Estradiol and G1 Reduce Infarct Size and Improve Immunosuppression after Experimental Stroke

Abstract

Reduced risk and severity of stroke in adult females is thought to depend on normal endogenous levels of estrogen, a well-known neuroprotectant and immunomodulator. In male mice, experimental stroke induces immunosuppression of the peripheral immune system, characterized by a reduction in spleen size and cell numbers and decreased cytokine and chemokine expression. However, stroke-induced immunosuppression has not been evaluated in female mice. To test the hypothesis that estradiol (E2) deficiency exacerbates immunosuppression after focal stroke in females, we evaluated the effect of middle cerebral artery occlusion on infarct size and peripheral and CNS immune responses in ovariectomized mice with or without sustained, controlled levels of 17-β–E2 administered by s.c. implant or the putative membrane estrogen receptor agonist, G1. Both E2- and G1-replacement decreased infarct volume and partially restored splenocyte numbers. Moreover, E2-replacement increased splenocyte proliferation in response to stimulation with anti-CD3/CD28 Abs and normalized aberrant mRNA expression for cytokines, chemokines, and chemokine receptors and percentage of CD4+CD25+FoxP3+ T regulatory cells observed in E2-deficient animals. These beneficial changes in peripheral immunity after E2 replacement were accompanied by a profound reduction in expression of the chemokine, MIP-2, and a 40-fold increased expression of CCR7 in the lesioned brain hemisphere. These results demonstrate for the first time that E2 replacement in ovariectomized female mice improves stroke-induced peripheral immunosuppression.

Inhibition of glycogen synthase kinase-3β enhances cognitive recovery after stroke: the role of TAK1

“…Although it is possible that there was a "floor" effect, this is unlikely as the residual infarct was still .30% of the ischemic hemisphere even after combination treatment, due to the length of the occlusion. Infarct in this model has the potential to be reduced to as low as 16% (Zhang et al 2010a). However, treatment with the GSK3b inhibitor had no effect on pTAK1 levels.…”

Recent Advances on the Role of G Protein-Coupled Receptors in Hypoxia-Mediated Signaling

“…In this regard, it has been demonstrated that GPER activation may decrease myocardial damage and increase functional recovery after ischemia-reperfusion (I/R) injury, which often induces dangerous complications like arrhythmia in patients with myocardial infarction (74)(75)(76)(77)(78). Likewise, in rat hearts of both sexes exposed to I/R injury, the activation of GPER reduced myocardial inflammation and infarct size as well as improved immunosuppression and myocardial mechanical performance (79)(80)(81). Interestingly, the expression levels of both GPER and HIF-1α were found to be increased in spontaneously hypertensive rat hearts compared to normotensive controls, suggesting that HIF-1α/ GPER signaling may represent a transduction mediator in certain conditions characterized by elevated blood pressure (74), which is tightly linked to hypoxia (82).…”

G protein-coupled estrogen receptor 1 mediates relaxation of coronary arteries via cAMP/PKA-dependent activation of MLCP

“…Conversely, deletion of Gper increases blood pressure (44). G-1 improves functional recovery from myocardial ischemia-reperfusion by reducing post-ischemic contractile dysfunction and infarct size, reduces brain infarct size, and prevents strokeinduced immunosuppression in rats (13,76). However, because of its novelty, the mechanism by which GPER mediates estrogen action is still unclear (38).…”