Estrogen Reduces Iron-Mediated Brain Edema and Neuronal Death
Our previous studies found that 17-β estradiol attenuates edema formation after intracerebral hemorrhage (ICH). As brain iron overload occurs after ICH and contributes to ICH-induced brain injury, the present study examined the effects of estrogen on iron
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Abstract Our previous studies found that 17-b estradiol attenuates edema formation after intracerebral hemorrhage (ICH). As brain iron overload occurs after ICH and contributes to ICH-induced brain injury, the present study examined the effects of estrogen on iron-induced brain injury in vivo and in vitro. There were two sets of experiments in this study. In the first set, male Sprague-Dawley rats were pretreated with 17-b estradiol or vehicle prior to an intracerebral injection of ferrous iron. Ferrous iron was injected into the right caudate and the rats were killed 24 h later for brain edema measurement. In the second set, primary cultured neurons were pretreated with different doses of 17-b estradiol or vehicle for 24 h. The cells were then exposed to ferrous iron for 48 h when culture medium was collected for lactate dehydrogenase measurement. Neuronal death was also assessed by live/dead cell assay. Estrogen pretreatment reduced brain water content (p < 0.01) 24 h after iron injection. Estrogen also protected against iron-induced cell death in cultured neurons. Estrogen reduces iron-induced brain edema in vivo and neuronal death in vitro suggesting estrogen could be a potential therapeutic agent for ICH. Keywords Brain edema • cerebral hemorrhage • estrogen • iron
Estrogen has been shown to confer strong brain protection in experimental cerebral ischemia (7,17) and we have found that brain edema is reduced when estrogen is given before or after ICH (9,12). The mechanisms involved in estrogeninduced protection are unknown. The present study investigated whether or not estrogen reduces iron-induced brain edema in vivo and neuronal death in vitro.
Materials and Methods Experimental Groups There were two groups of experiments in this study. In the first group, male Sprague-Dawley rats were pretreated with 17-b estradiol (5 mg/kg) or vehicle at 24 and 2 h prior to an intracerebral injection of ferrous iron. Ferrous iron (0.2 mM, 50 µL) was injected into the right caudate and the rats were killed 24 h later for brain water content measurement. In the second group, primary cultured neurons were pretreated with different doses of 17-b estradiol (10 nM to 10 µM) or vehicle for 24 h. The cultured neurons were then exposed to ferrous iron (500 µM) for 48 h when culture medium was collected for lactate dehydrogenase (LDH) measurement. Neuronal death was also assessed by live/dead cell assay.
Introduction Iron, a hemoglobin degradation product, accumulates in the brain after intracerebral hemorrhage (ICH) (18). ICHinduced brain iron overload contributes to both early and delayed brain injury (5,10,11). Y. Hua (*), Y. Gu, G. Xi, W. Liu, and R.F. Keep R5018 Biomedical Science Research Building Department of Neurosurgery University of Michigan 109 Zina Pitcher Place Ann Arbor, MI 48109-2200, USA e-mail: [email protected]
Animal Preparation and Intracerebral Injection The University of Michigan Committee on the Use and Care of Animals approved the protocols for these animal studies, which used male Sprague-Dawley rats a
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