Improvement of neuronal bioenergetics by neurosteroids: Implications for age-related neurodegenerative disorders

Abstract

The brain has high energy requirements to maintain neuronal activity. Consequently impaired mitochondrial function will lead to disease. Normal aging is associated with several alterations in neurosteroid production and secretion. Decreases in neurosteroid levels might contribute to brain aging and loss of important nervous functions, such as memory. Up to now, extensive studies only focused on estradiol as a promising neurosteroid compound that is able to ameliorate cellular bioenergetics, while the effects of other steroids on brain mitochondria are poorly understood or not investigated at all. Thus, we aimed to characterize the bioenergetic modulating profile of a panel of seven structurally diverse neurosteroids (progesterone, estradiol, estrone, testosterone, 3α-androstanediol, DHEA and allopregnanolone), known to be involved in brain function regulation. Of note, most of the steroids tested were able to improve bioenergetic activity in neuronal cells by increasing ATP levels, mitochondrial membrane potential and basal mitochondrial respiration. In parallel, they modulated redox homeostasis by increasing antioxidant activity, probably as a compensatory mechanism to a slight enhancement of ROS which might result from the rise in oxygen consumption. Thereby, neurosteroids appeared to act via their corresponding receptors and exhibited specific bioenergetic profiles. Taken together, our results indicate that the ability to boost mitochondria is not unique to estradiol, but seems to be a rather common mechanism of different steroids in the brain. Thus, neurosteroids may act upon neuronal bioenergetics in a delicate balance and an age-related steroid disturbance might be involved in mitochondrial dysfunction underlying neurodegenerative disorders.

Inflammasomes are neuroprotective targets for sex steroids

“…Further, treatment of peripheral blood mononuclear cells of preeclampsia patients with P in a dose-dependent manner inhibited TLR4 expression at the mRNA level [88]. However, P improves recovery after TBI and in neurodegenerative disorders by positively affecting ROS formation and NFkappaB signaling [89][90][91]. Both pathological stressors of cell physiology and function are, in turn, identified as leading stimulators and activators of the inflammasome multiprotein complexes [92,93].…”

Neurosteroidogenesis Today: Novel Targets for Neuroactive Steroid Synthesis and Action and Their Relevance for Translational Research

“…It was demonstrated (180) that such neuroactive steroids are able to improve neuronal bioenergetics significantly. Missense mutation(s) would abolish the catalytic activity of 17β-HSD10 in the isoleucine degradation pathway such that an accumulation of tiglylglycine and 2-methyl-3- hydroxybutyric acid in blood and the excretion of such isoleucine metabolites from urine is a common symptom in patients with 17β-HSD10 deficiency, which was therefore designated as 2-methyl-3- hydroxybutyryl-CoA dehydrogenase (MHBD) deficiency (181).…”

“…Among the many factors essential for keeping mitochondria healthy, the homeostasis of neuroactive steroids is particularly significant because of its impact on the bioenergetics of brain cells (180). Abnormality of mitochondrial structure and function underlies pathophysiological basis of neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease.…”

Reactive oxygen species: players in the cardiovascular effects of testosterone

“…Testosterone, DHEA and 3␣-androstanediol increase mitochondrial ROS levels, oxygen consumption rate and ATP levels in neuroblastoma cells. Moreover, testosterone increases mitochondrial respiratory capacity (74). Conversely, stanozolol (an anabolic androgenic steroid) decreases mitochondrial ROS and oxidative stress induced by acute exercise in rat skeletal muscle (167).…”