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					PHAR3001: Neuropharmacology 2006                                                        Louisa Lee
                                                                                Biomedical Sciences




To what extent does local metabolism influence
the actions of steroids on the nervous system and
how can this be exploited for drug development?
Metabolites of steroids are not only restricted to regulating body systems but have been found
to show some considerable influence over the actions of the nervous system. Neurosteroids,
related to steroid hormones but do not act on conventional intracelluar steroid receptors
(Rang & Dale, 2004) 1, may have clinical implications. The earliest discovery of such ideas was
in the 1940s where Hans Selye2 found that certain metabolites of progesterone were potent
sedatives and anaesthetics. Later on, Baulieu3 in 1981 introduced the term neurosteroid after
he discovered that high levels of dehydroepiandrorone sulfate (DHEAS) present in the brain
after gonadectomy and adrenalectomy. Though the pathways of synthesis of steroid
hormones has been well established with the intermediates identified (Ebner et al., 2006) 4,
research has found some interesting properties of such compounds. The fact that certain ‘sex
steroids’ are synthesised by steroidogenic endocrine glands, gonads and adrenal glands, they
are able to reach the brain and periphery via the bloodstream. They are able to cross the
blood-brain barrier, rapidly accumulating in nervous tissues after systemic administration, a
clear benefit to those looking to develop synthetic drugs for use in the clinic.

In 1984 (Harrison & Simmonds) 5, a potent and selective interaction of synthetic neurosteroid
alphaxalone with the GABAA receptor was demonstrated. Under alphaxalone administration
it was found that in guinea-pig olfactory slices that the GABAergic response was prolonged
suggesting some evidence of interaction between such receptors. (Schofield, 1989) 6 From
then on it was established that other naturally occuring steroids were potent positive
allosteric modulators of such a receptor, influencing the activity of GABAA in the central
nervous system. It was also found that systemic administration of steroids had pronounced
behavioural effects. (Lambert et al., 1995) 7 In particular, the metabolites of progesterone and
deoxycorticosterone have been established as positive allosteric modulators of GABAA
receptors, having behavioural effects such as analgesia, anxiolysis and sedation. (Lambert et
al., 2003) 8 GABA, being the most prevalent inhibitory neurotransmitter of the brain can be
subjected to enhancement through over-stimulation of GABAA receptors. Previous studies
have determined that certain neurones and glial cells are able to synthesise such
neurosteroids de novo in a paracrine manner, thus having a great influence on GABAergic
transmission. In the paper published by Lambert et al in 2003, there was evidence to suggest
that GABA-modulatory acitons of pregnane steroids are highly selective with such actions
being brain and neurone dependent.

The inhibitory neurotransmission mediated by GABAA receptors can also be modulated by
metabolties allopregnanolone and tetrahydro-deoxycorticosterone. The synthesis of
neurosteroids can be elevated somewhat during stress 9, pregnancy 10 and it has even been
found after ethanol consumption 11. The disruption of GABAergic transmission is core to
disorders such as panic, depression, schizophrenia, alcohol dependency and even in catalemic


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PHAR3001: Neuropharmacology 2006                                                         Louisa Lee
                                                                                 Biomedical Sciences



epilepsy 10, 12-15. Research conducted very recently by Hosie et al., identified the presence of
two binding sites in the transmembrane domains mediating the potentiation and direct
activation effects of neurosteroids. Enhancement by the steroid binding to the potentiation
site allows the function of the GABA receptor to be fulfilled. Such a revelation could be
fruitful in the development of drugs that target the subunit through the use of neurosteroid-
based ligands and transgenic models. It is also important to mention the senstivity of such
receptors. At low nanomolar concentrations of GABA as is apparent in stress 16, alcohol
intoxication11 and oestrus17 it has been found that GABA currents are potentitated. On the
other hand, at low submicromolar concentrations during parturition, the receptors are
activated directly. Such evidence had provided us with the understanding that there are two
distinct neurosteroid binding sites available. Although many may think that the distinction
between the concentrations is rather small, it is significant to note that the potency of such
neurosteroids is clearly extremely high.

It has been suggested in several literatures that progesterone (Schmacher et al., 2004) 18 has
not only reproductive implications but as also synthesis by astrocytes, oligodendrial, Schwann
and microglia cells. Its precursors are cholesterol and pregnenolone respectively but it is the
expression of enzyme 3-beta-hydroxysteroid dehydrogenase that allows progesterone
synthesis. Within the Schwann cells there has to be a necessary stimulus via neuronal activity
in order for progesterone to be released. Over there years it has been postulated that the
autocrine and paracrine funcitions of progesterone are likley to play an important roles in
myelin sheath formation, leading to a possible neuroprotective function of the diverse
hormone. Furthermore muscle strength on the murine model of the Wobbler mouse appeared
to increase and thus perhaps having beneficial effects on quality of life of the animal which
could in future be extended to humans. Such phenomena were found by taking cerebellar
slices specifically concerning the sciatic nerve and surrounding sensory neurones. This led to
a proposition that neurodegenerative diseases could possibly be alleviated or prevented for
some time as there could be a preservation of cognitive function during ageing of the nervous
system (Schumacher et al., 2004) 18.

From 1980s, there was early evidence to suggest that local metabolism of steroids could have
essential neuroprotective effects. (Atella et al., 1987, Stein et al, 2001) 19 Observations were
made where female rats recovered better from traumatic brain injury (TBI) with less oedema
than male rats. The females with elevated progesterone levels showed virtually no odema in
response to TBI as well as in male rats. Progesterone prevented secondary neuronal
degeneration and reduced behavioural impairments and so much so that even in a group
where the hormone was given 24 hours post injury, it was still effective. In Wobbler mice
where phantom motor degeneration was induced, at two months of age they were treated for
15 days with progesterone and it was noted that neuropathological changes within the spinal
regions were less severe and cell vacuolation was reduced with better preservation of
mitochondria and endoplasmic reticulum too. When pregnenolone was administered after
compression injury was sustained in the spinal cord, the motor function was improved,
reducing neuronal damage.


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PHAR3001: Neuropharmacology 2006                                                         Louisa Lee
                                                                                 Biomedical Sciences




The reason for why such effects may have been discovered is due to the effect of the
neuroactive steroids being rather diverse in their functions. Progesterone may well attenuate
the lipid peroxidation and deterioration of cell membranes by free radicals, thus preserving
the life of the neurone. (Roof et al, 1997, 2001) 20, 21 It may also have an auto-inhibitory
regulatory system that prevents, post-injury, excitotoxicity cell death. (Smith, 1991 & Ogata
1993) 22, 23 This may have great clinical implications since it is the excitotoxicity that causes
apoptosis and death of cells in disorders such as Alzheimer’s diease, Parkinson’s disease and
dementia, amongst others. Finally, another function of progesterone besides being a
reproductive hormone, is its role in controlling the gene expression of specific genes in
neuronal and glial cells that become hormone-sensitive post-injury. (De Nicola, 2003) 24
Whether the effect may be direct or indirect, there is certainly evidence to suggest that
progesterone is able to exert neuroprotection on or around the site of injury.

An extension to this idea is the fact that there may be a promyelinating effect of progesterone
that needs to be investigated further. Schwann cells were thought to express a functional 3β-
HSD (3β-hydroxysteroid dehydrogenase: the enzyme required to convert precursor
pregnenolone to progesterone), when the rat sciatic nerve was regenerated through axonal
inputs. As a result, the levels of progesterone were elevated within this area suggesting that
the hormone has a role in promyelination. In order to test this hypothesis, at first local
syntheis was blocked abd progesterone was injected. This has no effect, inhibiting the
myelination of axons whereas a high dose of progesterone alone promoted formation of the
myelin sheath. (Koenig et al., 1995) 25 Since this discovery an important question can be asked
as to whether progesterone is able to potentiatate myelin sheath formation in the brain and
spinal cord. The neurodegneration of the myelin sheath is commonly seen in patients with
multiple sclerosis and Pelizaeus-Merzbacher disease, both debiliatating in their nature and
perhaps in time there could be therapeutic drugs developed that may even prove to be
prophylactic as opposed to preventative. One slight drawback is that the research has been
conducted within the periphery to date and although proven successful, the process of
myelination is different within the CNS being activated by other transcription factors.
(Lemke, 1993) 26

Another field of research that has been conducted over the years can be found in relation to
the regulation of neuropsychiatric disorders seen in women. Such is the pattern induced by
the menstrual cycle and during pregnancy that some women are more prone to affective
disorders than others. There have been some ideas suggested by Amin27 et al, such as the
allosteric modulation of GABA receptors and the effect of reproductive hormones oestradiol,
progesterone and allopregnanolone. One particular disorder includes premenstrual dysphoric
disorder (PMDD) where during the second part of the luteal phase prior to menstruation, the
levels of allopregnanolone were reduced subjecting the sufferer to irratability, depression and
decreased interest and/or pleasure. So far the selective serotonin reuptake inhibitors (SSRIs)
such as paroxetine and fluoxetine have proven to be the most effective treatment since most
research has been carried out here. Other factors affecting the levels of allopregnanolone


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PHAR3001: Neuropharmacology 2006                                                       Louisa Lee
                                                                               Biomedical Sciences



include past psychiatric history, as such women will tend to have an inconsistent cortical
excitation and inhibition. Another factor is smoking where in the presence of nicotine, the
levels of allopregnanalone become elevated and this is particularly noticeable in the luteal
phase of the menstrual cycle. It was also found that smoking cessation is more difficult for
women than for men due to their susceptibility to depressive disorders. (Amin et al., 2006) 27

Another interesting concept is the fact that women with eplipesy experience an increase in
seizure frequency around the time of menstruation and during the luteal phase of the
menstrual cycle. This is termed as perimenstrual catamenial epilepsy where limited drugs
have been developed to alleviate this increasing problem. The increase frequency of seizures
can be allied to the withdrawal of progesterone, as can be observed as levels drop prior to
menstruation. Though ideally, natural progesterone would prove to be a good form of
treatment, the drawbacks include the side effects induced by complex hormonal actions.
More evidence has suggested that the conversion of progesterone into allopregnanolone and
other metabolites that act as endogenous allosteric modulators of inhibitory receptor GABAA.
The study carried out by Reddy & Rogawksi 28 in 2001 identified the fact that neuroactive
steroids effectively enhanced anticonvulsant activtiy in withdrawn animal models. This has
certainly drawn some light on the potential use of neuroactive steroids in stabilising
perimenstrual catamenial epilepsy in women, which could be more effective than the current
use of barbiturates such as phentobarbital.

Finally the essay will discuss the affective disorders induced by presence of neurosteroids.
Panic disorder has been associated with the elevated levels of DHEAS that appears to have
anxiogenic properties if present in large doses. Though not completely conclusive, it has been
found that levels of tetrahydroprogesterone (THP) can manifest social phobia and generalised
anxiety disorder. These concepts have yet to be developed further but it has been considered
that the less negative modulation of the GABAA receptor and less positive modulation of thbe
NMDA receptor may reduce such symptomatic effects seen in such patients. (Dubrovsky,
2006) 29 In a study by Reddy30 et al in 2005, progesterone receptor knockout mice were used
to show that the administration of progesterone was associated with a dose-dependent rise in
plasma allopregnanolone concentrations, which was accompanied with corresponding
anxiolytic effects. The knockout mice exhibited greater symptoms than the wild type though
when pretreated with 5α-reductase inhibitor, which blocks the conversion of progesterone to
allopregnanolone, anxiolyic activity was prevented. This has given some evidence that
progesterone receptors may not be essential to the manifestation of anxiolytic disorders.
(Reddy et al, 2005) 30

Having looked at the effect that local metabolism of steroids has on the nervous system it is
clear that there needs to be more extensive research to determine the multi-functional roles
of neurosteroids. Potential clinical benefits further research could enable us to develop
prophylactic drugs for neurodegnerative and affective disorders. It may also help us to
understand the rather complex nature of such diverse steroid hormones, particulary the
synthesis and metabolism of progesterone.


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PHAR3001: Neuropharmacology 2006                                                               Louisa Lee
                                                                                       Biomedical Sciences



References
1Rang, H. P., Dale, M. M., Ritter, J. M., Moore, P. K., 2004
‘Pharmacology’ Fifth Edition

3Baulieu E. E., Expos Annu Biochim Med 1980; 34:1-25
Steroid hormone receptors

4Ebner et al., Endocrinology 2006; 147(1): 179-90 Epub 2005 Oct 13
Identification of neuroactive steroids and their precursors and metabolites in adult male rat brain

5
Harrison N. L., & Simmonds M. A., Brain Res. 1984 Dec 10; 323(2): 287-92
Modulation of the GABA receptor complex by a steroid anaesthetic

6
Schofield P. R. Trends Pharmacol Sci 1989 Dec; 10(12): 476-8 Review
The GABAA receptor: molecular biology reveals a complex picture

7
Lambert J. J. et al., Trends Pharmacol Sci. 1995 Sep; 16(9): 295-303 Review
GABAA receptor function

8
Lambert J. J. et al. Progress in Neurobiology, 2003: 71: 67-80
Neurosteroid modulation of GABAA receptors

9Hosie et al., Nature 2006 23 Nov: Vol 444: doi:10.1038/nature05324
Endogenous neurosteroids regulate GABAA receptors through two discrete transmembrane sites

10Reddy D. S., Trends Pharmacol Sci. 2003: 24: 103-106
Is there a physiological role for the neurosteroid THDOC in stress-sensitive conditions?

11
 Stoffel-Wagner B., Ann. NY Acad. Sci. 2003: 1007, 64-78
Neurosteroid biosynthesis in the human brain and its clinical implications

12
 Kumar S., et al., Pharmacol. Ther. 2004, 101: 211-226
Ethanol regulation of gamma-aminobutyric acid A receptors: genomic and nongenomic mechanisms

13
 Bacstrom T et al., 2003 Ann NY Acad Sci 1007: 42-53
Pathogenesis in menstrual cycle-linked CNS disorders

14
 Finn D. A., et al., Pharmacol Ther 2004: 101: 91-112
The role of pregnane neurosteroids in ethanol withdrawal: behavioural genetic approaches

15
 Eser D et al Neuroscience 2006: 138: 1041-1048
Neuroactive steroids as modulators of depression and anxiety

16Purdy et al., Proc Natl Acad Sci USA. 1991: 88: 4552-4557
Stress-induced elevations of gamma-aminobutyric acid type A receptor-active steroids in the rat brain

17   Barbaccia M L et al Br J Pharmacol Ther, 1997: 120:1582-1588



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PHAR3001: Neuropharmacology 2006                                                               Louisa Lee
                                                                                       Biomedical Sciences



The effects of inhibitors of GABAergic transmission and stress on brain and plasma allopregnanolone
concentrations

18
 Schumacher M et al Growth Hormone % IGF Research, 2004: 14: S18-S33
Local synthesis and dual actions of progesterone in the nervous system: neuroprotection and
myelination

19
 Atella M J et al., Behav. Neural Biol 1987: 48:352-367
Hormonal state affects recovery from frontal cortex lesions in adult female rats

20
 Stein D G et al., Trends Neurosci 2001: 24: 386-391
Brain damage, sex hormones and recovery: a new role for progesterone and oestrogen?

21
 Roof R L et al., Mol Chem Neuropathol. 1997 May;31(1):1-11.
Progesterone protects against lipid peroxidation following traumatic brain injury in rats.

22Roof R L et al J Neurotrauma. 2000 Dec;17(12):1155-69.
Estrogen-related gender difference in survival rate and cortical blood flow after impact-acceleration
head injury in rats

23Smith S S Neuroscience 1991: 42: 309-320
Progesterone administration attenutates in acute CNS trauma and stroke: neuroprotective effects of
oestrogen and progesterone

24Ogata T. et al., Neuroscienc 1993: 44: 445-449
Steroid hormones protect spinal cord neurons from glutamate toxicity

25De Nicola A F et al Ann NY Acad Sci 2003: 1007: 317-328
Steroid effects on glial cells: detrimental or protective for spinal cord injury?

25
 Koenig H et al Science 1995: 268: 1500-1503
Progesterone synthesis and myelin formation by Schwann Cells

26
 Lemke G., 1993: 263-271
The molecular genetics of myelination: an update glia 7

27
 Amin Z. et al., Pharmacology, Biochemistry & Behaviour 2006: 84: 635-643
The interaction of neuroactive steroids and GABA in the development of neuropsychiatric disorders in
women

28
 . Dubrovsky B., Pharmacology Biochemistry & Behaviour 2006: 84: 655-655
Neurosteroids, neuroactive steroids and symptoms of affective disorders

29
 Reddy D. S., & Rogawski M A Epilepsia. 2001 Mar;42(3):337-44.
Enhanced anticonvulsant activity of neuroactive steroids in a rat model of catamenial epilepsy

30
 Reddy D S et al, 2005 Neuropharmacology. 2005 Jan;48(1):14-24.
Anxiolytic activity of progesterone in progesterone receptor knockout mice


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