Neuroactive steroids: potential therapeutic use in neurological and psychiatric disorders

doi:10.1016/S0165-6147(99)01318-8

Trends in Pharmacological Sciences

Volume 20, Issue 3, 1 March 1999, Pages 107-112

https://doi.org/10.1016/S0165-6147(99)01318-8 Get rights and content

Abstract

Neuroactive steroids are a novel class of positive allosteric modulators of the GABA_A receptor. Although neuroactive steroids are endogenous neuronal modulators, synthetic entities with improved oral bioavailability have recently been developed. These compounds demonstrate efficacy as anticonvulsants against a range of convulsant stimuli and demonstrate anti-epileptogenic activity in a kindling model of epilepsy. Efficacy has also been reported in preclinical models of anxiety, insomnia, migraine and drug dependence. Clinical evidence to date is generally supportive of these findings and indicates that neuroactive steroids are generally well tolerated. Taken as a whole, current data suggest that neuroactive steroids could have a future role in clinical practice. In this article, Maciej Gasior, Richard Carter and Jeffrey Witkin review preclinical and clinical evidence that forms the basis for predicting the potential therapeutic application of neuroactive steroids.

Section snippets

Epilepsy

Currently available anti-epileptic drugs neither provide adequate control of epileptic seizures nor prevent the development of progressive epileptic changes in humans (epileptogenesis)4, 5. Neuroactive steroids exhibit a broad anticonvulsant profile in animal seizure models (Table 1, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37) and this profile overlaps to a large extent with that of classical antiepileptic drugs³⁸.

Anxiety

Despite major advances in the past 30 years, the pharmacological management of anxiety remains imperfect; existing drugs are limited in their efficacy and produce side-effects44, 45. In a number of preclinical models predictive of anxiolytic effects in patients, neuroactive steroids have demonstrated efficacy (Table 1). Neuroactive steroids also attenuate stress-induced increases in plasma corticosterone and aggression⁴⁶ and CNS levels of endogenous neuroactive steroids are increased following

Insomnia

Both preclinical and clinical evidence suggest a use for neuroactive steroids in insomnia (Table 1). Progesterone shortens sleep latency, increases non-rapid-eye-movement (nREM) sleep duration and slightly suppresses slow-wave sleep in both rats⁴⁹ and humans⁵⁰. Effects of progesterone on these sleep-associated spectral changes appear to be mediated by the neuroactive A-ring reduced metabolites of progesterone⁵⁰. Indeed, systemically administered allopregnanolone reduces the latency to nREM

Anaesthesia

Neuroactive steroids have long been known to produce anaesthesia³ but the clinical development of neuroactive steroid anaesthetics⁵¹ has been hampered by side-effects. Development of the water-soluble, steroid anaesthetic ORG21465 (Box 1) was discontinued in 1996 due to initial excitatory effects upon i.v. administration. Development of another neuroactive steroid eltanolone was also abandoned after Phase III trials indicated a higher than anticipated incidence of urticaria⁵².

Migraine

Table 1 summarizes the effects of selected neuroactive steroids in preclinical models of migraine and effects under clinical investigation. Although the precise mechanisms underlying the pathogenesis of migraine are unknown, the disease is thought to be of combined neuronal and vascular origin. Progesterone, allopregnanolone and synthetic neuroactive steroids such as alphaxalone are effective in inhibiting trigeminal-evoked neurogenic inflammation in rat meninges through activation of a

Drug dependence

There is evidence to suggest a role for neuroactive steroids in certain phases of drug dependence (Table 1), for example allopregnanolone reverses the increased seizure susceptibility of rats undergoing ethanol withdrawal32, 33. In contrast to the cross-tolerance conferred to diazepam in rats during ethanol withdrawal, sensitization to the anticonvulsant effects of allopregnanolone is observed³⁴. These findings suggest a possible therapeutic use of neuroactive steroids in the treatment of some

Behavioural side-effects

As previously described, neuroactive steroids are generally capable of producing evidence of clinical efficacy at doses below those that produce motor side-effects. In cases where sedation has been observed²², tolerance to this side-effect can develop. For example, tolerance develops to the locomotor activity depressant effects of minaxolone in mice and no cross-tolerance is seen with temazepam⁵⁷. In addition, memory impairment, a clinical problem with benzodiazepine anxiolytics and some

Concluding remarks

Neuroactive steroids produce a spectrum of effects in animal models of CNS disorders that both overlap with those of other positive allosteric modulators of the GABA_A receptor and exhibit quantitative and qualitative differences. Preclinical evaluation has predicted the efficacy of neuroactive steroids in the treatment of several central pathophysiological states and neuroactive steroids have predicted therapeutic windows that compare favourably with those of drugs currently available for

Note added in proof

Although the results of an initial Phase II trial of ganaxolone for acute migraine were positive (see text), recently disclosed results from a second trial using a tablet formulation were not (CoCensys Press Release, 16/10/98). The trial was a doubleblind, placebo controlled study involving 325 female and male migraine patients. Although patients receiving ganaxolone reported pain relief at a rate in excess of those receiving placebo, the difference was not statistically significant.

Glossary

Chemical names

CCD3693:: 3α-hydroxy-3β-trifluoromethyl-19-nor-5β-pregnan-20-one
Co21068:: 3β-(4-acetylphenyl)ethynyl-3α,21-dihydroxy-5β-20-one-21-hemisuccinate Na
Co26749:: 3α,21-dihydroxy-3β-trifluoromethyl-19-nor-5β-pregnan-20-one
Co30593:: 3β-ethenyl-3α-hydroxy-5α-pregnan-20-one
Co60549:: 3α,21-dihydroxy-3β-trifluoromethyl-19-nor-5β-pregnan-20-one, 21-hemisuccinate
Co87071:: 3α,21-dihydroxy-3β-trifluoromethyl-5β-pregnan-20-one, 21-hemisuccinate
ORG20599:: 21-chloro-3α-hydroxy-2β-(4-morpholinyl)-5α-pregnan-20-one

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Positive allosteric modulators of γ-aminobutyric acid-A (GABA_A) receptors or GABAkines have been widely used medicines for over 70 years for anxiety, epilepsy, sleep, and other disorders. Traditional GABAkines like diazepam have safety and tolerability concerns that include sedation, motor-impairment, respiratory depression, tolerance and dependence. Multiple GABAkines have entered clinical development but the issue of side-effects has not been fully solved. The compounds that are presently being developed and commercialized include several neuroactive steroids (an allopregnanolone formulation (brexanolone), an allopregnanolone prodrug (LYT-300), Sage-324, zuranolone, and ganaxolone), the α2/3-preferring GABAkine, KRM-II-81, and the α2/3/5-preferring GABAkine PF-06372865 (darigabat). The neuroactive steroids are in clinical development for post-partum depression, intractable epilepsy, tremor, status epilepticus, and genetic epilepsy disorders. Darigabat is in development for epilepsy and anxiety. The imidazodiazepine, KRM-II-81 is efficacious in animal models for the treatment of epilepsy and post-traumatic epilepsy, acute and chronic pain, as well as anxiety and depression. The efficacy of KRM-II-81 in models of pharmacoresistant epilepsy, preventing the development of seizure sensitization, and in brain tissue of intractable epileptic patients bodes well for improved therapeutics. Medicinal chemistry efforts are also ongoing to identify novel and improved GABAkines. The data document gaps in our understanding of the molecular pharmacology of GABAkines that drive differential pharmacological profiles, but emphasize advancements in the ability to successfully utilize GABA_A receptor potentiation for therapeutic gain in neurology and psychiatry.
The imidazodiazepine, KRM-II-81: An example of a newly emerging generation of GABAkines for neurological and psychiatric disorders
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GABAkines, or positive allosteric modulators of γ-aminobutyric acid-A (GABA_A) receptors, are used for the treatment of anxiety, epilepsy, sleep, and other disorders.
The search for improved GABAkines, with reduced safety liabilities (e.g., dependence) or side-effect profiles (e.g., sedation) constituted multiple discovery and development campaigns that involved a multitude of strategies over the past century. Due to the general lack of success in the development of new GABAkines, there had been a decades-long draught in bringing new GABAkines to market. Recently, however, there has been a resurgence of efforts to bring GABAkines to patients, the FDA approval of the neuroactive steroid brexanolone for post-partum depression in 2019 being the first. Other neuroactive steroids are in various stages of clinical development (ganaxolone, zuranolone, LYT-300, Sage-324, PRAX 114, and ETX-155). These GABAkines and non-steroid compounds (GRX-917, a TSPO binding site ligand), darigabat (CVL-865), an α2/3/5-preferring GABAkine, SAN711, an α3-preferring GABAkine, and the α2/3-preferring GABAkine, KRM-II-81, bring new therapeutic promise to this highly utilized medicinal target in neurology and psychiatry. Herein, we also discuss possible conditions that have enabled the transition to a new age of GABAkines.
We highlight the pharmacology of KRM-II-81 that has the most preclinical data reported. KRM-II-81 is the lead compound in a new series of orally bioavailable imidazodiazepines entering IND-enabling safety studies. KRM-II-81 has a preclinical profile predicting efficacy against pharmacoresistant epilepsies, traumatic brain injury, and neuropathic pain. KRM-II-81 also produces anxiolytic- and antidepressant-like effects in rodent models. Other key features of the pharmacology of this compound are its low sedation rate, lack of tolerance development, and the ability to prevent the development of seizure sensitization.
Preclinical characterization of zuranolone (SAGE-217), a selective neuroactive steroid GABA<inf>A</inf> receptor positive allosteric modulator
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Zuranolone (SAGE-217) is a novel, synthetic, clinical stage neuroactive steroid GABA_A receptor positive allosteric modulator designed with the pharmacokinetic properties to support oral daily dosing. In vitro, zuranolone enhanced GABA_A receptor current at nine unique human recombinant receptor subtypes, including representative receptors for both synaptic (γ subunit-containing) and extrasynaptic (δ subunit-containing) configurations. At a representative synaptic subunit configuration, α₁β₂γ₂, zuranolone potentiated GABA currents synergistically with the benzodiazepine diazepam, consistent with the non-competitive activity and distinct binding sites of the two classes of compounds at synaptic receptors. In a brain slice preparation, zuranolone produced a sustained increase in GABA currents consistent with metabotropic trafficking of GABA_A receptors to the cell surface. In vivo, zuranolone exhibited potent activity, indicating its ability to modulate GABA_A receptors in the central nervous system after oral dosing by protecting against chemo-convulsant seizures in a mouse model and enhancing electroencephalogram β-frequency power in rats. Together, these data establish zuranolone as a potent and efficacious neuroactive steroid GABA_A receptor positive allosteric modulator with drug-like properties and CNS exposure in preclinical models. Recent clinical data support the therapeutic promise of neuroactive steroid GABA_A receptor positive modulators for treating mood disorders; brexanolone is the first therapeutic approved specifically for the treatment of postpartum depression. Zuranolone is currently under clinical investigation for the treatment of major depressive episodes in major depressive disorder, postpartum depression, and bipolar depression.
GABA-A receptor modulating steroids in acute and chronic stress; relevance for cognition and dementia?
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Cognitive dysfunction, dementia and Alzheimer's disease (AD) are increasing as the population worldwide ages. Therapeutics for these conditions is an unmet need. This review focuses on the role of the positive GABA-A receptor modulating steroid allopregnanolone (APα), it's role in underlying mechanisms for impaired cognition and of AD, and to determine options for therapy of AD. On one hand, APα given intermittently promotes neurogenesis, decreases AD-related pathology and improves cognition. On the other, continuous exposure of APα impairs cognition and deteriorates AD pathology. The disparity between these two outcomes led our groups to analyze the mechanisms underlying the difference. We conclude that the effects of APα depend on administration pattern and that chronic slightly increased APα exposure is harmful to cognitive function and worsens AD pathology whereas single administrations with longer intervals improve cognition and decrease AD pathology. These collaborative assessments provide insights for the therapeutic development of APα and APα antagonists for AD and provide a model for cross laboratory collaborations aimed at generating translatable data for human clinical trials.
Realising the therapeutic potential of neuroactive steroid modulators of the GABA<inf>A</inf> receptor
2020, Neurobiology of Stress
In the 1980s particular endogenous metabolites of progesterone and of deoxycorticosterone were revealed to be potent, efficacious, positive allosteric modulators (PAMs) of the GABA_A receptor (GABA_AR). These reports were followed by the discovery that such steroids may be synthesised not only in peripheral endocrine glands, but locally in the central nervous system (CNS), to potentially act as paracrine, or autocrine “neurosteroid” messengers, thereby fine tuning neuronal inhibition. These discoveries triggered enthusiasm to elucidate the physiological role of such neurosteroids and explore whether their levels may be perturbed in particular psychiatric and neurological disorders. In preclinical studies the GABA_AR-active steroids were shown to exhibit anxiolytic, anticonvulsant, analgesic and sedative properties and at relatively high doses to induce a state of general anaesthesia. Collectively, these findings encouraged efforts to investigate the therapeutic potential of neurosteroids and related synthetic analogues. However, following over 30 years of investigation, realising their possible medical potential has proved challenging. The recent FDA approval for the natural neurosteroid allopregnanolone (brexanolone) to treat postpartum depression (PPD) should trigger renewed enthusiasm for neurosteroid research. Here we focus on the influence of neuroactive steroids on GABA-ergic signalling and on the challenges faced in developing such steroids as anaesthetics, sedatives, analgesics, anticonvulsants, antidepressants and as treatments for neurodegenerative disorders.
Effects of noncontingent ethanol, DHEA, and pregnanolone administration on ethanol self-administration in outbred female rats
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Previous research from this laboratory demonstrated that male outbred rats (Long-Evans) can be trained to prefer ethanol (10% v/v) over water during 30-min home-cage sessions and that higher ethanol concentrations (18–32% v/v) can serve as a reinforcer under various operant schedules. Further, we have shown that two neurosteroids, dehydroepiandrosterone (DHEA) and pregnanolone, can readily decrease ethanol self-administration in males. The present study used the same procedures in an attempt to systematically replicate the previous findings in female outbred rats. Rats were first trained to self-administer ethanol in the home cage using a saccharin-fading procedure. Subsequently, a two-bottle preference test was initiated by substituting different ethanol concentrations after subjects reliably consumed 10% ethanol alone. Water was always available during this phase. Next, subjects were transitioned to a fixed-ratio 10 (FR-10) schedule of reinforcement with 0.1 mL of ethanol (18% v/v) serving as the reinforcer so that a concentration-effect curve could be established. Upon completion, subjects were transitioned to an FR-10 FR-20 multiple schedule of ethanol (32% v/v) and food reinforcement to determine whether noncontingent ethanol, DHEA, and pregnanolone could selectively decrease ethanol intake. Not surprisingly, female subjects preferentially consumed ethanol over water at concentrations of 3.2–18% (v/v) during the home-cage procedure, and significantly increased the mean dose of ethanol consumed and blood ethanol concentration (BEC). Similarly, increasing concentrations under an FR-10 schedule significantly increased the dose of ethanol presented and BEC compared to control (water). Finally, under the multiple schedule, noncontingent injections of ethanol (0.32–1.8 g/kg), DHEA (10–100 mg/kg), and pregnanolone (1.8–32 mg/kg) dose-dependently decreased food- and ethanol-maintained responding and the dose of ethanol presented. BEC was significantly decreased by the neurosteroids, but increased by ethanol due to its noncontingent administration. Together, these data replicate only a subset of the data previously obtained in males, suggesting there are sex differences particularly with respect to the effects of DHEA and pregnanolone.

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Published by Elsevier Ltd.

Trends in Pharmacological Sciences

ReviewNeuroactive steroids: potential therapeutic use in neurological and psychiatric disorders

Abstract

Section snippets

Epilepsy

Anxiety

Insomnia

Anaesthesia

Migraine

Drug dependence

Behavioural side-effects

Concluding remarks

Note added in proof

Glossary

Chemical names

Crit. Rev. Neurobiol.

Neuropharmacology

Drug Dev. Res.

Brain Res.

J. Pharmacol. Exp. Ther.

J. Pharmacol. Exp. Ther.

Pharmacol. Biochem. Behav.

J. Pharmacol. Exp. Ther.

Psychopharmacology

Br. J. Pharmacol.

Am. Assoc. Stud. Headache Syllabus

Alcohol Clin. Exp. Res.

Epilepsia

Am. J. Physiol.

Pharmacol. Biochem. Behav.

Trends Pharmacol. Sci.

J. Psychiatr. Res.

Epilepsia

Neurosci. Biobehav. Rev.

J. Pharmacol. Exp. Ther.

J. Pharmacol. Exp. Ther.

J. Pharmacol. Exp. Ther.

Ann. Neurol.

Brain Res.

Psychopharmacology

Eur. J. Pharmacol.

Soc. Neurosci. Abstr.

Review
Neuroactive steroids: potential therapeutic use in neurological and psychiatric disorders