Metyrapone Inhibition of &lt;sup&gt;3&lt;/sup&gt;H-Hydrocortisone Uptake and Binding in Various Brain Regions of the Pig

Stith, Rex D.; Person, R.J.; Dana, Richard C.

doi:10.1159/000122625

Cited by 11 publications

(6 citation statements)

References 5 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…There is no evidence that metyrapone acts directly on GABA A receptors. However, metyrapone does enter the brain (Stith et al, 1976). Its weak anticonvulsant activity at 0.5 h could be due to low potency effects on any of a number of anticonvulsant targets; an action on GABA A receptors cannot be excluded.…”

Section: Discussionmentioning

confidence: 99%

11β-Hydroxylase inhibitors protect against seizures in mice by increasing endogenous neurosteroid synthesis

Kamiński

Rogawski

2011

Neuropharmacology

View full text Add to dashboard Cite

Steroid 11β-hydroxylase (CYP11B1; EC 1.14.15.4) is a mitochondrial enzyme located in the zona fasciculata of the adrenal cortex and also in the brain that mediates the conversion of 11-deoxycortisol to cortisol and 11-deoxycorticosterone (DOC) to corticosterone. Inhibitors of CYP11B1, such as metyrapone and etomidate, reduce glucocorticoid synthesis and raise levels of DOC providing greater availability for metabolic conversion to the GABAA receptor modulating neurosteroid allotetrahydrodeoxycorticosterone (THDOC). Because THDOC is a potent anticonvulsant, it is plausible that CYP11B1 inhibitors could protect against seizures. Here we demonstrate that metyrapone affords dose-dependent protection against 6-Hz seizures 30 min after injection (ED50, 191 mg/kg), but is markedly more potent at 6 h (ED50, 30 mg/kg). Similarly, etomidate is also protective at 30 min and 6 h (ED50 values, 4.5 and 1.7 mg/kg). Finasteride, an inhibitor of neurosteroid synthesis, attenuated the anticonvulsant effects of both CYP11B1 inhibitors at 6 h, but not 30 min following their injection. Plasma THDOC levels measured by liquid chromatography-mass spectrometry were markedly increased 6 h after injection of both CYP11B1 inhibitors and this increase was attenuated by finasteride pretreatment. We conclude that inhibition of CYP11B1 causes delayed seizure protection due to slow build-up of neurosteroids. Early seizure protection is independent of neurosteroids.

show abstract

Section: Discussionmentioning

confidence: 99%

11β-Hydroxylase inhibitors protect against seizures in mice by increasing endogenous neurosteroid synthesis

Kamiński

Rogawski

2011

Neuropharmacology

View full text Add to dashboard Cite

show abstract

“…Fludrocortisone, a mineralocorticoid receptor agonist, exerts a strong inhibitory effect on both ACTH and cortisol after pretreatment with metyrapone during the circadian nadir (22). Metyrapone crosses the blood-brain barrier (31) and blocks, not only at the adrenal glands but also within the brain, the conversion of the endogenous precursor 11deoxycortisol to cortisol by inhibiting the action of 11-ßhydroxylase. Furthermore, it selectively blocks the activity of the 11ß-HSD1, which is present in the hippocampus, thereby preventing the regeneration of active cortisol (32,33).…”

mentioning

confidence: 99%

Mineralocorticoid Receptor-Mediated Inhibition of the Hypothalamic-Pituitary-Adrenal Axis in Aged Humans

Otte

Yassouridis

Jahn³

et al. 2003

The Journals of Gerontology Series A: Biological Sciences and M

View full text Add to dashboard Cite

In aged humans, diminished mineralocorticoid receptor (MR)-mediated feedback in the brain could contribute to impaired feedback regulation of the hypothalamic-pituitary-adrenal (HPA) axis, but no study specifically compared young and old individuals with regard to MR function. We examined 10 healthy young (mean age +/- SD [standard deviation] 26.1 +/- 2.9 years) and 10 elderly men (68.3 +/- 4.7 years) at the nadir of cortisol levels (2:00 pm-9:00 pm) when HPA activity is mainly controlled by the MR. After pretreatment with 3 g metyrapone to minimize the impact of basal endogenous cortisol secretion, participants received orally, in randomized order on two separate occasions, either 0.5 mg of the MR agonist fludrocortisone or placebo. Fludrocortisone significantly decreased maximum adrenocorticotropic hormone (ACTH) and cortisol concentrations in both groups. ACTH and cortisol values after fludrocortisone were significantly higher in older men compared with young men. Our results implicate that a decrease in MR-mediated negative feedback contributes to the diminished feedback activity in older humans.

show abstract

“…In contrast, the drug metyrapone (which crosses the BBB if administered systemically) (Stith et al, 1976), used in clinical and preclinical GC research, blocks both the adrenal and central synthesis of GCs, because it inhibits the action of P450c11β which is a common enzyme in both tissues' steroidogenic pathways. In addition, metyrapone selectively blocks the activity of the 11βHSD subtype 1, thereby preventing the regeneration of active cortisol (Raven et al, 1995;Sampath-Kumar et al, 1997).…”

Section: Complex Dynamics Of Gcs Reaching the Brainmentioning

confidence: 99%

Temporal control of glucocorticoid neurodynamics and its relevance for brain homeostasis, neuropathology and glucocorticoid-based therapeutics

Kalafatakis

Russell

Ζάρρος³

et al. 2016

Neuroscience & Biobehavioral Reviews

View full text Add to dashboard Cite

Glucocorticoids mediate plethora of actions throughout the human body. Within the brain, they modulate aspects of immune system and neuroinflammatory processes, interfere with cellular metabolism and viability, interact with systems of neurotransmission and regulate neural rhythms. The influence of glucocorticoids on memory and emotional behaviour is well known and there is increasing evidence for their involvement in many neuropsychiatric pathologies. These effects, which at times can be in opposing directions, depend not only on the concentration of glucocorticoids but also the duration of their presence, the temporal relationship between their fluctuations, the co-influence of other stimuli, and the overall state of brain activity. Moreover, they are region-and cell type-specific. The molecular basis of such diversity of effects lies on the orchestration of the spatiotemporal interplay between glucocorticoid-and mineralocorticoid receptors, and is achieved through complex dynamics, mainly mediated via the circadian and ultradian pattern of glucocorticoid secretion. More sophisticated methodologies are therefore required to better approach the study of these hormones and improve the effectiveness of glucocorticoid-based therapeutics.

show abstract

Metyrapone Inhibition of <sup>3</sup>H-Hydrocortisone Uptake and Binding in Various Brain Regions of the Pig

Cited by 11 publications

References 5 publications

11β-Hydroxylase inhibitors protect against seizures in mice by increasing endogenous neurosteroid synthesis

11β-Hydroxylase inhibitors protect against seizures in mice by increasing endogenous neurosteroid synthesis

Mineralocorticoid Receptor-Mediated Inhibition of the Hypothalamic-Pituitary-Adrenal Axis in Aged Humans

Temporal control of glucocorticoid neurodynamics and its relevance for brain homeostasis, neuropathology and glucocorticoid-based therapeutics

Contact Info

Product

Resources

About