Impact of 17beta-estradiol and progesterone on inflammatory and apoptotic microRNA expression after ischemia in a rat model.
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.
['Herzog|Rebecca|R|', 'Zendedel|Adib|A|', 'Lammerding|Leoni|L|', 'Beyer|Cordian|C|', 'Slowik|Alexander|A|']
D000818:Animals D017209:Apoptosis D002545:Brain Ischemia D004958:Estradiol D006728:Hormones D020244:Infarction, Middle Cerebral Artery D007249:Inflammation D008297:Male D035683:MicroRNAs D009474:Neurons D011374:Progesterone D051381:Rats D017208:Rats, Wistar D020521:Stroke
Progesterone Neuroprotection miRNA Estrogen Neuroinflammation Stroke