Abstract
Following brain injury, microglia assume a reactive-like state and secrete pro-inflammatory molecules that can potentiate damage. A therapeutic strategy that may limit microgliosis is of potential interest. In this context, selective estrogen receptor modulators, such as raloxifene and tamoxifen, are known to reduce microglia activation induced by neuroinflammatory stimuli in young animals. In the present study, we have assessed whether raloxifene and tamoxifen are able to affect microglia activation after brain injury in young and aged animals in time points relevant to clinics, which is hours after brain trauma. Volume fraction of MHC-II+ microglia was estimated according to the point-counting method of Weibel within a distance of 350 μm from the lateral border of the wound, and cellular morphology was measured by fractal analysis. Two groups of animals were studied: (1) young rats, ovariectomized at 2 months of age; and (2) aged rats, ovariectomized at 18 months of age. Fifteen days after ovariectomy animals received a stab wound brain injury and the treatment with estrogenic compounds. Our findings indicate that raloxifene and tamoxifen reduced microglia activation in both young and aged animals. Although the volume fraction of reactive microglia was found lower in aged animals, this was accompanied by important changes in cell morphology, where aged microglia assume a bushier and hyperplasic aspect when compared to young microglia. These data suggest that early regulation of microglia activation provides a mechanism by which selective estrogen receptors modulators (SERMs) may exert a neuroprotective effect in the setting of a brain trauma.
Highlights
Microglia are considered as the macrophages of the brain
Our previous observations showed that the age affected the cellular density in animals injected with vehicle (Figure 2), and that the selective estrogen receptors modulators (SERMs) reduced the fraction of reactive microglia reactive bordering the wound
In the present study we assessed the volume fraction of microglia immunoreactive for MHC-II and analyzed their morphology in young and aged animals subjected to penetrating brain injury
Summary
Microglia are considered as the macrophages of the brain. Trauma to the brain causes increased production of reactive oxygen species and oxidative stress, neuronal damage (Barreto et al, 2011) and elicits activation of astrocytes and microglia. Estrogens may exert neuroprotection after brain injury by regulating reactive astrocytes and microglia (Garcia-Estrada et al, 1993; García-Estrada et al, 1999; Barreto et al, 2007, 2009). Despite these protective effects of estradiol on brain, this hormone may produce some side effects in peripheral tissues, especially in women submitted to post-menopausal hormonal therapy. The transcriptional activity of estrogen receptors (ER) is regulated by their association with transcriptional cofactors that have a tissue or cell specific expression (Klinge, 2000; Belandia and Parker, 2003). The effect of estradiol on brain after damage is well explored, the role that SERMs may have is not clear
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