madman
Super Moderator
ABSTRACT
The neuroactive steroid allopregnanolone (ALLO) is an endogenous positive allosteric modulator of GABA type A receptor (GABAAR), and the down-regulation of its biosynthesis has been attributed to the development of mood disorders, such as depression, anxiety, and post-traumatic stress disorder (PTSD). ALLO mediated depression/anxiety involves GABAergic mechanisms and appears to be related to brain-derived neurotrophic factor (BDNF), dopamine receptor, glutamate neurotransmission, and Ca2+ channel. In the clinical, brexanolone, as a newly developed intravenous ALLO preparation, has been approved for the treatment of postpartum depression (PPD). In addition, traditional antidepressants such as selective serotonin reuptake inhibitors (SSRI) could reverse ALLO decline. Recently, the translocation protein (TSPO, 18 kDa), which involves in the speed-limiting step of ALLO synthesis, and ALLO derivatization have been identified as new directions for antidepressant therapy. This review provides an overview of ALLO researches in animal model and patients, discusses its role in the development and treatment of depression/anxiety, and directs its therapeutic potential in future
1. Introduction
Mood disorders are the most common types of neuropsychiatric illness and increasingly becoming a major cause of disability. Among them, depression and anxiety are the most devastating diseases, which affect the patients’ cognition and memory, leading to poor life quality [1–3]. The World Health Organization (WHO) survey found that the prevalence of mood disorders has increased rapidly in the past decade, with patients with depression and anxiety accounting for 4.4% and 3.6% of the global population, respectively [4]. Although depression and anxiety are classified as two different diseases according to diagnostic criteria, both have similar clinical characteristics and treatments [5]. In clinical, anxious depression is a common syndrome, manifesting in nearly half of patients suffering from both depression and anxiety [6,7]. Nowadays, there still a lack of effective treatments for depression and anxiety. Therefore, it is urgent to research and develop new antidepressants.
Allopregnanolone (3α, 5α-tetrahydroprogesterone, ALLO) is a member of the neurosteroid family. Various studies demonstrated that depressive and anxiety-like behaviors are associated with changes in ALLO level and return to normal after effective antidepressant treatment [8–12], suggesting the pathophysiological role and therapeutic potentials of ALLO in depression and anxiety. Brexanolone, a newly developed intravenous ALLO preparation has been approved by the United States Food and Drug Administration (FDA) in 2019 for the treatment of severe postpartum depression (PPD) [13,14].
*Here, we review ALLO researches in animal models and depression/ anxiety patients, to explore its role in the development of depression/ anxiety and therapeutic potential, and to discuss the future direction.
2. Synthesis of ALLO
Synthesis of neurosteroids begins with cholesterol or steroidal precursors (Fig. 1). The first step is the transport of cholesterol onto the inner mitochondrial membrane, which is mediated by the translocation protein (TSPO, 18 kDa) located on the outer mitochondrial membrane. On the inner mitochondrial membrane, cholesterol is cleaved through the side chains of the cytochrome-P-450 enzyme (P450scc) and metabolized to pregnenolone, a precursor to all neurosteroids, which is converted to progesterone by 3β-hydroxysteroid dehydrogenase (3β-HSD). Then, progesterone is reduced to 5α-dihydroprogesterone (5α-DHP) under the action of rate-limiting enzyme 5α-reductase, a key step in ALLO synthesis. Finally, 3α-hydroxysteroid dehydrogenase (3α-HSD) catalyzed the reduction of 5α-DHP to ALLO [15]. Remarkably, ALLO can also be oxidized to 5α-DHP via 3α-HSD.
3. Target of ALLO
*3.1. GABA type A receptor (GABAAR) is the main target of ALLO
GABA is an inhibitory neurotransmitter, which is released from the vesicle and activates the GABA receptor family in the postsynaptic membrane, acting as a neuronal suppressor [16]. It’s been hypothesized that GABAergic deficits are associated with the occurrence of a variety of depression [17]. In major depressive disorder (MDD) and chronic stress, the imbalance of excitation and inhibition in the prefrontal cortex (PFC) is related to the occurrence of depression [18,19]. Previous studies showed that GABA concentrations in the occipital cortex and PFC were significantly lower in patients with MDD [20,21], severe PPD [22], and postmenopausal women with depression [23]. Similarly, the output of GABAergic neurons in the medial prefrontal cortex (mPFC), as well as the expression of genes and proteins associated with GABA synthesis and transporters decreased in depressed mice with a chronic mild emergency [24]. These results suggested that the stimulation of GABAAR, the main type of GABA receptor, in PFC, may be a novel strategy for antidepressant therapy [25].
ALLO is an endogenous positive allosteric regulator of both synaptic and extra-synaptic GABAARs [26], which prolongs the decay time of GABA-gated ion channels, resulting in lengthening the opening time of GABA-activated chloride channels and enhancing the inhibitory effect of neurons [25,27]. The antidepressant/antianxiety effects of ALLO strongly correlate with fluctuations of GABAAR function and plasticity. The GABAAR agonists, diazepam and muscimol, had synergistic effects on ALLO-induced antianxiety in animal models of depression [28,29], whereas GABAAR antagonists flumazenil, bicuculline, and picrotoxin attenuated the anti-anxiety effects of ALLO [28–30]. These results corroborated that the antidepressant/antianxiety effects of ALLO are mediated by stimulation of GABAARs.
*3.2. ALLO-induced antidepressant effects through elevation of brain-derived neurotrophic factor (BDNF)
*3.3. Other targets
4. Depressive/anxiety-like behaviors are associated with changes in ALLO level
5. The role of ALLO in antidepressant therapy
6. Role of ALLO in antianxiety therapy
7. Role of ALLO in antidepressant/antianxiety effects of plant preparations and natural extracts
8. ALLO and PPD
*8.1. The pathophysiology role of ALLO and GABA in PPD
*8.2. ALLO used to treat PPD
9. Conclusion and future directions
As a member of the neurosteroid family, ALLO plays an important role in the development and treatment of mood disorders. Both animals and people with depression and anxiety have low levels of ALLO, and some antidepressant agents, such as fluoxetine, olanzapine, clozapine has been shown to have antidepressant and antianxiety effects by restoring ALLO. In addition, the release of brexanolone, a proprietary injection, marks a new milestone in PDD therapy. Nowadays, TSPO ligands and ALLO derivatives have become the new research direction in antidepressant treatment.
*9.1. TSPO has become a new target for antidepression and antianxiety therapy
*9.2. ALLO derivatization is a new direction in antidepressants research
*Thus, neuroactive steroids, especially ALLO, still are promising targets for the treatment of mood disorders
The neuroactive steroid allopregnanolone (ALLO) is an endogenous positive allosteric modulator of GABA type A receptor (GABAAR), and the down-regulation of its biosynthesis has been attributed to the development of mood disorders, such as depression, anxiety, and post-traumatic stress disorder (PTSD). ALLO mediated depression/anxiety involves GABAergic mechanisms and appears to be related to brain-derived neurotrophic factor (BDNF), dopamine receptor, glutamate neurotransmission, and Ca2+ channel. In the clinical, brexanolone, as a newly developed intravenous ALLO preparation, has been approved for the treatment of postpartum depression (PPD). In addition, traditional antidepressants such as selective serotonin reuptake inhibitors (SSRI) could reverse ALLO decline. Recently, the translocation protein (TSPO, 18 kDa), which involves in the speed-limiting step of ALLO synthesis, and ALLO derivatization have been identified as new directions for antidepressant therapy. This review provides an overview of ALLO researches in animal model and patients, discusses its role in the development and treatment of depression/anxiety, and directs its therapeutic potential in future
1. Introduction
Mood disorders are the most common types of neuropsychiatric illness and increasingly becoming a major cause of disability. Among them, depression and anxiety are the most devastating diseases, which affect the patients’ cognition and memory, leading to poor life quality [1–3]. The World Health Organization (WHO) survey found that the prevalence of mood disorders has increased rapidly in the past decade, with patients with depression and anxiety accounting for 4.4% and 3.6% of the global population, respectively [4]. Although depression and anxiety are classified as two different diseases according to diagnostic criteria, both have similar clinical characteristics and treatments [5]. In clinical, anxious depression is a common syndrome, manifesting in nearly half of patients suffering from both depression and anxiety [6,7]. Nowadays, there still a lack of effective treatments for depression and anxiety. Therefore, it is urgent to research and develop new antidepressants.
Allopregnanolone (3α, 5α-tetrahydroprogesterone, ALLO) is a member of the neurosteroid family. Various studies demonstrated that depressive and anxiety-like behaviors are associated with changes in ALLO level and return to normal after effective antidepressant treatment [8–12], suggesting the pathophysiological role and therapeutic potentials of ALLO in depression and anxiety. Brexanolone, a newly developed intravenous ALLO preparation has been approved by the United States Food and Drug Administration (FDA) in 2019 for the treatment of severe postpartum depression (PPD) [13,14].
*Here, we review ALLO researches in animal models and depression/ anxiety patients, to explore its role in the development of depression/ anxiety and therapeutic potential, and to discuss the future direction.
2. Synthesis of ALLO
Synthesis of neurosteroids begins with cholesterol or steroidal precursors (Fig. 1). The first step is the transport of cholesterol onto the inner mitochondrial membrane, which is mediated by the translocation protein (TSPO, 18 kDa) located on the outer mitochondrial membrane. On the inner mitochondrial membrane, cholesterol is cleaved through the side chains of the cytochrome-P-450 enzyme (P450scc) and metabolized to pregnenolone, a precursor to all neurosteroids, which is converted to progesterone by 3β-hydroxysteroid dehydrogenase (3β-HSD). Then, progesterone is reduced to 5α-dihydroprogesterone (5α-DHP) under the action of rate-limiting enzyme 5α-reductase, a key step in ALLO synthesis. Finally, 3α-hydroxysteroid dehydrogenase (3α-HSD) catalyzed the reduction of 5α-DHP to ALLO [15]. Remarkably, ALLO can also be oxidized to 5α-DHP via 3α-HSD.
3. Target of ALLO
*3.1. GABA type A receptor (GABAAR) is the main target of ALLO
GABA is an inhibitory neurotransmitter, which is released from the vesicle and activates the GABA receptor family in the postsynaptic membrane, acting as a neuronal suppressor [16]. It’s been hypothesized that GABAergic deficits are associated with the occurrence of a variety of depression [17]. In major depressive disorder (MDD) and chronic stress, the imbalance of excitation and inhibition in the prefrontal cortex (PFC) is related to the occurrence of depression [18,19]. Previous studies showed that GABA concentrations in the occipital cortex and PFC were significantly lower in patients with MDD [20,21], severe PPD [22], and postmenopausal women with depression [23]. Similarly, the output of GABAergic neurons in the medial prefrontal cortex (mPFC), as well as the expression of genes and proteins associated with GABA synthesis and transporters decreased in depressed mice with a chronic mild emergency [24]. These results suggested that the stimulation of GABAAR, the main type of GABA receptor, in PFC, may be a novel strategy for antidepressant therapy [25].
ALLO is an endogenous positive allosteric regulator of both synaptic and extra-synaptic GABAARs [26], which prolongs the decay time of GABA-gated ion channels, resulting in lengthening the opening time of GABA-activated chloride channels and enhancing the inhibitory effect of neurons [25,27]. The antidepressant/antianxiety effects of ALLO strongly correlate with fluctuations of GABAAR function and plasticity. The GABAAR agonists, diazepam and muscimol, had synergistic effects on ALLO-induced antianxiety in animal models of depression [28,29], whereas GABAAR antagonists flumazenil, bicuculline, and picrotoxin attenuated the anti-anxiety effects of ALLO [28–30]. These results corroborated that the antidepressant/antianxiety effects of ALLO are mediated by stimulation of GABAARs.
*3.2. ALLO-induced antidepressant effects through elevation of brain-derived neurotrophic factor (BDNF)
*3.3. Other targets
4. Depressive/anxiety-like behaviors are associated with changes in ALLO level
5. The role of ALLO in antidepressant therapy
6. Role of ALLO in antianxiety therapy
7. Role of ALLO in antidepressant/antianxiety effects of plant preparations and natural extracts
8. ALLO and PPD
*8.1. The pathophysiology role of ALLO and GABA in PPD
*8.2. ALLO used to treat PPD
9. Conclusion and future directions
As a member of the neurosteroid family, ALLO plays an important role in the development and treatment of mood disorders. Both animals and people with depression and anxiety have low levels of ALLO, and some antidepressant agents, such as fluoxetine, olanzapine, clozapine has been shown to have antidepressant and antianxiety effects by restoring ALLO. In addition, the release of brexanolone, a proprietary injection, marks a new milestone in PDD therapy. Nowadays, TSPO ligands and ALLO derivatives have become the new research direction in antidepressant treatment.
*9.1. TSPO has become a new target for antidepression and antianxiety therapy
*9.2. ALLO derivatization is a new direction in antidepressants research
*Thus, neuroactive steroids, especially ALLO, still are promising targets for the treatment of mood disorders
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