Involvement of neuroactive steroids in hippocampal disorders: lesson from animal models

Abstract

Steroids secreted from peripheral endocrine glands and acting on the brain are called neuroactive steroids. Under physiological conditions, neuroactive steroids modulate multiple brain functions, and in aging, trauma or neurodegeneration their role varies from neuroprotective to neurotoxic depending on the chemical properties of the steroid. In this regard, it is known that excess levels of adrenal steroids (gluco and mineralocorticoids) sensitize the hippocampus to the deleterious effects of a pathological environment, whereas the sex hormone estradiol is a powerful hippocampal neuroprotectant. We studied the protective role of estrogens in the ailing hippocampus in animal models of aging and age-associated diseases such as diabetes mellitus and hypertension of genetic (SHR) or mineralocorticoid origin. These models present in common a glucocorticoid or mineralocorticoid overdrive, a process that exacerbates hippocampal neuropathology, according to: (1) decreased proliferation of neuronal progenitors in the subgranular zone (SGZ) of the dentate gyrus (DG); (2) astroglial reactivity, with increased expression of the glial fibrillary acidic protein (GFAP); and (3) decreased neuronal density in the hilus of the DG. These pathological changes were reversible by treatment with estrogens, which ameliorated the hippocampal parameters in middle age mice and models of diabetes and hypertension. Thus, estradiol treatment stimulated progenitor proliferation in the SGZ, normalized the density of GFAP+ astrocytes, and avoided the loss of hilar neurons. Given the important role of the hippocampus in learning, memory and neuroendocrine events, estrogens may offer therapeutic advantages for the treatment of brain disturbances accompanying systemic diseases and aging.