BackgroundStroke could lead to serious morbidity, of which ischemic stroke counts for majority of the cases. Inflammation plays an important role in the pathogenesis of ischemic stroke, thus drugs targeting inflammation could be potentially neuroprotective. Estradiol was shown to be neuroprotective as well as anti‐inflammatory in animal models of ischemic stroke with unclear mechanism. We hypothesize that the anti‐inflammatory and neuroprotective effect of estradiol is mediated by the estradiol receptor G protein‐coupled estrogen receptor 1 (GPER) expressed on microglia.MethodsWe have generated the rat global cerebral ischemic model and the primary microglia culture to study the neuroprotective and anti‐inflammatory effect of estradiol. We have further used pharmacological methods and siRNA knockdown approach to study the underlying mechanism.ResultsWe found that estradiol reduced the level of proinflammatory cytokines including IL‐1β and TNF‐α, both in vivo and in vitro. We also found that the specific GPER agonist G1 could reduce the level of IL‐1β (P = 0 P = 0.0017, one‐way ANOVA and post hoc test) and TNF‐α (P < 0.0001) in the primary microglia culture. Moreover, the specific GPER antagonist G15 was able to abolish the anti‐inflammatory effect of estradiol. Estradiol failed to reduce the level of IL‐1β (P = 0.4973, unpaired Student's t‐test) and TNF‐α (P = 0.1627) when GPER was knocked down.ConclusionsOur studies have suggested that GPER expressed on microglia mediated the anti‐inflammatory effect of estradiol after ischemic stroke. Our studies could potentially help to develop more specific drugs to manage inflammation postischemic stroke.

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The damage of white matter, primarily myelinated fibers, in the central nervous system (CNS) of temporal lobe epilepsy (TLE) patients has been recently reported. However, limited data exist addressing the types of changes that occur to myelinated fibers inside the hippocampus as a result of TLE. The current study was designed to examine this issue in a lithium-pilocarpine rat model. Investigated by electroencephalography (EEG), Gallyas silver staining, immunohistochemistry, western blotting, transmission electron microscopy, and stereological methods, the results showed that hippocampal myelinated fibers of the epilepsy group were degenerated with significantly less myelin basic protein (MBP) expression relative to those of control group rats. Stereological analysis revealed that the total volumes of hippocampal formation, myelinated fibers, and myelin sheaths in the hippocampus of epilepsy group rats were decreased by 20.43%, 49.16%, and 52.60%, respectively. In addition, epilepsy group rats showed significantly greater mean diameters of myelinated fibers and axons, whereas the mean thickness of myelin sheaths was less, especially for small axons with diameters from 0.1 to 0.8µm, compared to control group rats. Finally, the total length of the myelinated fibers in the hippocampus of epilepsy group rats was significantly decreased by 56.92%, compared to that of the control group, with the decreased length most prominent for myelinated fibers with diameters from 0.4 to 0.8µm. This study is the first to provide experimental evidence that the integrity of hippocampal myelinated fibers is negatively affected by inducing epileptic seizures with pilocarpine, which may contribute to the abnormal propagation of epileptic discharge.

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