ferrous-citrate and Brain-Injuries

Premenopausal women have better survival than men after intracerebral hemorrhage, which is associated with iron overproduction and autophagy induction. To examine the participation of neuronal autophagy and estrogen receptor α (ERα) in the E 2-mediated protection, PC12 neurons treated with Atg7 (autophagy-related protein 7) siRNA, rapamycin (an autophagy inducer), or Erα siRNA were applied. To study whether autophagy involves in β-estradiol 3-benzoate (E 2)-mediated neuroprotection against iron-induced striatal injury, castration and E 2 capsule implantation were performed at 2 weeks and 24 h, respectively, before ferrous citrate (FC) infusion into the caudate nucleus (CN) of Sprague Dawley male and female rats. Furthermore, the role of neuronal autophagy in the sex difference of FC-induced CN injury was confirmed by using conditional knockout Atg7 in dopamine receptor 2 (DRD2)-containing neurons in mice. The results showed that the suppression of FC-induced autophagy by E 2 was abolished by Erα siRNA preincubation. Atg7 silencing simulates and rapamycin diminishes E 2-mediated neuroprotection against FC-induced neurotoxicity. In vivo, FC induced a lower degree of autophagy, autophagic cell death, injury severity, histological lesion and behavioral deficit in female rats than in males. E 2 implantation decreased the levels of both FC-induced autophagy and injury in ovariectomized rats. Moreover, the sex difference of FC-induced CN injury was diminished in Atg7 knockout mice. Thus, suppression of autophagy by E 2 via ERα contributes to less severity of iron-induced brain injury in females than in male. This finding opens up the prospect for a therapeutic strategy targeting autophagic inhibition for patients suffering from intracerebral iron overload.

Topics: Animals; Autophagy; Autophagy-Related Protein 7; Brain Injuries; Castration; Caudate Nucleus; Cerebral Hemorrhage; Citric Acid; Cytoprotection; Estradiol; Estrogen Receptor alpha; Female; Ferrous Compounds; Humans; Iron; Male; Mice; Mice, Knockout; Microtubule-Associated Proteins; Neostriatum; Neurotoxins; PC12 Cells; Protective Agents; Rats; Receptors, Dopamine D2; Sex Characteristics; Signal Transduction; Ubiquitin-Activating Enzymes

Accumulation of iron after intracerebral hemorrhage causes free radical formation and oxidative damage resulting in liquefaction. The aim of this study was the investigation of molecular mechanisms underlying estrogen-mediated neuroprotective effect against iron-induced brain injury in vivo.. Age-matched male and female Sprague-Dawley rats were stereotaxically infused with either ferrous citrate (FC) or saline (10 muL) into the right caudate nucleus. Beta-estradiol 3-benzoate (E(2)) capsule was implanted subcutaneously at 24 hours before infusion of FC. The severity of brain injury and neurological deficits were measured by histological quantification and forelimb asymmetry test, respectively. The role of thioredoxin (Trx) in E(2)-mediated neuroprotective effect was examined by intrastriatal administration of a Trx reductase inhibitor, 5,5-dithiobis-(2-nitrobenzoic acid), and small interfering RNA.. FC induced greater brain injury in male rats than females. E(2) treatment reduced FC-induced brain injury in both sexes. E(2) significantly increased protein level and activity of Trx in the caudate nucleus of females but not males. Administration of female rats with 5,5-dithiobis-(2-nitrobenzoic acid) or Trx small interfering RNA to the caudate nucleus decreased the protective effect of E(2) against FC-induced injury. The protein and mRNA levels of estrogen receptor alpha, but not estrogen receptor beta, were more abundant in the caudate nucleus of female rats.. Increase of brain Trx activity might play an important role in the E(2)-mediated neuroprotective effect against FC-induced brain injury in female rats. Understanding of the sex differences in the Trx-mediated neuroprotective effect by E(2) might help in improving treatment of brain dysfunction after hemorrhagic stroke and/or head trauma.

Topics: Animals; Brain Injuries; Citric Acid; Estradiol; Female; Ferrous Compounds; Male; Neuroprotective Agents; Rats; Rats, Sprague-Dawley; Sex Characteristics; Thioredoxins