Activation of the G Protein-Coupled Estrogen Receptor (GPER) Increases Neurogenesis and Ameliorates Neuroinflammation in the Hippocampus of Male Spontaneously Hypertensive Rats

  • Julieta Correa
  • Santiago Ronchetti
  • Florencia Labombarda
  • Alejandro F. De Nicola
  • Luciana PietraneraEmail author
Original Research


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.


GPER Estrogens Hippocampus Hypertension Neurogenesis 



This work was supported by grants from the Ministry of Science and Technology-Agencia Nacional de Promoción Científica y Tecnológica (PICT 2012-0009 and PICT 2012-0820), the National Research Council of Argentina (PIP 112 20170100002CO), the University of Buenos Aires (Ubacyt 20020170100224BA).

Author contributions

All authors contributed to the study conception and design. Material preparation, data collection and analysis was performed by JC and SR. FL and AFDN have made substantial contributions to the analysis and interpretation of data and revised the manuscript critically for important intellectual content. The first draft of the manuscript was written by LP and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.


These funding sources did not have a role in the collection, analysis and interpretation of data, nor in the writing of the report and the decision to submit the paper for publication.

Compliance with Ethical Standards

Conflict of interest

The authors report that they have no conflict of interest.


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Authors and Affiliations

  1. 1.Laboratory of Neuroendocrine BiochemistryInstituto de Biología y Medicina ExperimentalBuenos AiresArgentina
  2. 2.Department of Human Biochemistry, Faculty of MedicineUniversity of Buenos AiresBuenos AiresArgentina

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