madman
Super Moderator
Abstract
Allopregnanolone, a 3α,5α-progesterone metabolite, acts as a potent allosteric modulator of the γ-aminobutyric acid type A receptor. In the present review, the synthesis of this neuroactive steroid occurring in the nervous system is discussed with respect to physiological and pathological conditions. In addition, its physiological and neuroprotective effects are also reported. Interestingly, the levels of this neuroactive steroid, as well as its effects, are sex-dimorphic, suggesting a possible gender medicine based on this neuroactive steroid for neurological disorders. However, allopregnanolone presents low bioavailability and extensive hepatic metabolism, limiting its use as a drug. Therefore, synthetic analogs or a different therapeutic strategy able to increase allopregnanolone levels have been proposed to overcome any pharmacokinetic issues.
1 | INTRODUCTION
Progesterone (PROG) not only comprises a physiological regulator of reproduction,1-5 but also exerts important effects on the nervous system. Indeed, this neuroactive steroid regulates the development of neurones6-9 and glial cells,10-13 as well as the myelination process.14-18 In addition, PROG exerts important protective effects in neurodegenerative and psychiatric disorders.15,19-27 However, whether the effects of PROG are the result of itself and/or its metabolites is still poorly considered. Among PROG metabolites, the effects of allopregnanolone (ALLO), also known as tetrahydro-progesterone, in the nervous system have attracted the attention of several researchers. Therefore, even if many aspects of this neurosteroid remain to be clarified, the extensive literature on it is now available. In the present review, we discuss the state of the art of this neuroactive steroid, considering its synthesis, mechanism of action, and physiological and protective effects. In addition, whether neurodegenerative and psychiatric disorders, as well as peripheral steroid contents, influence the amount of this neuroactive steroid in the nervous system and whether sex dimorphism may occur are also taken into consideration.
2 | SYNTHESIS AND MECHANISM OF ACTION
In the nervous system, PROG is actively converted by the enzyme 5αreductase (5α-R) into dihydro-progesterone (DHP) and subsequently by the action of the enzymes 3α-hydroxysteroid oxidoreductase or 3β-hydroxysteroid oxidoreductase into ALLO and isoallopregnanolone (ie, the 3β-isomer of ALLO).28,29 Two isoforms of 5α-R, called type 1 and type 2, are responsible for the metabolism of neuroactive steroids, including PROG.30-33 Type 1 isoform is expressed in cortical, hippocampal, and olfactory bulb glutamatergic neurons and in some output neurons of the amygdala and thalamus,34 with high levels in the midbrain, corpus callosum, anterior commissure, optic chiasm, pons, and spinal cord,33,35,36 and particularly in purified myelin preparations obtained from the rat brain.35,37,38 At the cellular level, this isoform has been detected in oligodendrocytes and neurons,39- 41 in microglia42 and astrocytes,39,40 and in Schwann cells.43-46 Type 2 isoform is widely expressed from the forebrain to the brain stem and cerebellum of the adult rat47 and also highly expressed in the spinal cord, particularly in oligodendrocytes.36
Four human 3α-hydroxysteroid oxidoreductases (HSOR) isozymes, but only one isoform in rats, have been cloned so far.48 3α-HSOR and 3β-HSOR has been identified in the central nervous system (CNS)49; in particular, 3α-HSOR has been detected in the rat cerebral cortex, cerebellum 50 and spinal cord,36 whereas, in the mouse brain, it is co-localized with 5α-R type 1 in neurons of the cerebral cortex, hippocampus, olfactory bulb, amygdala, and thalamus.34 At the cellular level, in addition to neurons, 3α-HSOR also appears to be highly localized in cultures of type 1 astrocytes39,40 and oligodendrocytes.36,51 Interestingly, the formation of ALLO by 3α-HSOR decreases with the differentiation of oligodendrocytes.51
Interestingly, in the context of the growing literature regarding the role of the gut microbiota-brain axis in human health and disease,52-57 it is important to highlight that, as recently demonstrated, local steroidogenesis also occurs in the adult male rat colon.58 In particular, the levels of ALLO detected in this tissue are significantly higher than those present in plasma. In addition, the mRNA levels of 3α-HSOR present in the adult male rat colon are significantly higher than those present in the cerebral cortex.58
The metabolic conversions by the enzymes 5α-R, 3α-HSOR and 3β-HSOR has a deep impact on the mechanism of action of PROG. Indeed, although DHP, similar to its precursor, is still able to interact with the intracellular PROG receptor, ALLO and isoallopregnanolone interact with the GABAA receptor. In particular, ALLO is a potent ligand of this non-classical steroid receptor,59,60 whereas isoallopregnanolone does not bind directly to the GABAA receptor61 but, instead, antagonizes the effect of ALLO on the GABAA receptor.62,63 In this context, it is important to recall the molecular composition of the GABAA receptor (Figure 1). This pentameric ionotropic receptor is able to respond differently to benzodiazepines, ALLO, or to other modulators depending on the subunit composition. In mammals, it can consist of 19 subunits, grouped in eight classes: α(1-6), β(1-3) γ(1-3), δ, ε, θ, π and ρ(1-3).64 In the brain, the most common subunit combination includes two α1, two β2, and one γ2 subunit,64,65 with a binding site for modulators placed at the interface between α and β subunits.66 Despite the fact that receptors containing the δ subunit, mainly located extrasynaptically, are the most sensitive to neurosteroid modulation,67-69 these molecules, and ALLO in particular, may affect GABAA receptor function in other ways. For example, they can promote the phosphorylation of α4 or β3 subunits.70,71 On the other hand, the composition of GABAA subunits may be altered by continuous administration of PROG or ALLO72 (Figure 1). A deeper presentation of GABAA receptor composition and ligand binding is provided in other recent reviews.72-74
3 | LEVELS OF ALLO UNDER PHYSIOLOGICAL AND PATHOLOGICAL CONDITIONS
3.1 | Physiological conditions
*The levels of ALLO in the nervous system, as well as of the other PROG metabolites are also affected by neurodegenerative and psychiatric disorders. These changes have been demonstrated to be different in males and females, in agreement with many neurodegenerative and psychiatric disorders showing sex-dimorphic features. Some examples of them are discussed in the following subsections.
3.2 | Pathological conditions
3.2.1 | Mood disorders
*Several clinical and experimental observations have clearly shown that the plasma and/or CSF levels of ALLO are altered in stress-related disorders and psychiatric diseases, such as anxiety-like behavior and depression, post-partum depression, and post-partum anxiety.82-92
*Another interesting example of alteration in ALLO levels is represented by post-finasteride syndrome (PFS). Finasteride (commercially named Propecia or Proscar) is an inhibitor of two isoforms of the 5α-R (ie, type 1 and 2), although it has a higher affinity for type 2 in humans.132,133 Approved in 1997 for the treatment of androgenetic alopecia at 1 mg day-1 , this drug has been shown to lead to a significant reduction in the progression of baldness and the stimulation of new hair growth.134 5α-R inhibitors have generally been described as well-tolerated and relatively safe drugs; however, recent observations have led to a more critical re-evaluation of these concepts (Figure 2). Indeed, 5α-R inhibitors not only induced side effects during the treatment but also may persist after drug discontinuation inducing the so-named PFS. Among these serious adverse side effects, there are sexual side effects (ie, low libido, erectile dysfunction, decreased arousal, and difficulty in achieving orgasm), depression, anxiety, and cognitive complaints.135 Data obtained in PFS patients show a decrease in the plasma levels of ALLO.136 It is interesting to note that, also in an experimental model of PFS, the plasma levels of this neuroactive steroid were decreased. This alteration was associated with a decrease in ALLO levels in the cerebral cortex,137 where a decrease in the gene expression of GABAA receptor α4 and β3 subunits was observed137 (Figure 2).
3.2.2 | Neurodegenerative disorders
4 | EFFECTS OF ALLO UNDER PHYSIOLOGICAL AND PATHOLOGICAL CONDITIONS
4.1 | Physiological effects
4.2 | Effects of ALLO in pathological conditions
*Altogether, these observations indicate that ALLO may be considered as a potential candidate for the treatment of psychiatric,276 traumatic277, and neurodegenerative disorders.278,279 However, one of the disadvantages of the treatment with natural ALLO is represented by its rapid metabolism and low oral bioavailability.87 On this basis, extensive research has been devoted to synthesizing analogs of ALLO,280-283 showing promising neuroprotective effects.205,277,284-286 In particular, as depicted in Figure 4, two synthetic analogs, such as ganaxolone and brexanolone, appear to be very promising.
5 | CONCLUSIONS
As defined many decades ago,311 neuroactive steroids represent important physiological modulators of the nervous system. They are involved in basic processes such as myelination, neuronal transmission, and brain maturation. Among the natural neuroactive steroids, ALLO has received particular attention because of its relevance in such processes. Concerning ALLO physiology, many issues have to be taken into account. For example, its levels are linked to the expression of the enzymatic complex of 5α-R/3α-HSOR, thus producing a different profile in relation to the nervous structure being considered. In addition, neuroactive steroid plasma levels, as well as sex, have an influence on the levels of ALLO in the nervous system.
In addition, as more recently explored, neuroactive steroids are also neuroprotective agents. Among them, ALLO appears to be particularly relevant because of its implication in neuropathological situations. Up to now, its importance in depression and anxiety, in neurodegenerative diseases (eg, AD, PD, and diabetes mellitus), in traumatic events (eg, spinal cord trauma, nerve injury), and in inflammatory environments (eg, MS, ischemia), is becoming increasingly evident. ALLO exerts its protective effects mainly by interaction with the GABAA receptor, although, as a result of the ability of the enzyme 3α-HSOR to retro-convert ALLO into DHP, this steroid may also interact with the PROG receptor. The unfavorable pharmacokinetic of ALLO limits its therapeutic potential, as observed in many experimental paradigms. Thus, alternative strategies have been explored. For example, synthetic analogs have been successfully applied to several pathological conditions, also leading to their inclusion in clinical practice. An alternative to the synthetic ALLO derivative administration is represented by the pharmacological stimulation of steroidogenesis, and consequently ALLO synthesis, by specific ligands.
In conclusion, a deeper investigation of the mechanisms involved in the protective effects of neuroactive steroids in general, and of ALLO in particular is needed to propose new therapeutic strategies based on this neuroactive steroid for the treatment of neuropathological conditions.
Allopregnanolone, a 3α,5α-progesterone metabolite, acts as a potent allosteric modulator of the γ-aminobutyric acid type A receptor. In the present review, the synthesis of this neuroactive steroid occurring in the nervous system is discussed with respect to physiological and pathological conditions. In addition, its physiological and neuroprotective effects are also reported. Interestingly, the levels of this neuroactive steroid, as well as its effects, are sex-dimorphic, suggesting a possible gender medicine based on this neuroactive steroid for neurological disorders. However, allopregnanolone presents low bioavailability and extensive hepatic metabolism, limiting its use as a drug. Therefore, synthetic analogs or a different therapeutic strategy able to increase allopregnanolone levels have been proposed to overcome any pharmacokinetic issues.
1 | INTRODUCTION
Progesterone (PROG) not only comprises a physiological regulator of reproduction,1-5 but also exerts important effects on the nervous system. Indeed, this neuroactive steroid regulates the development of neurones6-9 and glial cells,10-13 as well as the myelination process.14-18 In addition, PROG exerts important protective effects in neurodegenerative and psychiatric disorders.15,19-27 However, whether the effects of PROG are the result of itself and/or its metabolites is still poorly considered. Among PROG metabolites, the effects of allopregnanolone (ALLO), also known as tetrahydro-progesterone, in the nervous system have attracted the attention of several researchers. Therefore, even if many aspects of this neurosteroid remain to be clarified, the extensive literature on it is now available. In the present review, we discuss the state of the art of this neuroactive steroid, considering its synthesis, mechanism of action, and physiological and protective effects. In addition, whether neurodegenerative and psychiatric disorders, as well as peripheral steroid contents, influence the amount of this neuroactive steroid in the nervous system and whether sex dimorphism may occur are also taken into consideration.
2 | SYNTHESIS AND MECHANISM OF ACTION
In the nervous system, PROG is actively converted by the enzyme 5αreductase (5α-R) into dihydro-progesterone (DHP) and subsequently by the action of the enzymes 3α-hydroxysteroid oxidoreductase or 3β-hydroxysteroid oxidoreductase into ALLO and isoallopregnanolone (ie, the 3β-isomer of ALLO).28,29 Two isoforms of 5α-R, called type 1 and type 2, are responsible for the metabolism of neuroactive steroids, including PROG.30-33 Type 1 isoform is expressed in cortical, hippocampal, and olfactory bulb glutamatergic neurons and in some output neurons of the amygdala and thalamus,34 with high levels in the midbrain, corpus callosum, anterior commissure, optic chiasm, pons, and spinal cord,33,35,36 and particularly in purified myelin preparations obtained from the rat brain.35,37,38 At the cellular level, this isoform has been detected in oligodendrocytes and neurons,39- 41 in microglia42 and astrocytes,39,40 and in Schwann cells.43-46 Type 2 isoform is widely expressed from the forebrain to the brain stem and cerebellum of the adult rat47 and also highly expressed in the spinal cord, particularly in oligodendrocytes.36
Four human 3α-hydroxysteroid oxidoreductases (HSOR) isozymes, but only one isoform in rats, have been cloned so far.48 3α-HSOR and 3β-HSOR has been identified in the central nervous system (CNS)49; in particular, 3α-HSOR has been detected in the rat cerebral cortex, cerebellum 50 and spinal cord,36 whereas, in the mouse brain, it is co-localized with 5α-R type 1 in neurons of the cerebral cortex, hippocampus, olfactory bulb, amygdala, and thalamus.34 At the cellular level, in addition to neurons, 3α-HSOR also appears to be highly localized in cultures of type 1 astrocytes39,40 and oligodendrocytes.36,51 Interestingly, the formation of ALLO by 3α-HSOR decreases with the differentiation of oligodendrocytes.51
Interestingly, in the context of the growing literature regarding the role of the gut microbiota-brain axis in human health and disease,52-57 it is important to highlight that, as recently demonstrated, local steroidogenesis also occurs in the adult male rat colon.58 In particular, the levels of ALLO detected in this tissue are significantly higher than those present in plasma. In addition, the mRNA levels of 3α-HSOR present in the adult male rat colon are significantly higher than those present in the cerebral cortex.58
The metabolic conversions by the enzymes 5α-R, 3α-HSOR and 3β-HSOR has a deep impact on the mechanism of action of PROG. Indeed, although DHP, similar to its precursor, is still able to interact with the intracellular PROG receptor, ALLO and isoallopregnanolone interact with the GABAA receptor. In particular, ALLO is a potent ligand of this non-classical steroid receptor,59,60 whereas isoallopregnanolone does not bind directly to the GABAA receptor61 but, instead, antagonizes the effect of ALLO on the GABAA receptor.62,63 In this context, it is important to recall the molecular composition of the GABAA receptor (Figure 1). This pentameric ionotropic receptor is able to respond differently to benzodiazepines, ALLO, or to other modulators depending on the subunit composition. In mammals, it can consist of 19 subunits, grouped in eight classes: α(1-6), β(1-3) γ(1-3), δ, ε, θ, π and ρ(1-3).64 In the brain, the most common subunit combination includes two α1, two β2, and one γ2 subunit,64,65 with a binding site for modulators placed at the interface between α and β subunits.66 Despite the fact that receptors containing the δ subunit, mainly located extrasynaptically, are the most sensitive to neurosteroid modulation,67-69 these molecules, and ALLO in particular, may affect GABAA receptor function in other ways. For example, they can promote the phosphorylation of α4 or β3 subunits.70,71 On the other hand, the composition of GABAA subunits may be altered by continuous administration of PROG or ALLO72 (Figure 1). A deeper presentation of GABAA receptor composition and ligand binding is provided in other recent reviews.72-74
3 | LEVELS OF ALLO UNDER PHYSIOLOGICAL AND PATHOLOGICAL CONDITIONS
3.1 | Physiological conditions
*The levels of ALLO in the nervous system, as well as of the other PROG metabolites are also affected by neurodegenerative and psychiatric disorders. These changes have been demonstrated to be different in males and females, in agreement with many neurodegenerative and psychiatric disorders showing sex-dimorphic features. Some examples of them are discussed in the following subsections.
3.2 | Pathological conditions
3.2.1 | Mood disorders
*Several clinical and experimental observations have clearly shown that the plasma and/or CSF levels of ALLO are altered in stress-related disorders and psychiatric diseases, such as anxiety-like behavior and depression, post-partum depression, and post-partum anxiety.82-92
*Another interesting example of alteration in ALLO levels is represented by post-finasteride syndrome (PFS). Finasteride (commercially named Propecia or Proscar) is an inhibitor of two isoforms of the 5α-R (ie, type 1 and 2), although it has a higher affinity for type 2 in humans.132,133 Approved in 1997 for the treatment of androgenetic alopecia at 1 mg day-1 , this drug has been shown to lead to a significant reduction in the progression of baldness and the stimulation of new hair growth.134 5α-R inhibitors have generally been described as well-tolerated and relatively safe drugs; however, recent observations have led to a more critical re-evaluation of these concepts (Figure 2). Indeed, 5α-R inhibitors not only induced side effects during the treatment but also may persist after drug discontinuation inducing the so-named PFS. Among these serious adverse side effects, there are sexual side effects (ie, low libido, erectile dysfunction, decreased arousal, and difficulty in achieving orgasm), depression, anxiety, and cognitive complaints.135 Data obtained in PFS patients show a decrease in the plasma levels of ALLO.136 It is interesting to note that, also in an experimental model of PFS, the plasma levels of this neuroactive steroid were decreased. This alteration was associated with a decrease in ALLO levels in the cerebral cortex,137 where a decrease in the gene expression of GABAA receptor α4 and β3 subunits was observed137 (Figure 2).
3.2.2 | Neurodegenerative disorders
4 | EFFECTS OF ALLO UNDER PHYSIOLOGICAL AND PATHOLOGICAL CONDITIONS
4.1 | Physiological effects
4.2 | Effects of ALLO in pathological conditions
*Altogether, these observations indicate that ALLO may be considered as a potential candidate for the treatment of psychiatric,276 traumatic277, and neurodegenerative disorders.278,279 However, one of the disadvantages of the treatment with natural ALLO is represented by its rapid metabolism and low oral bioavailability.87 On this basis, extensive research has been devoted to synthesizing analogs of ALLO,280-283 showing promising neuroprotective effects.205,277,284-286 In particular, as depicted in Figure 4, two synthetic analogs, such as ganaxolone and brexanolone, appear to be very promising.
5 | CONCLUSIONS
As defined many decades ago,311 neuroactive steroids represent important physiological modulators of the nervous system. They are involved in basic processes such as myelination, neuronal transmission, and brain maturation. Among the natural neuroactive steroids, ALLO has received particular attention because of its relevance in such processes. Concerning ALLO physiology, many issues have to be taken into account. For example, its levels are linked to the expression of the enzymatic complex of 5α-R/3α-HSOR, thus producing a different profile in relation to the nervous structure being considered. In addition, neuroactive steroid plasma levels, as well as sex, have an influence on the levels of ALLO in the nervous system.
In addition, as more recently explored, neuroactive steroids are also neuroprotective agents. Among them, ALLO appears to be particularly relevant because of its implication in neuropathological situations. Up to now, its importance in depression and anxiety, in neurodegenerative diseases (eg, AD, PD, and diabetes mellitus), in traumatic events (eg, spinal cord trauma, nerve injury), and in inflammatory environments (eg, MS, ischemia), is becoming increasingly evident. ALLO exerts its protective effects mainly by interaction with the GABAA receptor, although, as a result of the ability of the enzyme 3α-HSOR to retro-convert ALLO into DHP, this steroid may also interact with the PROG receptor. The unfavorable pharmacokinetic of ALLO limits its therapeutic potential, as observed in many experimental paradigms. Thus, alternative strategies have been explored. For example, synthetic analogs have been successfully applied to several pathological conditions, also leading to their inclusion in clinical practice. An alternative to the synthetic ALLO derivative administration is represented by the pharmacological stimulation of steroidogenesis, and consequently ALLO synthesis, by specific ligands.
In conclusion, a deeper investigation of the mechanisms involved in the protective effects of neuroactive steroids in general, and of ALLO in particular is needed to propose new therapeutic strategies based on this neuroactive steroid for the treatment of neuropathological conditions.
