... |
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