Precursors of the neurosteroids.

Abstract

In addition to the neurosteroids pregnenolone and dehydroepiandrosterone, organic solvent extracts of rat brains contain related compounds that react with various reagents to yield additional amounts of these ketosterolds. Among the chemicals producing these increments are triethylamine, HCI, FeCl3, and Pb(OAc) In a recent paper (1), estimates of the concentrations of five steroids and their conjugates in mammalian brains were recorded. Also described were the techniques used for the separation, identification, and quantification of these socalled neurosteroids. An unusual feature of the reported findings was the relatively high concentrations of steroidal conjugates, which were designated "sulfolipids." Following from our previous experience with analogous conjugates of cholesterol (2), we found that there appear to exist in mammalian brain nonpolar conjugates of neurosteroids, particularly pregnenolone (3f3hydroxy-5-pregnen-20-one) and dehydroepiandrosterone (3f-hydroxy-5-androsten-17-one).These, when treated with an organic base such as triethylamine or pyridine, were converted to a steroid sulfate that could be identified and quantified (after acid hydrolysis) as the free steroid. Some of these conjugates appeared to be present in relatively high concentrations in brain, suggesting that these conjugates play a physiological role in the nervous system.The experiments described in this paper bear on these substances. More The second part was separated into its ketonic and nonketonic (part B) components by treatment with polystyrenebenzyloxime resin to remove carbonyl compounds (8), including the endogenous ketosteroids and their derivatives. Sample B was dissolved in 20 ml of benzene containing 2 ml of acetic acid and a bolus of 200,000 dpm of tritiated pregnenolone. The oxime resin (100 mg) was added, and the suspension was stirred for 2 hr at room temperature. A check of the tritium content of the supernatant revealed that >90% of the tritiated steroid had bound to the resin. The reaction was allowed to proceed to Abbreviation: P450scc, side chain-cleaving P450.

Novel lipoidal derivatives of pregnenolone and dehydroepiandrosterone and absence of their sulfated counterparts in rodent brain

“…Considering that the concentration of endogenous unconjugated PREG was in the range of 3-5 ng/g and assuming that experimental losses during the workup were roughly similar for free and lipoidal steroids, the range of L-PREG levels in the whole adult male rat brain is estimated to be 210-350 ng/g ‫1ف(‬ nmol/g) using our methodology. These very surprising concentrations seem to support the quantitative results of Lieberman's group (43) concerning high levels of so-called PREG sulfolipid in rat brain and the release of large amounts of PREG after treatment of organic brain extracts with several chemicals (53).…”

“…The proposed structure of these steroid derivatives was characterized by an oxygen-sulfur bond between the steroid at position C-3 and the lipid moiety. Prasad et al (53) questioned this hypothesis because they found that the material from which PREG (and DHEA to a lesser extent) was liberated by treatment with an organic Fig. 7.…”

Neuroactive Steroid 3α-Hydroxy-5α-Pregnan-20-One Modulates Electrophysiological and Behavioral Actions of Ethanol

“…The absence of a correlation between central and circulating 3␣,5␣-THP levels could be attributable to different time courses for steroid production or metabolism between the periphery and brain. Although it is premature to conclude that brain levels are independent of peripheral steroid sources, evidence suggests that neurosteroid biosynthesis in brain may include novel nonenzymatic pathways (Lieberman and Prasad, 1990;Prasad et al, 1994;Cascio et al, 1998).…”

Role of Neuroactive Steroid Allopregnanolone in Antipsychotic-like Action of Olanzapine in Rodents

“…of the neurosteroid ALLO and neurosteroidogenic agents like the MDR agonist FGIN 1-27 or i.p. injection of the neurosteroid precursor progesterone (Bitran et al, 2000;Paul and Purdy, 1992;Romeo et al, 1992;Rupprecht et al, 1993;Prasad et al, 1994;Lambert et al, 1995) also dose specifically antagonized these behaviors. Indeed, we and others have recently demonstrated the neuroleptic-like properties of the neurosteroid ALLO and its precursor progesterone.…”