Neuroprotection and sex steroid hormones: evidence of estradiol mediated protection in hypertensive encephalopathy

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.