Articles: pregnanolone.
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Pharmacol. Biochem. Behav. · Jun 1993
Anxiolytic effect of progesterone is associated with increases in cortical allopregnanolone and GABAA receptor function.
The effects of a SC injection of progesterone (0, 1, or 4 mg) on locomotor behavior and exploration of an elevated plus-maze were examined in ovariectomized rats. At the completion of the behavioral tests, blood serum and cerebral cortical level of the 3 alpha-hydroxy ring-A metabolite of progesterone, 3 alpha-hydroxy-5 alpha-pregnan-20-one (allopregnanolone), was also assessed. GABA-stimulated 36Cl- influx was studied in cortical synaptoneurosomes from a subgroup of ovariectomized females treated with vehicle or 4 mg progesterone. ⋯ A dose-dependent increase in allopregnanolone level was found in serum and cortical homogenates. Studies of GABA-stimulated Cl- influx demonstrated that progesterone treatment increased the sensitivity of cortical synaptoneurosomes to GABA (i.e., decreased the EC50) and increased the maximal efficacy with which GABA stimulated Cl- transport (i.e., increased the Emax). Together, these data support the hypothesis that the psychotropic effects observed after progesterone administration are due to the bioconversion of progesterone to allopregnanolone, which subsequently augments GABAA receptor-mediated function.
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Since the 1940s several preclinical investigations have demonstrated the anaesthetic activity of a series of structurally related pregnanes without notable endocrine action. One of the most active of these is pregnanolone (3-alpha-hydroxy-5-beta-pregnane-20-one), which is a naturally occurring metabolite of progesterone. Pregnanolone is not soluble in water, which has prevented its use for clinical research. ⋯ Three patients in this group also did not stop counting (dose: 0.29 mg/kg body weight). Blood pressure remained stable in all patients but 1 throughout the observation period. In 1 patient there was an alarming rise in blood pressure from 160/90 mmHg before to 200/100 mmHg 3 min after the injection.(ABSTRACT TRUNCATED AT 400 WORDS)
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The effects of intracerebroventricular administration of reduced metabolites of progesterone on locomotor activity and on exploration in the elevated plus-maze were assessed in adult female rats. Allopregnanolone (3 alpha-hydroxy-5 alpha-pregnan-20-one; 1.25, 5.0, and 10 micrograms) and pregnanolone (3 alpha-hydroxy-5 beta-pregnan-20-one; 2.5, 5.0, and 10 micrograms) elicited anxiolytic effects and, at the highest dose tested, allopregnanolone resulted in sedation. ⋯ The anxiolytic response to pregnanolone was blocked by picrotoxin (0.75 mg/kg, i.p.), a dose that by itself did not affect behavior in the plus-maze. These data suggest that the anxiolytic effect of 3 alpha-hydroxy metabolites of progesterone is mediated by brain GABAA receptors in a stereospecific manner, and are in good agreement with the well-documented in vitro effects of these steroids as potent modulators of the GABAA receptor.
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Comparative Study
Anaesthetic properties of pregnanolone emulsion. A comparison with alphaxolone/alphadolone, propofol, thiopentone and midazolam in a rat model.
The anaesthetic properties of pregnanolone emulsion, a new steroid preparation for intravenous administration, were evaluated in rats and compared to those of Althesin, propofol, thiopentone and midazolam. The therapeutic index was found to be 50% higher than that of Althesin and 6-8 times higher than those of propofol, thiopentone and midazolam. Induction with pregnanolone emulsion was reliable and fast, with only minor excitatory side effects, although induction time was longer compared to Althesin, propofol and thiopentone. ⋯ Recovery was rapid and smooth, and the proportion of sleeping time to recovery time was higher than found for the other four anaesthetics. No cumulative effects were seen on repeated administration and there were no venous sequelae. The results indicate that pregnanolone emulsion may provide a short-acting, less cumulative and less toxic alternative to existing intravenous anaesthetic agents.
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Comparative Study
Pregnanolone emulsion. A new steroid preparation for intravenous anaesthesia: an experimental study in mice.
The anaesthetic activity of pregnanolone (a metabolite of progesterone) in emulsion formulation administered intravenously to male mice was compared with that of Althesin. The loss of righting reflex for 15 seconds was used to estimate the anaesthetic effect. The mean anaesthetic dose (AD50) for the pregnanolone emulsion was 5.25 mg/kg and for Althesin, 2.8 mg/kg. ⋯ The onset of action was fast for both drugs, with only minor signs of excitation, and recovery was rapid and without excitation. The results indicate that the anaesthetic properties of pregnanolone emulsion are very similar to those of Althesin. Further studies will show whether it can fill the major vacuum left in anaesthetic practice after the withdrawal of Althesin.