title: Impact of 17beta-estradiol and progesterone on inflammatory and apoptotic microRNA expression after ischemia in a rat model.
abstract: 17β-estradiol (E2) and progesterone (P) are neuroprotective factors in the brain preventing neuronal death under different injury paradigms. In previous studies, we demonstrated that both steroids dampen neuronal damage, improve local energy metabolism and attenuate pro-inflammatory responses. MicroRNAs (miRNAs) are small regulators of distinct target genes on the RNA level. Their expression patterns are misbalanced in several neurological disorders. To explore the regulatory mechanisms of steroid hormones on selected miRNAs and their validated targets in ischemia, we used the transient middle cerebral artery occlusion (tMCAO) model. 12-week old male rats were subjected to 2h tMCAO and expression patterns of miR-223, miR-200c, miR-375, miR-199 and miR-214 (all -3p) were determined. Using semi-quantitative real time PCR, we examined the role of E2 or P as regulatory factors for miRNAs and theirs target genes. Besides miR-375, all mentioned miRNAs showed a steady increase with a peak at 72h post tMCAO, whereas highest levels of miR-375 were detected at 12h post tMCAO. E2 or P selectively dampened miR-223 and miR-214 but further boosted miR-375 levels. With respect to the miR-223 regulated target genes NR2B and GRIA2 which both decreased after tMCAO, E2 and P application reversed this effect. Further, steroid treatment inhibited the hypoxia-induced increase of the miR-375 target genes Bcl-2 and RAD1. These findings provide new insights into the regulatory role of neuroprotection mediated by sex steroids in the brain. Both hormones are capable of influencing the expression of miRNAs which are relevant during neuropathological processes. Thereby, E2 and P indirectly control pro-apoptotic and -inflammatory gene translation and provide a mechanism to dampen explosive tissue damage.
authors.affiliation: Institute of Neuroanatomy, RWTH Aachen University, 52074 Aachen, Germany.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Herzog
authors.affiliation: Institute of Neuroanatomy, RWTH Aachen University, 52074 Aachen, Germany; Department of Anatomical Sciences, Faculty of Medicine, Giulan University of Medical Sciences, Rasht, Iran.
authors.forename: Adib
authors.initials: A
authors.lastname: Zendedel
authors.affiliation: Institute of Neuroanatomy, RWTH Aachen University, 52074 Aachen, Germany.
authors.forename: Leoni
authors.initials: L
authors.lastname: Lammerding
authors.affiliation: Institute of Neuroanatomy, RWTH Aachen University, 52074 Aachen, Germany; JARA-Brain, 52074 Aachen, Germany.
authors.forename: Cordian
authors.initials: C
authors.lastname: Beyer
authors.affiliation: Institute of Neuroanatomy, RWTH Aachen University, 52074 Aachen, Germany. Electronic address: aslowik@ukaachen.de.
authors.forename: Alexander
authors.initials: A
authors.lastname: Slowik
mesh_terms: D000818:Animals; D017209:Apoptosis; D002545:Brain Ischemia / Q000378:metabolism*; D004958:Estradiol / Q000378:metabolism*; D006728:Hormones / Q000378:metabolism; D020244:Infarction, Middle Cerebral Artery / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism*; D008297:Male; D035683:MicroRNAs / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D011374:Progesterone / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D020521:Stroke / Q000378:metabolism
chemical_list: D006728:Hormones; D035683:MicroRNAs; D011374:Progesterone; D004958:Estradiol
keywords: Estrogen; Neuroinflammation; Neuroprotection; Progesterone; Stroke; miRNA