Horm Metab Res. 2017 Jan;49(1):16-22. doi: 10.1055/s-0042-119201.

Neuroactive Steroids in Acute Ischemic Stroke: Association with Cognitive, Functional, and Neurological Outcomes.

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It is interesting to ask why certain nervous system diseases such as neurodegenerative conditions (i.e. Alzheimer’s, Parkinson’s and Huntington’s diseases), mental diseases (i.e. depression) or neurovascular disorder (i.e. ischemic stroke) (Reeves et al., 2008, Casas et al., 2017) are more prevalent in the last decades of life (Andersen et al., 1999, Pekmezovic et al., 2007). Also, why males are more susceptible to these diseases at a younger age than females? On the other hand, if we observe the newborns situation, why does ischemic stroke has a higher death rate in male than in female? (Manwani et al., 2013). Is it just a statistical value or does the female nervous system has special endogenous neuroprotection? This different presentation of neurological disorders respect to age and sex would be due to a differential neuroendocrinological condition between man and woman. That is, until the 1980s, sex hormones (such as estradiol, progesterone and testosterone) were considered as regulators of sexual behavior and reproduction. However, in the last few years there has been increased knowledge regarding the functional role of steroid hormones in the nervous system. With the advent of new molecular techniques, alternative actions of these molecules were demonstrated in both health and disease conditions (Bourque M, et al 2009).

Neuroactive steroids

Steroids hormones (i.e. progesterone, estrogen, testosterone, cortisol) are chemical molecules derive from cholesterol and their main source are peripheral glands such as gonads, (testes and ovaries), adrenal glands and placenta (Melcangi et al, 2008). However, observations made in the eighties by Baulieu (Baulieu EE, 1981; Corpechot C et al, 1981) it showed that some steroids such as pregnenolone, dihydroepiandrosterone and their sulfated forms pregnenolone sulfate and dihydroepiandrosterone sulfate, respectively, were in higher concentrations in the brain than in rodent plasma. In addition, the concentration of these steroids remained unchanged in the brain 15 days after the removal of the peripheral glands responsible for steroidogenesis (gonads and adrenal cortex), suggesting that the biosynthesis of these steroids could occur in the brain (Corpechot C et al, 1993).

The term neuroactive steroid refers to steroids that, regardless of their origin, are able to modulate physiological functions of the central and peripheral nervous system (Dubrovsky B, 2005, Melcangi et al, 2008). This term was proposed for all synthetic and natural steroids that could rapidly alter the excitability of neurons by binding to the membrane receptor (Paul and Purdy, 1992). Neuroactive steroids include molecules that are synthesized in the central nervous system (i.e., neurosteroids), molecules synthesized in peripheral glands (i.e., steroid hormones) and synthetic molecules (Melcangi et al., 2008). (Figure 1).



Fig 1. History evolution about effects of neuroactive steroids and its synthesis tissues. The observation that Baulieu shown in the eighties marked a break point in the line of time in relationship with the classical concept about effect of steroids in health conditions.


Synthesis of neuroactive steroids

The biosynthesis of all neuroactive steroids begins with the enzymatic conversion of cholesterol to pregnenolone (Mensah Nyasan et al, 1999). The limiting step in steroidogenesis is the transport of cholesterol to the inner mitochondrial membrane where the first steroidogenic enzyme is the P450scc (cytocrome P450 side chain cleavage), which transforms cholesterol into pregnenolone. There are two proteins that mediate the translocation of cytoplasmic cholesterol to the inner mitochondrial membrane: the protein of acute regulation of steroidogenesis (StAR, steroidogenic acute regulatory protein) and the mitochondrial benzodiazepine receptor (MBR, mitochondrial-type benzodiazepine receptor). The StAR protein appears to interact with the MBR receptor to facilitate the transport of cholesterol through the mitochondrial membrane (Belelli D y cols, 2005). It has been proposed that this protein captures cholesterol from the outer mitochondrial membrane and transfers it to the MBR, which would form the cholesterol channel and transport it to the internal mitochondrial membrane to be used as a substrate of the enzyme P450scc (Sierra A, 2004).

Several studies have demonstrated the presence of enzymes responsible for steroidogenesis in the nervous system (i.e. 3β-hydroxysteroid dehydrogenase, cytochrome P450c17, 5α-reductase, 3α-hydroxysteroid oxido-reductase, 17β-hydroxysteroid dehydrogenase and aromatase) (Mensah Nyasan AG et al, 1999). These enzymes are able to synthesize steroids from cholesterol and metabolize the peripheral steroids that reach the nervous system through the bloodstream. The major steroidogenic cells in the nervous system are neurons and glial cells. (Figure 2).



Fig 2. The biosynthesis of all neuroactive steroids begins with the enzymatic conversion of cholesterol to pregnenolone. The limiting step in steroidogenesis is the transport of cholesterol to the inner mitochondrial membrane where the first steroidogenic enzyme is the P450scc.There are two proteins that mediate the translocation of cytoplasmic cholesterol to the inner mitochondrial membrane: the protein of acute regulation of steroidogenesis (StAR, steroidogenic acute regulatory protein) and the mitochondrial benzodiazepine receptor (MBR, mitochondrial-type benzodiazepine receptor).


General action mechanism of neuroactive steroids

Neuroactive steroids are involved in a large number of neurophysiological and behavioral processes. The mechanisms by which they exert these functions can be divided into 2 types (Mellon S, 1994):

Genomic: The lipophilic nature of these steroid molecules causes them to be able to bind to specific intracellular receptors and thereby modulate cellular functionality. This action is exerted by regulating the expression of specific genes encoding subunits of neurotransmitter receptors, either by joining the promoter region (acting as a transcription factor) or it bind to proteins located at the site of transcription regulation.

Non-Genomic: Neuroactive steroids are able to bind to specific sites of certain neurotransmitter receptors and it modifying neuronal excitability by modulating the frequency and / or the opening time of the ion channels.


Neuroactive steroid in health conditions

Physiological effects of progesterone, estradiol and testosterone as neuroactive steroids

Neuroactive steroids regulate a variety of functions in the nervous system. In the adult brain testoesterone, estradiol and progsterone are involved in the endocrine control of reproduction. In addition to their hormonal role in neuroendocrine events and reproduction these hormones exert an homeostatic control of brain function, regulating synaptic plasticity adult neurogenesis and cognition (Casas et al. 2011; Casas et al 2012; Casas et al. 2013). Giuliani et al. (2013) showed that the modulatory action of allopregnanolone in the hypothalamus could have an important biological function to the accurate fine tuning of the neuronal circuitries that control the neurosecretion related to the sexual development of the female rat. Such effects could increase possibly, the efficacy of other well-known factors such as estradiol, progesterone and kisspeptin on the gonadotropins release hormones network activity.

The protective effects exerted by neuroactive steroids have been well ascertained in several experimental models of CNS and PNS pathologies. For instance, estradiol and progesterone exert neuroprotective actions in different animal models of Alzheimer disease, Parkinson’s disease (Casas et al, 2011; Yunes et al. 2015), epilepsy (Frye et al., 2009), excitotoxicity, stroke, motoneuron degeneration, multiple sclerosis and demyelination, traumatic brain injury and spinal cord injury.

Protective effects of testosterone have been reported in experimental models of Parkinson’s disease . In multiple sclerosis patients, an improvement in cognitive performance and slowing of brain atrophy were observed after one year application of transdermal testosterone gel. Moreover, as recently reported by a pilot clinical trial performed in relapsing-remitting multiple sclerosis, gray matter loss was no longer evident during testosterone treatment.

In clinical Trial ProTECT treatment with progesterone following moderate and severe cranial brain trauma significantly reduced mortality at 30 days of neurotrauma (Wright y cols, 2007). In another clinical Trial POPART`MUS it observed that 3-month treatment with estradiol and nomegestrol acetate in women with relapsing-remitting multiple sclerosis significantly reduced the rate of relapse of this disease in the first 3 months postpartum compared to patients who did not receive any treatment (el-Etr y cols, 2005).


Neuroactive steroid in neurovascular disorder

Stroke changes in the levels of neuroactive steroids in the brain have been assessed by gas chromatography/mass spectrometry after middle cerebral artery occlusion. Six hours after surgery a significant increase in the levels of progesterone and its derivative dihydroprogesterone was observed (Chen et al., 1999). In the recently work developed by Casas et al. (2017) showed that that higher levels of cortisol and estradiol were associated with more pronounced neurological, cognitive and functional deficits in women compared to men during acute ischemic stroke. They propose that in elderly patients, high levels of circulating neuroactive steroids like cortisol and estradiol could potentiate acute ischemic stroke mediated neuropathology in the ischemic and penumbra areas.



Fig 3. Sequence of events after brain ischemic injury. (1) Ischemic stroke induces a strong activation of the hypothalamic-pituitary-adrenal (HPA) axis (2), with increases in adrenal cortisol and andregen secretion (3). Cortisol play an important role in brain ischemia (4). In postmenopausal women and elderly men, estrogen synthesis is predominantly extragonadal (5), due to the aromatase expressed by white adipose tissue and other peripheral tissues. One of the stimulatory factors for estrogen synthesis in the white adipose tissue is cortisol. Estrogen showed deleterious effects in neurological, cognitive and functional outcomes in patients.



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