Title:Neuroprotection and Sex Steroid Hormones: Evidence of Estradiol- Mediated Protection in Hypertensive Encephalopathy
Volume: 12
Issue: 11
Author(s): A.F. De Nicola, M.E. Brocca, L. Pietranera and L.M. Garcia-Segura
Affiliation:
Keywords:
Estradiol, hippocampus, hypertension, hypothalamus, neuroprotection, excitotoxicity, mineralocorticoid receptor
Abstract: Besides their effects on reproduction, estrogens exert neuroprotective effects for brain diseases. Thus, estrogens
ameliorate the negative aspects of aging and age-associated diseases in the nervous system, including hypertension.
Within the brain, the hippocampus is sensitive to the effects of hypertension, as exemplified in a genetic model, the
spontaneously hypertensive rat (SHR). In the dentate gyrus of the hippocampus, SHR present decreased neurogenesis,
astrogliosis, low expression of brain derived neurotrophic factor (BDNF), decreased number of neurons in the hilus and
increased basal levels of the estrogen-synthesizing enzyme aromatase, with respect to the Wistar Kyoto (WKY)
normotensive strain. In the hypothalamus, SHR show increased expression of the hypertensinogenic peptide arginine
vasopressin (AVP) and its V1b receptor. From the therapeutic point of view, it was highly rewarding that estradiol
treatment decreased blood pressure and attenuated brain abnormalities of SHR, rendering hypertension a suitable model to
test estrogen neuroprotection. When estradiol treatment was given for 2 weeks, SHR normalized their faulty brain
parameters. This was shown by the enhancement of neurogenesis in the dentate gyrus, according to increased
bromodeoxyuridine incorporation and doublecortin labeling, decreased reactive astrogliosis, increased BDNF mRNA and
protein expression in the dentate gyrus, increased neuronal number in the hilus of the dentate gyrus and a further
hyperexpression of aromatase. The presence of estradiol receptors in hippocampus and hypothalamus suggests the
possibility of direct effects of estradiol on brain cells. Successful neuroprotection produced by estradiol in hypertensive
rats should encourage the treatment with non-feminizing estrogens and estrogen receptor modulators for age-associated
diseases.
