Sexual hormones regulate the redox status and mitochondrial function in the brain. Pathological implications

Abstract

Compared to other organs, the brain is especially exposed to oxidative stress. In general, brains from young females tend to present lower oxidative damage in comparison to their male counterparts. This has been attributed to higher antioxidant defenses and a better mitochondrial function in females, which has been linked to neuroprotection in this group. However, these differences usually disappear with aging, and the incidence of brain pathologies increases in aged females. Sexual hormones, which suffer a decrease with normal aging, have been proposed as the key factors involved in these gender differences. Here, we provide an overview of redox status and mitochondrial function regulation by sexual hormones and their influence in normal brain aging. Furthermore, we discuss how sexual hormones, as well as phytoestrogens, may play an important role in the development and progression of several brain pathologies, including neurodegenerative diseases such as Alzheimer's and Parkinson's diseases, stroke or brain cancer.

Keywords: Aging; Brain; Mitochondrial function; Redox homeostasis; Sex differences; Sex hormones.

Graphical abstract

Fig. 1

Mechanisms involved in the regulation of redox homeostasis by estradiol. Estradiol can exert its effects by binding to the ERs (ERα or ERβ) or to GPER. Active ERs may bind to the promoter of target genes, which contain an ERE element. Genomic effects include the upregulation of several mitochondrial and metabolic genes, as well as anti-inflammatory and anti-apoptotic genes. Non-genomic effects, such as a reduction of oxidative stress, apoptosis avoidance or anti-inflammatory effects, are mediated through several protein kinases activated by these estrogen receptors.