Brain-derived estrogen exerts anti-inflammatory and neuroprotective actions in the rat hippocampus

Abstract

17β-estradiol (E2) has been implicated to play a critical role in neuroprotection, synaptic plasticity, and cognitive function. Classically, the role of gonadal-derived E2 in these events is well established, but the role of brain-derived E2 is less clear. To address this issue, we investigated the expression, localization, and modulation of aromatase and local E2 levels in the hippocampus following global cerebral ischemia (GCI) in adult ovariectomized rats. Immunohistochemistry (IHC) revealed that the hippocampal regions CA1, CA3 and dentate gyrus (DG) exhibited high levels of immunoreactive aromatase staining, with aromatase being co-localized primarily in neurons in non-ischemic animals. Following GCI, aromatase became highly expressed in GFAP-positive astrocytes in the hippocampal CA1 region at 2–3 days post GCI reperfusion. An ELISA for E2 and IHC for E2 confirmed the GCI-induced elevation of local E2 in the CA1 region and that the increase in local E2 occurred in astrocytes. Furthermore, central administration of aromatase antisense (AS) oligonucleotides, but not missense (MS) oligonucleotides, blocked the increase in aromatase and local E2 in astrocytes after GCI, and resulted in a significant increase in GCI-induced hippocampal CA1 region neuronal cell death and neuroinflammation. As a whole, these results suggest that brain-derived E2 exerts important neuroprotective and anti-inflammatory actions in the hippocampal CA1 region following GCI.

International Union of Basic and Clinical Pharmacology. XCVII. G Protein–Coupled Estrogen Receptor and Its Pharmacologic Modulators

“…Estrogens, both gonadally and brain derived (Zhang et al, 2014b), mediate extensive effects in the central and peripheral nervous system, including regulation of the hypothalamus-pituitary-gonadal axis (discussed above), sexual behavior, synaptic plasticity, mood, memory, cognition, and pain sensation . Although many of these effects likely involve genomic and rapid signaling by ERa and potentially ERb (Bean et al, 2014), as well as a multitude of additional pharmacologically defined but otherwise unidentified estrogen receptors (e.g., ER-X, Gq-mER) (Toran-Allerand, 2004;Kelly and Ronnekleiv, 2013), increasing evidence indicates that predominantly rapid signaling via GPER has multiple roles in E2-mediated neurologic functions (Raz et al, 2008;Srivastava and Evans, 2013).…”

Steroid modulation of neurogenesis: Focus on radial glial cells in zebrafish

“…With respect to hormones, estradiol, is recognized as a major modulator of adult vertebrate neuronal plasticity [39,40] and neurogenesis under physiological conditions and many data also demonstrated its neuroprotective actions in damaged brains [35,[41][42][43][44][45][46][47].…”

Characterization of β-Estradiol 3-Glucuronidation in Rat Brain

“…26) A β-estradiol-generating enzyme, aromatase, is expressed at high levels in the hippocampus CA1-CA3 regions. 27) Because UGT is an enzyme involved in the degradation of β-estradiol, high β-estradiol glucuronidation activity in the hippocampus would serve to maintain β-estradiol levels in the hippocampus. β-Estradiol 3-glucuronidation in the cerebellum was fitted to the Hill equation (Fig.…”