RESUMO
For many decades to date, neuroendocrinologists have delved into the key contribution of gonadal hormones to the generation of sex differences in the developing brain and the expression of sex-specific physiological and behavioral phenotypes in adulthood. However, it was not until recent years that the role of sex chromosomes in the matter started to be seriously explored and unveiled beyond gonadal determination. Now we know that the divergent evolutionary process suffered by X and Y chromosomes has determined that they now encode mostly dissimilar genetic information and are subject to different epigenetic regulations, characteristics that together contribute to generate sex differences between XX and XY cells/individuals from the zygote throughout life. Here we will review and discuss relevant data showing how particular X- and Y-linked genes and epigenetic mechanisms controlling their expression and inheritance are involved, along with or independently of gonadal hormones, in the generation of sex differences in the brain.
Assuntos
Diferenciação Sexual , Cromossomo Y , Feminino , Masculino , Animais , Diferenciação Sexual/genética , Cromossomos Sexuais/genética , Cromossomos Sexuais/metabolismo , Caracteres Sexuais , Hormônios Gonadais/metabolismo , Encéfalo/metabolismo , Epigênese Genética , Cromossomo XRESUMO
Several X-linked genes are involved in neuronal differentiation and may contribute to the generation of sex dimorphisms in the brain. Previous results showed that XX hypothalamic neurons grow faster, have longer axons, and exhibit higher expression of the neuritogenic gene neurogenin 3 (Ngn3) than XY before perinatal masculinization. Here we evaluated the participation of candidate X-linked genes in the development of these sex differences, focusing mainly on Kdm6a, a gene encoding for an H3K27 demethylase with functions controlling gene expression genome-wide. We established hypothalamic neuronal cultures from wild-type or transgenic Four Core Genotypes mice, a model that allows evaluating the effect of sex chromosomes independently of gonadal type. X-linked genes Kdm6a, Eif2s3x and Ddx3x showed higher expression in XX compared to XY neurons, regardless of gonadal sex. Moreover, Kdm6a expression pattern with higher mRNA levels in XX than XY did not change with age at E14, P0, and P60 in hypothalamus or under 17ß-estradiol treatment in culture. Kdm6a pharmacological blockade by GSK-J4 reduced axonal length only in female neurons and decreased the expression of neuritogenic genes Neurod1, Neurod2 and Cdk5r1 in both sexes equally, while a sex-specific effect was observed in Ngn3. Finally, Kdm6a downregulation using siRNA reduced axonal length and Ngn3 expression only in female neurons, abolishing the sex differences observed in control conditions. Altogether, these results point to Kdm6a as a key mediator of the higher axogenesis and Ngn3 expression observed in XX neurons before the critical period of brain masculinization.
Assuntos
Genes Ligados ao Cromossomo X/genética , Histona Desmetilases/genética , Histonas/genética , Hipotálamo/fisiologia , Neurônios/fisiologia , Diferenciação Sexual/genética , Animais , Axônios/fisiologia , Feminino , Masculino , Camundongos , Proteínas do Tecido Nervoso/genética , Caracteres SexuaisRESUMO
Tibolone (TIB), a selective tissue estrogenic activity regulator (STEAR) in clinical use by postmenopausal women, activates hormonal receptors in a tissue-specific manner. Estrogenic activity is present mostly in the brain, vagina, and bone, while the inactive forms predominate in the endometrium and breast. Conflicting literature on TIB's actions has been observed. While it has benefits for vasomotor symptoms, bone demineralization, and sexual health, a higher relative risk of hormone-sensitive cancer has been reported. In the brain, TIB can improve mood and cognition, neuroinflammation, and reactive gliosis. This review aims to discuss the systemic effects of TIB on peri- and post-menopausal women and its role in the brain. We suggest that TIB is a hormonal therapy with promising neuroprotective properties.
Assuntos
Encéfalo/efeitos dos fármacos , Moduladores de Receptor Estrogênico/farmacologia , Menopausa/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Norpregnenos/farmacologia , Encéfalo/imunologia , Encéfalo/metabolismo , Moduladores de Receptor Estrogênico/efeitos adversos , Feminino , Humanos , Menopausa/imunologia , Menopausa/metabolismo , Norpregnenos/efeitos adversosRESUMO
Hypothalamic neurons show sex differences in neuritogenesis, female neurons have longer axons and higher levels of the neuritogenic factor neurogenin 3 (Ngn3) than male neurons in vitro. Moreover, the effect of 17-ß-estradiol (E2) on axonal growth and Ngn3 expression is only found in male-derived neurons. To investigate whether sex chromosomes regulate these early sex differences in neuritogenesis by regulating the E2 effect on Ngn3, we evaluated the growth and differentiation of hypothalamic neurons derived from the "four core genotypes" mouse model, in which the factors of "gonadal sex" and "sex chromosome complement" are dissociated. We showed that sex differences in neurite outgrowth are determined by sex chromosome complement (XX > XY). Moreover, E2 increased the mRNA expression of Ngn3 and axonal length only in XY neurons. ERα/ß expressions are regulated by sex chromosome complement; however, E2-effect on Ngn3 expression in XY neurons was only fully reproduced by PPT, a specific ligand of ERα, and prevented by MPP, a specific antagonist of ERα. Together our data indicate that sex chromosomes regulate early development of hypothalamic neurons by orchestrating not only sex differences in neuritogenesis, but also regulating the effect of E2 on Ngn3 expression through activation of ERα in hypothalamic neurons.
Assuntos
Axônios , Fatores de Transcrição Hélice-Alça-Hélice Básicos/fisiologia , Estradiol/fisiologia , Hipotálamo/metabolismo , Proteínas do Tecido Nervoso/fisiologia , Neurônios/metabolismo , Cromossomos Sexuais , Animais , Feminino , Masculino , CamundongosRESUMO
The high concentrations of free fatty acids as a consequence of obesity and being overweight have become risk factors for the development of different diseases, including neurodegenerative ailments. Free fatty acids are strongly related to inflammatory events, causing cellular and tissue alterations in the brain, including cell death, deficits in neurogenesis and gliogenesis, and cognitive decline. It has been reported that people with a high body mass index have a higher risk of suffering from Alzheimer's disease. Hormones such as oestradiol not only have beneficial effects on brain tissue, but also exert some adverse effects on peripheral tissues, including the ovary and breast. For this reason, some studies have evaluated the protective effect of oestrogen receptor (ER) agonists with more specific tissue activities, such as the neuroactive steroid tibolone. Activation of ERs positively affects the expression of pro-survival factors and cell signalling pathways, thus promoting cell survival. This review aims to discuss the relationship between lipotoxicity and the development of neurodegenerative diseases. We also elaborate on the cellular and molecular mechanisms involved in neuroprotection induced by oestrogens.
Assuntos
Encéfalo/metabolismo , Estrogênios/metabolismo , Ácidos Graxos não Esterificados/metabolismo , Inflamação/metabolismo , Neuroglia/metabolismo , Animais , Encéfalo/patologia , Humanos , Inflamação/patologia , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/patologia , Neuroglia/patologia , Transdução de Sinais/fisiologiaRESUMO
Palmitic acid (PA) induces several metabolic and molecular changes in astrocytes, and, it is involved in pathological conditions related to neurodegenerative diseases. Previously, we demonstrated that tibolone, a synthetic steroid with estrogenic, progestogenic and androgenic actions, protects cells from mitochondrial damage and morphological changes induced by PA. Here, we have evaluated which estrogen receptor is involved in protective actions of tibolone and analyzed whether tibolone reverses gene expression changes induced by PA. Tibolone actions on astrocytic cells were mimicked by agonists of estrogen receptor α (ERα) and ß (ERß), but the blockade of both ERs suggested a predominance of ERß on mitochondria membrane potential. Expression analysis showed a significant effect of tibolone on genes associated with inflammation such as IL6, IL1B and miR155-3p. It is noteworthy that tibolone attenuated the increased expression of TERT, TERC and DNMT3B genes induced by palmitic acid. Our results suggest that tibolone has anti-inflammatory effects and can modulate pathways associated with DNA methylation and telomeric complex. However, future studies are needed to elucidate the role of epigenetic mechanisms and telomere-associated proteins on tibolone actions.
Assuntos
Astrócitos/metabolismo , Receptor alfa de Estrogênio/metabolismo , Inflamação/patologia , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Norpregnenos/farmacologia , Ácido Palmítico/toxicidade , Astrócitos/efeitos dos fármacos , Linhagem Celular , Epigênese Genética/efeitos dos fármacos , Estradiol/farmacologia , Receptor alfa de Estrogênio/agonistas , Receptor alfa de Estrogênio/antagonistas & inibidores , Receptor beta de Estrogênio/agonistas , Receptor beta de Estrogênio/antagonistas & inibidores , Receptor beta de Estrogênio/metabolismo , Humanos , Inflamação/genética , Nitrilas/farmacologia , Fenóis , Substâncias Protetoras/farmacologia , Pirazóis , Telomerase/genética , Telomerase/metabolismo , Telômero/metabolismo , Fatores de Transcrição/metabolismoRESUMO
Microglial cells become dystrophic with aging; this phenotypic alteration contributes to basal central nervous system (CNS) neuroinflammation being a risk factor for age related neurodegenerative diseases. In previous studies we have observed that insulin like growth factor 1 (IGF1) gene therapy is a feasible approach to target brain cells, and that is effective to modify inflammatory response in vitro and to ameliorate cognitive or motor deficits in vivo. Based on these findings, the main aim of the present study is to investigate the effect of IGF1 gene therapy on microglia distribution and morphology in the senile rat. We found that IGF1 therapy leads to a region-specific modification of aged microglia population.
RESUMO
Traumatic brain injury (TBI) is a serious public health problem. It may result in severe neurological disabilities and in a variety of cellular metabolic alterations for which available therapeutic strategies are limited. In the last decade, the use of estrogenic compounds, which activate protective mechanisms in astrocytes, has been explored as a potential experimental therapeutic approach. Previous works have suggested estradiol (E2) as a neuroprotective hormone that acts in the brain by binding to estrogen receptors (ERs). Several steroidal and nonsteroidal estrogenic compounds can imitate the effects of estradiol on ERs. These include hormonal estrogens, phytoestrogens and synthetic estrogens, such as selective ER modulators or tibolone. Current evidence of the role of astrocytes in mediating protective actions of estrogenic compounds after TBI is reviewed in this paper. We conclude that the use of estrogenic compounds to modulate astrocytic properties is a promising therapeutic approach for the treatment of TBI.