Selective Estrogen Receptor Modulators Decrease Reactive Astrogliosis in the Injured Brain: Effects of Aging and Prolonged Depletion of Ovarian Hormones

Abstract

After brain injury, astrocytes acquire a reactive phenotype characterized by a series of morphological and molecular modifications, including the expression of the cytoskeletal protein vimentin. Previous studies have shown that estradiol down-regulates reactive astrogliosis. In this study we assessed whether raloxifene and tamoxifen, two selective estrogen receptor modulators, have effects similar to estradiol in astrocytes. We also assessed whether aging and the timing of estrogenic therapy after ovariectomy influence the action of the estrogenic compounds. Four groups of animals were studied: 1) young rats, ovariectomized at 2 months of age; 2) middle-aged rats, ovariectomized at 8 months of age; 3) aged rats, ovariectomized at 18 months of age; and 4) aged rats, ovariectomized at 2 months and sham operated at 18 months of age. Fifteen days after ovariectomy or sham surgery, animals received a stab wound brain injury and the treatment with the estrogenic compounds. The number of vimentin-immunoreactive astrocytes after injury was significantly higher in the hippocampus of aged rats after a long-term ovariectomy compared with aged animals after a short-term ovariectomy and middle-aged rats. In addition, reactive astrocytes were more numerous in the two groups of aged animals than in young animals. Despite these differences, the estrogenic compounds reduced reactive astrogliosis in all animal groups. These findings indicate that estradiol, raloxifene, and tamoxifen are potential candidates for the control of astrogliosis in young and older individuals and after a prolonged depletion of ovarian hormones.

Glial cells and energy balance

“…Indeed, astrocytes express receptors for estrogens, androgens and progesterone (Pfaff & Keiner 1973, Garcia-Segura et al 1996b, Melcangi et al 2001, Garcia-Ovejero et al 2005 and sex steroids are reported to modulate the glial response to HFD (Louwe et al 2012, Morselli et al 2014. Sex steroids exert neuroprotective effects in various brain regions, with glial cells participating in this phenomenon (Azcoitia et al 2003, Garcia-Ovejero et al 2005, Barreto et al 2009, Ghorbanpoor et al 2014); thus, it is possible that sex hormones could protect against the deleterious effects of HFD-induced obesity on hypothalamic metabolic neuronal circuits by actions on the neighboring glia.…”

Contribution of estrogen receptors alpha and beta in the brain response to traumatic brain injury

“…In the cortex, estradiol may alter gene transcription directly via ERs in astrocytes and microglia. 5 Estradiol regulates neuroinflammatory genes via ERa and ERb in the frontal cortex of female rats. 41 Despite the fact that ERb has been shown to be expressed widely in the CNS in adult mice, 33 in most neurological disease models, the protective effect of estrogen treatment has been shown to be mediated through ERa and has been associated with antiinflammatory effects.…”

Astrocytes Role in Parkinson: A Double-Edged Sword

“…Reactive astrogliosis is the main reaction of astrocytes following brain insults such as infection, trauma [33][34], α-synuclein accumulation [35], ischemia [36][37] and neurodegenerative diseases [3]. This process involves both molecular and morphological changes in the astrocytes, including increased expression of GFAP, vimentin and nestin, uptake of excitotoxic glutamate, protection from oxidative stress by the production of GSH, neuroprotection by release of adenosine, degradation of amyloid-beta peptides, facilitation of blood-brain barrier, increased formation of gap junctions between astrocytes, formation of scars and, in some cases release of inflammatory cytokines, including tumor necrosis factor-α (TNF-α), and production of ROS [3,35,[38][39][40].…”