Activation of the G Protein-Coupled Estrogen Receptor (GPER) Increases Neurogenesis and Ameliorates Neuroinflammation in
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ORIGINAL RESEARCH
Activation of the G Protein‑Coupled Estrogen Receptor (GPER) Increases Neurogenesis and Ameliorates Neuroinflammation in the Hippocampus of Male Spontaneously Hypertensive Rats Julieta Correa1 · Santiago Ronchetti1 · Florencia Labombarda1,2 · Alejandro F. De Nicola1,2 · Luciana Pietranera1,2 Received: 16 July 2019 / Accepted: 22 November 2019 © Springer Science+Business Media, LLC, part of Springer Nature 2019
Abstract It is known that spontaneously hypertensive rats (SHR) present a marked encephalopathy, targeting vulnerable regions such as the hippocampus. Abnormalities of the hippocampus of SHR include decreased neurogenesis in the dentate gyrus (DG), partial loss of neurons in the hilus of the DG, micro and astrogliosis and inflammation. It is also known that 17β-estradiol (E2) exert neuroprotective effects and prevent hippocampal abnormalities of SHR. The effects of E2 may involve a variety of mechanisms, including intracellular receptors of the ERα and ERβ subtypes or membrane-located receptors, such as the G protein-coupled estradiol receptor (GPER). We have now investigated the protective role of GPER in SHR employing its synthetic agonist G1. To accomplish this objective, 5 month-old male SHR received 150 μg/day of G1 during 2 weeks. At the end of this period, we analyzed neuronal progenitors by staining for doublecortin (DCX), and counted the number of glial fibrillary acidic protein (GFAP)-labeled astrocytes and Iba1-stained microglial cells by computerized image analysis. We found that G1 activation of GPER increased DCX+ cells in the DG and reduced GFAP+ astrogliosis and Iba1+ microgliosis in the CA1 region of hippocampus. We also found that the high expression of proinflammatory makers IL1β and cyclooxygenase 2 (COX2) of SHR was decreased after G1 treatment, which correlated with a change of microglia phenotype from the activated to a resting morphology. Additionally, G1 treatment increased the anti-inflammatory factor TGFβ in SHR hippocampus. Altogether, our results suggest that activation of GPER plays a neuroprotective role on the encephalopathy of SHR, an outcome resembling E2 effects but avoiding secondary effects of the natural hormone. Keywords GPER · Estrogens · Hippocampus · Hypertension · Neurogenesis
Introduction Essential hypertension in humans is accompanied with morphological and functional alterations of the central nervous system (CNS), including the hippocampus. There are many animal models of cerebrovascular diseases. The spontaneously hypertensive rat (SHR) is a genetic model that Julieta Correa and Santiago Ronchetti contributed equally to this manuscript. * Luciana Pietranera [email protected] 1
Laboratory of Neuroendocrine Biochemistry, Instituto de Biología y Medicina Experimental, Vuelta de Obligado 2490, 1428 Buenos Aires, Argentina
Department of Human Biochemistry, Faculty of Medicine, University of Buenos Aires, Buenos Aires, Argentina
2
replicates many of the pathological outcomes of essential hypertension (Meneses et al. 1996; Tay
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