Modulatory effect of 17β-estradiol on myeloid cell infiltration into the male rat brain after ischemic stroke

• Published in: The Journal of steroid biochemistry and molecular biology 2020-09, Vol.202, p.105667-105667, Article 105667
• Main Authors: Scheld, M., Heymann, F., Zhao, W., Tohidnezhad, M., Clarner, T., Beyer, C., Zendedel, A.
• Format: Article
• Language: English
• Subjects: 17β-Estradiol; Animals; Brain; Brain injury; CD11b antigen; CD11c antigen; CD40 antigen; CD45 antigen; Cytokines - immunology; Estradiol - pharmacology; Estradiol - therapeutic use; Estrogen; Estrogens; Flow cytometry; Gene expression; Gene flow; Infarction, Middle Cerebral Artery - drug therapy; Infarction, Middle Cerebral Artery - immunology; Infiltration; Inflammation; Ischemia; Macrophages; Macrophages - drug effects; Male; Microglia; Microglia - drug effects; Monocytes; Neuroprotection; Neuroprotective Agents - pharmacology; Neuroprotective Agents - therapeutic use; Rats, Wistar; Reperfusion; Rodents; Stroke; Stroke - drug therapy; Stroke - immunology
• ISSN: 0960-0760; 1879-1220
• DOI: 10.1016/j.jsbmb.2020.105667

•Estradiol substitution significantly reduced the cortical infarct area and improved neurological scoring in the tMCAO model.•tMCAO increased CD45+ and CD45+CD11b+CD11c+ cell percentages.•Estradiol prevented the increase in CD45+ and CD45+CD11b+CD11c+ cell numbers.•Estradiol selectively regulated neuroinflammatory responses mediated by microglia- or infiltrated macrophage signaling. Ischemic stroke is the leading cause of human disability and mortality in the world. Neuroinflammation is the main pathological event following ischemia which contributes to secondary brain tissue damage and is driven by infiltration of circulating immune cells such as macrophages. Because of neuroprotective properties against ischemic brain damage, estrogens have the potential to become of therapeutic interest. However, the exact mechanisms of neuroprotection and signaling pathways is not completely understood. In the current study, 12-week-old male Wistar rats underwent an experimental ischemia by occluding the middle cerebral artery transiently (tMCAO) for 1 h. Male rats subjected to tMCAO were randomly assigned to receive 17β-estradiol or vehicle treatment. The animals were sacrificed 72 h post tMCAO, transcardially perfused and the brains were proceeded either for TTC staining and gene analysis or for flow cytometry (CD45, CD11b, CD11c, CD40). We found that 17β-estradiol substitution significantly reduced the cortical infarct which was paralleled by an improved Garcia test scoring. Flow cytometry revealed that CD45+ cells as well as CD45+CD11b+CD11c+ cells were massively increased in tMCAO animals and numbers were nearly restored to sham levels after 17β-estradiol treatment. Gene expression analysis showed a reperfusion time-dependent upregulation of the markers CD45, CD11b and the activation marker CD40. The reduction in gene expression after 72 h of reperfusion and simultaneous 17β-estradiol substitution did not reach statistical significance. These data indicate that 17β-estradiol alleviated the cerebral ischemia-reperfusion injury and selectively suppressed the activation of the neuroinflammatory cascade via reduction of the number of activated microglia or infiltrated monocyte-derived macrophages in brain.