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THP Levels (thp + level)
Selected AbstractsReduced metabolites mediate neuroprotective effects of progesterone in the adult rat hippocampus.DEVELOPMENTAL NEUROBIOLOGY, Issue 9 2006The synthetic progestin medroxyprogesterone acetate (Provera) is not neuroprotective Abstract The ovarian hormone progesterone is neuroprotective in different experimental models of neurodegeneration. In the nervous system, progesterone is metabolized to 5,-dihydroprogesterone (DHP) by the enzyme 5,-reductase. DHP is subsequently reduced to 3,,5,-tetrahydroprogesterone (THP) by a reversible reaction catalyzed by the enzyme 3,-hydroxysteroid dehydrogenase. In this study we have analyzed whether progesterone metabolism is involved in the neuroprotective effect of the hormone in the hilus of the hippocampus of ovariectomized rats injected with kainic acid, an experimental model of excitotoxic cell death. Progesterone increased the levels of DHP and THP in plasma and hippocampus and prevented kainic-acid-induced neuronal loss. In contrast to progesterone, the synthetic progestin medroxyprogesterone acetate (MPA, Provera) did not increase DHP and THP levels and did not prevent kainic-acid-induced neuronal loss. The administration of the 5,-reductase inhibitor finasteride prevented the increase in the levels of DHP and THP in plasma and hippocampus as a result of progesterone administration and abolished the neuroprotective effect of progesterone. Both DHP and THP were neuroprotective against kainic acid. However, the administration of indomethacin, a 3,-hydroxysteroid dehydrogenase inhibitor, blocked the neuroprotective effect of both DHP and THP, suggesting that both metabolites are necessary for the neuroprotective effect of progesterone. In conclusion, our findings indicate that progesterone is neuroprotective against kainic acid excitotoxicity in vivo while the synthetic progestin MPA is not and suggest that progesterone metabolism to its reduced derivatives DHP and THP is necessary for the neuroprotective effect of the hormone. © 2006 Wiley Periodicals, Inc. J Neurobiol, 2006 [source] Inhibiting Biosynthesis and/or Metabolism of Progestins in the Ventral Tegmental Area Attenuates Lordosis of Rats in Behavioural OestrusJOURNAL OF NEUROENDOCRINOLOGY, Issue 9 2005S. M. Petralia Abstract In the ventral tegmental area (VTA), lordosis of rats is facilitated by 5,-pregnan-3,-ol-20-one (3,,5,-THP). Central 3,,5,-THP results from metabolism of peripheral progesterone, from the ovaries and/or adrenals, by sequential enzymatic activity of 5,-reductase and 3,-hydroxysteroid oxidoreductase (3,-HSOR). In addition, in glial cells, cholesterol is converted into pregnenolone by the P450 side-chain cleavage enzyme (P450scc), which is then metabolized to progesterone by 3,-hydroxysteroid dehydrogenase, and subsequently reduced to 3,,5,-THP. We hypothesize that, in the VTA, formation of 3,,5,-THP by both metabolism and biosynthesis is necessary for facilitation of lordosis of female rats. In Experiment 1, naturally-receptive rats received bilateral VTA infusions of a P450scc inhibitor, digitoxin (1 µg/side); a 5,-reductase inhibitor, finasteride (10 µg/side); digitoxin (1 µg/side) + finasteride (10 µg/side); or vehicle and were tested 3 h later for lordosis. In Experiment 2, the effects of VTA infusions of digitoxin, finasteride, digitoxin + finasteride, or vehicle on lordosis and midbrain and plasma 3,,5,-THP levels were examined. In Experiment 3, we investigated whether infusions of 3,,5,-THP to the VTA reinstated lordosis and midbrain 3,,5,-THP levels following administration of inhibitors. VTA infusions of digitoxin, finasteride, or digitoxin + finasteride, significantly and similarly reduced lordosis and midbrain, but not plasma 3,,5,-THP levels, compared to vehicle. Following receipt of inhibitor infusions, 3,,5,-THP to the VTA restored lordosis and midbrain 3,,5,-THP levels. These data suggest that, in the VTA, both central biosynthesis of progesterone and metabolism of progesterone (from central and/or peripheral sources) to 3,,5,-THP are important for mediating lordosis of rats. [source] Differential Effects of Ethanol on Serum GABAergic 3,,5,/3,,5, Neuroactive Steroids in Mice, Rats, Cynomolgus Monkeys, and HumansALCOHOLISM, Issue 3 2010Patrizia Porcu Background:, Acute ethanol administration increases plasma and brain levels of progesterone and deoxycorticosterone-derived neuroactive steroids (3,,5,)-3-hydroxypregnan-20-one (3,,5,-THP) and (3,,5,)-3,21-dihydroxypregnan-20-one (3,,5,-THDOC) in rats. However, little is known about ethanol effects on GABAergic neuroactive steroids in mice, nonhuman primates, or humans. We investigated the effects of ethanol on plasma levels of 3,,5,- and 3,,5,-reduced GABAergic neuroactive steroids derived from progesterone, deoxycorticosterone, dehydroepiandrosterone, and testosterone using gas chromatography-mass spectrometry. Methods:, Serum levels of GABAergic neuroactive steroids and pregnenolone were measured in male rats, C57BL/6J and DBA/2J mice, cynomolgus monkeys, and humans following ethanol administration. Rats and mice were injected with ethanol (0.8 to 2.0 g/kg), cynomolgus monkeys received ethanol (1.5 g/kg) intragastrically, and healthy men consumed a beverage containing 0.8 g/kg ethanol. Steroids were measured after 60 minutes in all species and also after 120 minutes in monkeys and humans. Results:, Ethanol administration to rats increased levels of 3,,5,-THP, 3,,5,-THDOC, and pregnenolone at the doses of 1.5 g/kg (+228, +134, and +860%, respectively, p < 0.001) and 2.0 g/kg (+399, +174, and +1125%, respectively, p < 0.001), but not at the dose of 0.8 g/kg. Ethanol did not alter levels of the other neuroactive steroids. In contrast, C57BL/6J mice exhibited a 27% decrease in serum 3,,5,-THP levels (p < 0.01), while DBA/2J mice showed no significant effect of ethanol, although both mouse strains exhibited substantial increases in precursor steroids. Ethanol did not alter any of the neuroactive steroids in cynomolgus monkeys at doses comparable to those studied in rats. Finally, no effect of ethanol (0.8 g/kg) was observed in men. Conclusions:, These studies show clear species differences among rats, mice, and cynomolgus monkeys in the effects of ethanol administration on circulating neuroactive steroids. Rats are unique in their pronounced elevation of GABAergic neuroactive steroids, while this effect was not observed in mice or cynomolgus monkeys at comparable ethanol doses. [source] Ethanol-induced elevation of 3,-hydroxy-5,-pregnan-20-one does not modulate motor incoordination in ratsALCOHOLISM, Issue 8 2004Rahul T. Khisti Background: Ethanol administration elevates the levels of GABAergic neuroactive steroids in brain and contributes to some of its behavioral actions. In the present study, we investigated whether such elevation of GABAergic neuroactive steroids contributes to the motor incoordinating effects of ethanol. Methods: Sprague-Dawley rats were administered ethanol (2 g/kg intraperitoneally) or saline, and the level of 3,-hydroxy-5,-pregnan-20-one (3,,5,-THP) was measured across time in cerebral cortex and in various brain regions at the peak time by radioimmunoassay. To study whether increases in GABAergic neuroactive steroids are responsible for the motor incoordinating actions of ethanol, rats were subjected to chemical (5,-reductase inhibitor, finasteride) and surgical (adrenalectomy) manipulations before receiving ethanol (2 g/kg intraperitoneally) injections. The rats were then subjected to different paradigms to evaluate motor impairment including the Majchrowicz motor intoxication rating scale, Rotarod test, and aerial righting reflex task at different time points. Results: The radioimmunoassay of 3,,5,-THP in different brain regions showed that ethanol increases 3,,5,-THP levels by 3- and 9-fold in cerebral cortex and hippocampus, respectively. There was no change in 3,,5,-THP levels in cerebellum and midbrain. The time course of 3,,5,-THP elevations in the cerebral cortex showed significant increases 20-min after ethanol injection with a peak at 60 min. In contrast, motor toxicity peaked between 5 and 10 min after ethanol injections and gradually decreased over time. Furthermore, adrenalectomy or pretreatment with finasteride (2 × 50 mg/kg, subcutaneously) did not reduce motor incoordinating effects of ethanol as assessed by the Majchrowicz intoxication rating score, Rotarod test, or aerial righting reflex task. Conclusions: Ethanol increases GABAergic neuroactive steroids in a time- and brain region-selective manner. The role of neuroactive steroids in alcohol action is specific for certain behaviors. Alcohol-induced deficits in motor coordination are not mediated by elevated neuroactive steroid biosynthesis. [source] ORIGINAL RESEARCH,BASIC SCIENCE: Fluoxetine-Induced Decrements in Sexual Responses of Female Rats and Hamsters Are Reversed by 3,,5,-THPTHE JOURNAL OF SEXUAL MEDICINE, Issue 8 2010Cheryl A. Frye PhD ABSTRACT Introduction., Sexual dysfunction, as a result of selective-serotonin reuptake inhibitor (SSRI) treatment among women, is relatively common and is a factor in medication compliance. The mechanisms that underlie these side-effects of SSRIs are not well-understood. SSRIs can alter activity of catabolic enzymes that are involved in progesterone's conversion to 5,-pregnan-3,-ol-20-one (3,,5,-THP). 3,,5,-THP plays a key role in female reproductive physiology and behavior. Aims., This study aimed to determine whether 3,,5,-THP, in the midbrain ventral tegmental area (VTA) may be a potential mechanism for fluoxetine's reduction in sexual responding of female rodents. We hypothesized that if fluoxetine induces decrements in sexual responding in part through actions of 3,,5,-THP, then fluoxetine will inhibit sexual receptivity concomitant with reducing 3,,5,-THP levels, effects which can be reversed by 3,,5,-THP administration. Methods., Experiment 1 investigated effects of acute systemic fluoxetine [20 mg/kg intraperitoneal (IP)] and/or 3,,5,-THP [500 µg, subcutaneous (SC)] administration on sexual responding of ovariectomized, hormone-primed rats. Experiment 2 examined effects of 3,,5,-THP administration to the midbrain VTA (100 ng) on fluoxetine-induced decrements in lordosis of ovariectomized, hormone-primed rats and hamsters. Main Outcome Measures., Sexual responding was determined in rats and hamsters. For rats, the percentage of times that the lordosis response occurred following mounting by a sexually-vigorous male (lordosis quotients) was utilized. For hamsters, lateral displacement, the pelvic movement that females will make to facilitate intromissions by a male hamster, was utilized. Results., Fluoxetine significantly reduced lordosis, and this was reversed SC 3,,5,-THP. Intra-VTA 3,,5,-THP attenuated fluoxetine's detrimental effects on lordosis quotients and lateral displacement of rats and hamsters, respectively. Conclusions., Thus, fluoxetine's effects to disrupt female sexual responses may involve its effects on progestogens in the midbrain VTA. Frye CA, and Rhodes ME. Fluoxetine-induced decrements in sexual responses of female rats and hamsters are reversed by 3,,5,-THP. J Sex Med 2010;7:2670,2680. [source] | ||||||||||