Neuroactive steroids, their metabolites, and neuroinflammation (original) (raw)

Steroids and neuroprotection: New advances

Frontiers in Neuroendocrinology, 2009

Gonadal hormones exert neuroprotective actions. In addition, it has become evident that the local synthesis of these molecules in the central nervous system may prevent or reduce neurodegeneration. The neuroprotective actions of steroids involve neurons, glial cells and blood vessels, are exerted via steroid receptor signaling initiated at the nuclear or membrane level and steroid receptor independent mechanisms. They include the regulation of phosphatases and kinases and the regulation of the expression of molecules controlling inflammation and apoptosis. In addition, mitochondria have emerged as new central targets for neuroprotective actions of steroids. These neuroprotective actions have been documented in different experimental models of neurological alterations, including motoneuron injury, Parkinson's disease, traumatic brain injury, multiple sclerosis, stroke and Alzheimer's disease. In addition, steroids promote serotonergic neuronal function and protect against affective disorders. This special issue of Frontiers in Neuroendocrinology contains a collection of reviews of the most recent ideas and findings on these various aspects of sex steroid-dependent neuroprotection.

Milestones on Steroids and the Nervous System: 10 Years of Basic and Translational Research

2012

During the last ten years, the conference on "Steroids and Nervous System" held in Torino (Italy) was an important international point of discussion for scientists involved in this exciting and expanding research field. The present review aimed to recapitulate the main topics that were presented through the various editions of the meeting. Two broad areas were explored: the impact of gonadal hormones on brain circuits and behaviour, and the mechanism of action of neuroactive steroids. Relationships among steroids, brain and behaviour, the sexual differentiation of the brain and the impact of gonadal hormones, the interactions of exogenous steroidal molecules (endocrine disrupters) with neural circuits and behaviour, and how gonadal steroids modulate the behaviour of GnRH neurones were the topics of several lectures and symposia during this series of meetings. At the same time, many contributions were dedicated to the biosynthetic pathways, the physiopathological relevance of neurosteroids, and the demonstration of the cellular localization of different enzymes involved in neurosteroidogenesis, the mechanisms by which steroids may exert some of their effects, both classical and non-classical action of different steroids, the role of neuroactive steroids on neurodegeneration, neuroprotection and the response of the neural tissue to injury. In these 10 years, this field has significantly advanced and neuroactive steroids have emerged as new potential therapeutic tools to counteract neurodegenerative events.

The Role of Steroid Hormones in the Modulation of Neuroinflammation by Dietary Interventions

Frontiers in Endocrinology, 2016

Steroid hormones, such as sex hormones and glucocorticoids, have been demonstrated to play a role in different cellular processes in the central nervous system, ranging from neurodevelopment to neurodegeneration. Environmental factors, such as calorie intake or fasting frequency, may also impact on such processes, indicating the importance of external factors in the development and preservation of a healthy brain. The hypothalamic-pituitary-adrenal axis and glucocorticoid activity play a role in neurodegenerative processes, including in disorders such as in Alzheimer's and Parkinson's diseases. Sex hormones have also been shown to modulate cognitive functioning. Inflammation is a common feature in neurodegenerative disorders, and sex hormones/ glucocorticoids can act to regulate inflammatory processes. Intermittent fasting can protect the brain against cognitive decline that is induced by an inflammatory stimulus. On the other hand, obesity increases susceptibility to inflammation, while metabolic syndromes, such as diabetes, are associated with neurodegeneration. Consequently, given that gonadal and/or adrenal steroids may significantly impact the pathophysiology of neurodegeneration, via their effect on inflammatory processes, this review focuses on how environmental factors, such as calorie intake and intermittent fasting, acting through their modulation of steroid hormones, impact on inflammation that contributes to cognitive and neurodegenerative processes.

Impact of sex steroids on neuroinflammatory processes and experimental multiple sclerosis

Frontiers in Neuroendocrinology, 2009

Synthetic and natural estrogens as well as progestins modulate neuronal development and activity. Neurons and glia are endowed with high-affinity steroid receptors. Besides regulating brain physiology, both steroids conciliate neuroprotection against toxicity and neurodegeneration. The majority of data derive from in vitro studies, although more recently, animal models have proven the efficaciousness of steroids as neuroprotective factors. Indications for a safeguarding role also emerge from first clinical trials. Gender-specific prevalence of degenerative disorders might be associated with the loss of hormonal activity or steroid malfunctions. Our studies and evidence from the literature support the view that steroids attenuate neuroinflammation by reducing the pro-inflammatory property of astrocytes. This effect appears variable depending on the brain region and toxic condition. Both hormones can individually mediate protection, but they are more effective in cooperation. A second research line, using an animal model for multiple sclerosis, provides evidence that steroids achieve remyelination after demyelination. The underlying cellular mechanisms involve interactions with astroglia, insulin-like growth factor-1 responses, and the recruitment of oligodendrocytes.

Steroid synthesis and metabolism in the nervous system: Trophic and protective effects

Journal of Neurocytology, 2000

Steroids influence the activity and plasticity of neurons and glial cells during early development, and they continue to exert trophic and protective effects in the adult nervous system. Steroids are produced by the gonads and adrenal glands and reach the brain, the spinal cord and the peripheral nerves via the bloodstream. However, some of them, named “neurosteroids”, can also be

Therapeutic implications of brain steroidogenesis

hmbci, 2010

The nervous system is a steroidogenic tissue and several steroids synthesized locally in the brain, such as pregnenolone, progesterone and estradiol, modulate neuronal and glial physiology and are neuroprotective. The brain upregulates steroidogenesis at sites of injury as part of a program triggered by neural tissue to cope with neurodegenerative insults. Pharmacological targets to increase brain steroidogenesis and promote neuroprotection include the molecules that transport cholesterol to the inner mitochondrial membrane, where the first enzyme for steroidogenesis is located. Furthermore, the human gene encoding aromatase, the enzyme that synthesizes estradiol, is under the control of different tissue-specific promoters, and it is therefore conceivable that selective aromatase modulators can be developed that will enhance the expression of the enzyme and the consequent increase in estrogen formation in the brain but not in other tissues.

Brain steroidogenesis: emerging therapeutic strategies to prevent neurodegeneration

Journal of Neural Transmission, 2005

Decreasing levels of gonadal steroids with aging are associated to an increase in cognitive, neurological and psychiatric disturbances. Estradiol is neuroprotective in animal models of neurodegeneration. However, the effects of hormonal replacement therapy on brain function in postmenopausal women are controversial. A possible alternative to hormonal replacement therapy is to increase local brain steroidogenesis, since experimental studies indicate that local estrogen formation in the brain is neuroprotective.

Microglial Dependent Protective Effects of Neuroactive Steroids

Microglial cells are extremely important for homeostasis of the CNS. Upon brain damage, microglia become reactive in response to inflammatory stimuli and lead to the secretion of inflammatory cytokines. Because microglia have the ability of adjusting their steady state to an active phenotype that modulates the CNS environment, chronic activation of microglia has an important role in mediating neuroinflammatory brain diseases. Depending upon the nature and degree of the injury stimulus, microglial activity may alternate, either to acute and mild responses-sometimes beneficial-or chronic and severe that may result in neurodegeneration. In this context, proper and controlled activation of microglia should be considered as a potential neuroprotective strategy against neurodegeneration. More recently, the use of estrogenic compounds to regulate microgliosis has shown promising results, and is currently being investigated due to their potential pharmacologic ability in the regulation of inflammation. In this review, we highlight the role of microglia-mediated damage and discuss the effect of neurosteroids in reducing the adverse impact of inflammation in the brain.