Expression of 5α‐Reductase and 3α‐Hydroxisteroid Oxidoreductase in the Hippocampus of Patients with Chronic Temporal Lobe Epilepsy

Stoffel‐Wagner, Birgit; Beyenburg, Stefan; Watzka, Matthias; Blümcke, Ingmar; Bauer, Jürgen; Schramm, Johannes; Bidlingmaier, F.; Elger, Christian E.

doi:10.1111/j.1528-1157.2000.tb00133.x

Cited by 60 publications

(37 citation statements)

References 51 publications

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“…Our detection of HSD17B7 mRNA in human CNS is a novel finding. We also detected SRD5A2 transcripts within hippocampus and cerebellum, although a previous study had failed to find it in human hippocampus (Stoffel-Wagner et al 2000), possibly due to a lack of sensitivity in their assay, as our C t results for this gene were high (w35 cycles in hippocampus), signifying low levels of transcription. Given the use of homogenised brain tissue in this study, it was not possible to assess whether gene transcription is solely neuronal or glial, or whether it occurs in both cell types.…”

Section: Discussionmentioning

confidence: 79%

The transcription of steroidogenic genes in the human cerebellum and hippocampus: a comparative survey of normal and Alzheimer's tissue

MacKenzie¹,

Dewar²,

Stewart³

et al. 2007

Journal of Endocrinology

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Steroid actions on brain tissue have been implicated in processes such as blood pressure regulation and neurodegeneration, including the progression of Alzheimer's disease (AD). mRNAs from all of the genes required for de novo synthesis from cholesterol of aldosterone and corticosterone (equivalent to cortisol in humans) have been identified in rat brain, together with abundant steroid hormone receptors, but the situation in human brain requires clarification. We used real-time RT-PCR to assess whether transcription of 13 steroid-associated genes occurs in human hippocampus and cerebellum, and to identify whether transcription of these genes is significantly altered in cases of AD. Frozen post-mortem samples of hippocampus and cerebellum from patients with AD (nZ7) and age-matched controls free from neurological disease at the time of death (nZ9) were used. We found all of the genes under investigation to be transcribed within normal and AD hippocampus and cerebellum except for CYP11B1 (11b-hydroxylase), CYP11B2 (aldosterone synthase) and CYP17 (17a-hydroxylase). No significant differences in mRNA levels were observed between the AD tissue and the equivalent control tissue, although significant regional differences in gene transcription were observed between hippocampus and cerebellum in AD and control samples. The absence of key mRNAs from human hippocampus and cerebellum rules out the de novo generation of aldosterone, cortisol or the sex steroids within these regions. However, the pattern of gene expression does suggest that the mineralocorticoid 11-deoxycorticosterone can be generated de novo. There is no evidence of a link between AD and altered steroid biosynthesis within human hippocampus and cerebellum.

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Section: Discussionmentioning

confidence: 79%

The transcription of steroidogenic genes in the human cerebellum and hippocampus: a comparative survey of normal and Alzheimer's tissue

MacKenzie¹,

Dewar²,

Stewart³

et al. 2007

Journal of Endocrinology

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“…The most widely studied are allopregnanolone, THDOC, and androstanediol (Fig.1). There is now compelling evidence that all of the enzymes required for the biosynthesis of the neurosteroids from cholesterol are present in the brain (Stoffel-Wagner et al, 2000; 2003). Allopregnanolone and related neurosteroids are produced via sequential A-ring reduction of the steroid hormones by 5α-reductase and 3α-hydroxysteroid-oxidoreductase isoenzymes (Reddy, 2009a).…”

Section: Neurosteroid Biosynthesis In the Brainmentioning

confidence: 99%

Neurosteroids and their role in sex-specific epilepsies

Reddy

2014

Neurobiology of Disease

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Neurosteroids are involved in sex-specific epilepsies. Allopregnanolone and related endogenous neurosteroids in the brain control excessive neuronal excitability and seizure susceptibility. Neurosteroids activate GABA-A receptors, especially extrasynaptic αβδ-GABA-A receptor subtypes that mediate tonic inhibition and thus dampen network excitability. Our studies over the past decade have shown that neurosteroids are broad-spectrum anticonvulsants and confer seizure protection in various animal models. Neurosteroids also exert antiepileptogenic effects. There is emerging evidence on a critical role for neurosteroids in the pathophysiology of the sex-specific forms of epilepsies such as catamenial epilepsy, a menstrual cycle-related seizure disorder in women. Catamenial epilepsy is a neuroendocrine condition in which seizures are clustered around specific points in the menstrual cycle, most often around the perimenstrual or periovulatory period. Apart from ovarian hormones, fluctuations in neurosteroid levels could play a critical role in this gender-specific epilepsy. Neurosteroids also regulate the plasticity of synaptic and extrasynaptic GABA-A receptors in the hippocampus and other regions involved in epilepsy pathology. Based on these studies, we proposed a neurosteroid replacement therapy for catamenial epilepsy. Thus, neurosteroids are novel drug targets for pharmacotherapy of epilepsy.

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“…of progesterone, are not totally inactive but may have significant biological effects. 3a,5a-Tetrahydro-progesterone (3a,5a-TH-P) and 3a,5b-TH-P are ligands for the gamma-aminobutyric acid A receptor and have anesthetic, anxiolytic and anticonvulsant potency (21)(22)(23)(24). 5b-Dihydro(DH)-P reduces myometrial contractions (25) and shows pyrogenic effects (21).…”

Section: Introductionmentioning

confidence: 99%

Agonistic and antagonistic properties of progesterone metabolites at the human mineralocorticoid receptor

Quinkler

Meyer

Bumke-Vogt

et al. 2002

European Journal of Endocrinology

120

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Objective: Progesterone binds to the human mineralocorticoid receptor (hMR) with nearly the same affinity as do aldosterone and cortisol, but confers only low agonistic activity. It is still unclear how aldosterone can act as a mineralocorticoid in situations with high progesterone concentrations, e.g. pregnancy. One mechanism could be conversion of progesterone to inactive compounds in hMR target tissues. Design: We analyzed the agonist and antagonist activities of 16 progesterone metabolites by their binding characteristics for hMR as well as functional studies assessing transactivation. Methods: We studied binding affinity using hMR expressed in a T7-coupled rabbit reticulocyte lysate system. We used co-transfection of an hMR expression vector together with a luciferase reporter gene in CV-1 cells to investigate agonistic and antagonistic properties. Results: Progesterone and 11b-OH-progesterone (11b-OH-P) showed a slightly higher binding affinity than cortisol, deoxycorticosterone and aldosterone. 20a-dihydro(DH)-P, 5a-DH-P and 17a-OH-P had a 3-to 10-fold lower binding potency. All other progesterone metabolites showed a weak affinity for hMR. 20a-DH-P exhibited the strongest agonistic potency among the metabolites tested, reaching 11.5% of aldosterone transactivation. The agonistic activity of 11b-OH-P, 11a-OH-P and 17a-OH-P was 9, 5.1 and 4.1% respectively. At a concentration of 100 nmol/l, progesterone, 17a-OH-P and 20a-DH-P inhibit nearly 75, 40 and 35% of the transactivation by aldosterone respectively. All other progesterone metabolites tested demonstrate weaker affinity, and agonistic and antagonistic potency. Conclusions: The binding affinity for hMR and the agonistic and antagonistic activity diminish with increasing reduction of the progesterone molecule at C20, C17 and at ring A. We assume that progesterone metabolism to these compounds is a possible protective mechanism for hMR. 17a-OH-P is a strong hMR antagonist and could exacerbate mineralocorticoid deficiency in patients with congenital adrenal hyperplasia.

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Expression of 5α‐Reductase and 3α‐Hydroxisteroid Oxidoreductase in the Hippocampus of Patients with Chronic Temporal Lobe Epilepsy

Cited by 60 publications

References 51 publications

The transcription of steroidogenic genes in the human cerebellum and hippocampus: a comparative survey of normal and Alzheimer's tissue

The transcription of steroidogenic genes in the human cerebellum and hippocampus: a comparative survey of normal and Alzheimer's tissue

Neurosteroids and their role in sex-specific epilepsies

Agonistic and antagonistic properties of progesterone metabolites at the human mineralocorticoid receptor

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