ERK activation by zeranol has neuroprotective effect in cerebral ischemia reperfusion.

Incidence of stroke increases in postmenopausal women with dangerous consequences. In this study we used zeranol to protect ovariectomized (OVX) rats against cerebral I/R damage and our target is to identify the mechanism of its protection, in addition to investigating whether this mechanism inhibits inflammation (by preventing glial cell activation) and apoptosis. First 18 ovariectomized rats were allocated into 3 groups: I/R group, zeranol+ I/R group and U0126, MEK1/2 inhibitor + zeranol+ I/R group. After 24 h reperfusion, protein expression of total extracellular signal-regulated protein kinase (t-ERK1/2), phosphorylated extracellular signal-regulated protein kinase (p-ERK1/2), Bcl-2, and Bax were quantified. Second 36 female rats were allocated into 3 groups: sham group, I/R group (after ovariectomy by 7 weeks, rats exposed to cerebral I/R) and zeranol group (after ovariectomy by 2 weeks, rats received zeranol for 5 weeks). After 24 h of reperfusion, the following parameters were measured; total nitrate/nitrite, interleukin-10, myeloperoxidase, caspase-3, and finally immunohistochemistry analysis of glial fibrillary acidic protein, cyclooxygenase-2 in cortex and hippocampus (CA1) regions were performed. U-0126 administration reversed the neuroprotective effect induced by zeranol through decreasing ratio of p-ERK1/2:ERK1/2 and Bcl-2/Bax in brain tissue. Activation of ERK signaling pathway by zeranol caused reduction in brain apoptosis and inflammation. Zeranol showed protective effect in OVX rats that were exposed to cerebral I/R by activation of ERK signaling pathway which was blocked by U0126. This protective effect in turns led to decrease inflammation and apoptosis. Representative diagram presenting the mechanistic pathway of zeranol against I/R injury in OVX rats. ER: estrogen receptor; MEK1/2: mitogen activated protein kinase; p-ERK: phosphorylated extracellular signal regulated protein kinase 1/2; iNOS: inducible nitric oxide sunthase; IL-10: interleukin-10; GFAP: glial fibrillary acidic protein; COX-2: cyclooxygenase-2; MPO: myeloperoxidase; Bax: Bcl-2 associated x protein; Bcl-2: B-cell lymphoma 2. Unlabelled Image [ABSTRACT FROM AUTHOR]