Disease relevance of Allopregnanolone

• The allopregnanolone-induced [Ca2+]i rise was inhibited by picrotoxin and bicuculline but was unaffected by tetrodotoxin or by pretreatment of neurons with pertussis toxin [1].
• There is strong evidence that allopregnanolone and THDOC are involved in the pathophysiology of premenstrual syndrome, catamenial epilepsy, major depression, and stress-sensitive brain disorders [2].
• High serum allopregnanolone levels in girls with precocious puberty [3].
• Patients with chronic hypertension, with or without superimposed severe preeclampsia, showed serum allopregnanolone levels significantly higher than those of healthy women at the same gestational age (P < 0.01) [4].
• Diminished allopregnanolone enhancement of GABA(A) receptor currents in a rat model of chronic temporal lobe epilepsy [5].

Psychiatry related information on Allopregnanolone

• The neurosteroid allopregnanolone is reduced in prefrontal cortex in Alzheimer's disease [6].
• Decreased cerebrospinal fluid allopregnanolone levels in women with posttraumatic stress disorder [7].
• Dependent measures included self-reported mood states, psychomotor performance, and plasma levels of triazolam, estradiol, progesterone, and allopregnanolone [8].
• The aim of this study was to determine the association of allopregnanolone levels with improvement of mood and behavioral symptoms following antidepressant treatment for severe premenstrual syndrome [9].
• The highest doses of flesinoxan, (+)8-OH-DPAT, and allopregnanolone suppressed locomotion, whereas CP-94,253, TFMPP, and midazolam stimulated motor activity [10].

High impact information on Allopregnanolone

• Decreased production of allopregnanolone apparently contributes to the pathology of NP-C; thus, neurosteroid treatment may be useful in ameliorating progression of the disease [11].
• Further, GABA(A) receptors exhibited a tonic inhibitory influence upon oxytocin release in vivo, and allopregnanolone helped to restrain oxytocin neuron in vitro firing only before parturition, when the alpha1:alpha2 subunit mRNA ratio was still high [12].
• ALLO and T0901317 therapy preserved Purkinje cells, suppressed cerebellar expression of microglial-associated genes and inflammatory mediators, and reduced infiltration of activated microglia in the cerebellar tissue [13].
• Social isolation (SI) of male mice lasting >4 weeks is associated with aggression toward intruders and a down-regulation of brain allopregnanolone (Allo) content [14].
• With specific radioimmunoassays, rapid (less than 5 min) and robust (4- to 20-fold) increases of allopregnanolone and allotetrahydroDOC were detected in the brain (cerebral cortex and hypothalamus) and in plasma of rats after exposure to ambient temperature swin stress [15].

Chemical compound and disease context of Allopregnanolone

• PURPOSE: Perimenstrual catamenial epilepsy may in part be due to withdrawal of the endogenous progesterone-derived neurosteroid allopregnanolone that potentiates gamma-aminobutyric acidA (GABA(A)) receptor-mediated inhibition [16].
• Tolerance to allopregnanolone-induced hypothermia was greater in COLD mice than in HOT mice, but only COLD-1 mice showed cross-tolerance to ethanol [17].
• The neuroactive steroid allopregnanolone (ALLO) is stress sensitive, negatively modulates the HPA axis, and has been implicated in mood disorders [18].
• METHODS: Plasma concentrations of allopregnanolone, pregnenolone sulphate, and dehydroepiandrosterone sulphate were measured in 12 unmedicated male patients with generalized social phobia and 12 matched healthy male volunteers [19].
• Results show that pregnenolone sulfate (5 ng) increased by 12%, whereas allopregnanolone (2 ng) decreased by 24%, the duration of paradoxical sleep in the 24 h interval following injection compared to control recordings [20].

Biological context of Allopregnanolone

• Neonatal administration of allopregnanolone delays the onset of neurological symptoms, increases Purkinje and granule cell survival, reduces cortical GM2 and GM3 ganglioside accumulation and doubles the lifespan of NP-C mice [11].
• We found that magnocellular oxytocin neurons in adult female rats exhibit an endogenous GABA(A) receptor subunit switch around parturition: a decrease in alpha1:alpha2 subunit mRNA ratio correlated with a decrease in allopregnanolone potentiation and increase in decay time constant of the GABA(A) receptor-mediated IPSCs in these cells [12].
• Recently, allopregnanolone and allotetrahydroDOC have also been measured in brain and plasma where their levels have been shown to fluctuate in response to stress and during the estrous and menstrual cycles of rats and humans, respectively [21].
• Interfering with PROG's metabolism to, or the biosynthesis of, 3alpha-hydroxy-5alpha-pregnan-20-one (3alpha,5alpha-TH PROG or allopregnanolone), the most effective endogenous GBR agonist, in the VTA attenuates female sexual behavior in rodents [22].
• Finally, PMDD women with greater levels of premenstrual anxiety and irritability had significantly reduced allopregnanolone levels in the luteal phase relative to less symptomatic PMDD women [23].

Anatomical context of Allopregnanolone

• However, allopregnanolone, but not allotetrahydroDOC, was still present in the cerebral cortex (greater than 3 ng/g) after adrenalectomy [15].
• Moreover, the content of allopregnanolone in brains of sham-operated as well as ADX/CX rats was nonuniformly distributed (olfactory bulb > striatum > cortex > hippocampus) and was one to two orders of magnitude higher than in plasma or liver [24].
• These experiments suggest that the brain, like adrenals and gonads, is a steroidogenic organ which produces allopregnanolone as one of its own most important physiologically relevant steroids [24].
• Identification of fatty acid esters of pregnenolone and allopregnanolone from bovine corpora lutea [25].
• Neurosteroids (such as estrogen, progesterone, and allopregnanolone) are synthesized in the central and peripheral nervous system, in addition to other tissues [26].

Associations of Allopregnanolone with other chemical compounds

• In addition, a pharmacological study using the hormones progesterone, 17 beta-estradiol, mifepristone (intracellular progesterone receptor antagonist), tamoxifen (intracellular estrogen receptor antagonist), and allopregnanolone (progesterone metabolite) was performed to determine their effects on AY-induced seizures [27].
• Impairments in spatial learning and memory: ethanol, allopregnanolone, and the hippocampus [28].
• We have shown that the 3beta-hydroxypregnane steroid UC1011 can inhibit allopregnanolone-induced learning impairment and chloride uptake potentiation in vitro and in vivo [26].
• The ratios of individual PI were similar to those found previously around parturition: about 25:10:7:1 for allopregnanolone, pregnanolone, isopregnanolone, and epipregnanolone, respectively [29].
• METHODS: Neurosteroid levels (allopregnanolone, pregnenolone, dehydroepiandrosterone [DHEA]) were determined in postmortem PFC in 14 male subjects with AD and 15 cognitively intact male control subjects by gas chromatography/mass spectrometry preceded by high-performance liquid chromatography purification [6].

Gene context of Allopregnanolone

• Kinetics of allopregnanolone formation catalyzed by human 3 alpha-hydroxysteroid dehydrogenase type III (AKR1C2) [30].
• The response (area under the curve) of ACTH, allopregnanolone and cortisol to CRH was significantly lower in amenorrheic women compared with controls (P<0.001, P<0.05, P<0.05 respectively) [31].
• The neurosteroids allopregnanolone and pregnanolone activated PXR and induced transcription of a CYP3A4-luciferase reporter [32].
• CYP2D4 and CYP2D6 which are the predominant CYP2D isoforms in the rat and human brain, respectively, possess 21-hydroxylation activity for both progesterone and allopregnanolone [33].
• USVs between 30 and 80 kHz, grid crossing, and rectal temperature were measured in separate groups of mouse pups following subcutaneous administration of 5-HT1A and 5-HT1B receptor agonists and antagonists, the neurosteroid allopregnanolone, or the benzodiazepine midazolam [10].

Analytical, diagnostic and therapeutic context of Allopregnanolone

• Whereas no changes were found at vaginal delivery, serum allopregnanolone and progesterone levels were significantly lower at delivery by emergency cesarean section (P < 0.01) [4].
• Throughout the entire treatment period the allopregnanolone group exhibited shorter non-rapid eye movement sleep (non-REMS) latencies, prolonged REMS latencies, longer non-REMS episodes, more pre-REMS and less low-frequency, but higher spindle activity in the electroencephalogram (EEG) within non-REMS than the placebo group [34].
• The sleep patterns of the placebo and allopregnanolone group did not differ significantly before and after treatment [34].
• The concentrations of diazepam and allopregnanolone giving half-maximal responses were not affected by denervation [35].
• Plasma progesterone and allopregnanolone levels were measured by gas chromatography/electron capture negative chemical ionization mass spectrometry [36].

References