Selective Oestrogen Receptor Agonists Rescued Hippocampus Parameters in Male Spontaneously Hypertensive Rats

Abstract

Spontaneously hypertensive rats (SHR) show pronounced hippocampus alterations, including low brain-derived neurotrophic factor (BDNF) expression, reduced neurogenesis, astrogliosis and increased aromatase expression. These changes are reverted by treatment with 17β-oestradiol. To determine which oestradiol receptor (ER) type is involved in these neuroprotective effects, we used agonists of the ERα [propylpyrazole triol (PPT)] and the ERβ [diarylpropionitrite (DPN)] given over 2 weeks to 4-month-old male SHR. Wistar Kyoto normotensive rats served as controls. Using immunocytochemistry, we determined glial fibrillary protein (GFAP)+ astrocytes in the CA1, CA3 and hilus of the dentate gyrus of the hippocampus, aromatase immunostaining in the hilus, and doublecortin (DCX)+ neuronal progenitors in the inner granular zone of the dentate gyrus. Brain-derived neurotrophic factor mRNA was also measured in the hippocampus by the quantitative polymerase chain reaction. In SHR, PPT had no effect on blood pressure, decreased astrogliosis, slightly increased BDNF mRNA, had no effect on the number of DCX+ progenitors, and increased aromatase staining. Treatment with DPN decreased blood pressure, decreased astrogliosis, increased BDNF mRNA and DCX+ progenitors, and did not modify aromatase staining. We hypothesise that, although both receptor types may participate in the previously reported beneficial effects of 17β-oestradiol in SHR, receptor activation with DPN may preferentially facilitate BDNF mRNA expression and neurogenesis. The results of the present study may help in the design of ER-based neuroprotection for the encephalopathy of hypertension.

Molecular mechanisms and cellular events involved in the neuroprotective actions of estradiol. Analysis of sex differences

“…Azcoitia, et al Frontiers in Neuroendocrinology xxx (xxxx) xxxx estradiol in different brain injury models is well established. These include cellular and animal models of focal and global ischemia (Suzuki et al, 2009;Zhang et al, 2009Zhang et al, , 2017Guo et al, 2012; Tables 1 and 2), chronic hypertension (Pietranera et al, 2016), Parkinsońs disease (Morissette et al, 2008;Al Sweidi et al, 2012), Alzheimer's disease (Guerra et al, 2004; Table 1) and multiple sclerosis (J. Feng et al, 2013;Spence et al, 2013;Table 2;Fig.…”

“…The selective ERβ agonist WAY 200,070 is also neuroprotective in transient global cerebral ischemia (Miller et al, 2005) and the specific ERβ ligand 4-(1-phenyl-cyclohexyl)-phenol (AC-131) has been shown to exert neuroprotective actions in a model of focal stroke in rats (Madinier et al, 2014). The ERβ selective agonist DPN is neuroprotective in the hippocampus of chronic hypertensive rats (Pietranera et al, 2016) and increases GFAP expression in astrocytes and decreases neuronal apoptosis in co-cultures of astrocytes and neurons exposed to oxygen glucose deprivation and reperfusion (Ma et al, 2016). Protective actions of DPN and other ERβ ligands, such has indazole-Cl and WAY-202041, have been also characterized in mouse models of multiple sclerosis, where they stimulate endogenous myelination and functional recovery (Atkinson et al, 2019;Khalaj et al, 2016;Karim et al, 2018Karim et al, , 2019) (see also Section 4.8).…”

“…Brain derived neurotrophic factor (BDNF) is involved in numerous physiological actions of estradiol in the brain and also mediates the neuroprotective actions of the hormone. For instance, estradiol increases BDNF expression in the hippocampus in rat models of hypertensive encephalopathy (Pietranera et al, 2015(Pietranera et al, , 2016 Table 2) and BDNF mediates the neuroprotective actions of estradiol against NMDA induced excitotoxicity in cultured hippocampal slices (Aguirre and Baudry, 2009) and in animal models of global cerebral ischemia (Yang et al, 2010; Table 2). Both IGF-1, acting on IGF-1 receptor, and BDNF, acting on TrkB receptor, activate PI3K/Akt and ERK signaling that, as mentioned before, mediate numerous neuroprotective actions of estradiol.…”

“…The hormone also increases neurogenesis in the SGL of ovariectomized female mice and rats Cheng et al, 2013) submitted to brain ischemia, in the SGL of diabetic mice (Saravia et al, 2006) and in the SGL of rats with hypertensive encephalopathy (Pietranera et al, 2015; Table 2). Althoigh both ERα and ERβ are involved in the regulation of neurogenesis by estradiol, in hypertensive rats the ERβ agonist DPN is more active in increasing neurogenesis than the ERα agonist 4,4′,4″-(4-propyl-[1H]-pyrazole-1,3,5-triyl)trisphenol (PPT) (Pietranera et al, 2016).…”

“…IGF-1 and BDNF, which are known to upregulate adult neurogenesis in the rodent brain, may mediate the effects of estradiol on adult neurogenesis under physiological conditions and after brain injury (Mendez et al, 2006;Pietranera et al, 2016). In addition, in adult male rats submitted to brain ischemia, estradiol post-stroke treatment induces an increase in neurogenesis in the ischemic ipsilateral SVZ in parallel to an increase in hypoxia-inducible factor 1α (HIF-1α) and vascular endothelial growth factor (VEGF) (Zheng et al, 2013; Table 2).…”