LA DIFFERENZIAZIONE SESSUALE DEL CERVELLO NON È SOLO UNA QUESTIONE DI ORMONI

One of the key events occurring during fetal brain development is the induction of permanent morpho-functional sexual differences in many brain areas. This "imprinting" mechanism, operating on a plastic brain within a narrow sensitive window, leads to gender-specific responses to the same stimulus both in neurochemistry/neuroendocrinology, and in some behavioral responses. The origin of CNS dimorphism is a topic that has fascinated neuroscientists for more than 60 years. The conventional view of brain sexual differentiation proposes that the masculine or feminine brain organization depends on the presence or absence of early gonadal steroid exposure: prenatal testosterone (T) surge in males induces both the masculinization and the defeminization of some brain nuclei, while in the absence of fetal gonadal hormones, as in females, the brain appears to feminize spontaneously. Some effects of T depend on its conversion to estradiol or DHT, two active metabolites formed by the enzymes aromatase and 5alpha-reductase type 2, respectively. Many studies carried out on rodents in our and in other laboratories clarified that estradiol and DHT are implicated in both masculinization and defeminization; on the contrary, T as such and DHT seem to be the main brain organizers in men. However, the most recent research, briefly discussed in this paper, has now clarified that the hormonal environment alone is not sufficient to trigger the whole process and that a precise coordination and interaction among hormonal signals, neuronal genome and the epigenome are pivotal to the genesis of brain gender-specific differentiation. Given the complexity of the whole process, it is not surprising that any external perturbation that brain sex differentiation may have heavy consequences on several parameters. Some possible variations related to prenatal exposure to environmental pollutants that interfere with the hormonal activity and/or the epigenome will be briefly analyzed in the final part of the paper

A selective alpha1D-adrenoreceptor antagonist inhibits human prostate cancer cell proliferation and motility "in vitro"

The progression of prostate cancer (PC) to a metastatic hormone refractory disease is the major contributor to the overall cancer mortality in men, mainly because the conventional therapies are generally ineffective at this stage. Thus, other therapeutic options are needed as alternatives or in addition to the classic approaches to prevent or delay tumor progression. Catecholamines participate to the control of prostate cell functions by the activation of alpha1-adrenoreceptors (alpha1-AR) and increased sympathetic activity has been linked to PC development and evolution. Molecular and pharmacological studies identified three alpha1-AR subtypes (A, B and D), which differ in tissue distribution, cell signaling, pharmacology and physiological role. Within the prostate, alpha1A-ARs mainly control stromal cell functions, while alpha1B- and alpha1D- subtypes seem to modulate glandular epithelial cell growth. The possible direct contribution of alpha1D-ARs in tumor biology is supported by their overexpression in PC. The studies here presented investigate the "in vitro" antitumor action of A175, a selective alpha1D-AR antagonist we have recently obtained by modifying the potent, but not subtype-selective alpha1-AR antagonist (S)-WB4101, in the hormone-refractory PC3 and DU145 PC cell lines. The results indicate that A175 has an alpha1D-AR-mediated significant and dose-dependent antiproliferative action that possibly involves the induction of G0/G1 cell cycle arrest, but not apoptosis. In addition, A175 reduces cell migration and adhesiveness to culture plates. In conclusion, our work clarified some cellular aspects promoted by alpha1D-AR activity modulation and supports a further pharmacological approach in the cure of hormone-refractory PC, by targeting specifically this AR subtype