Studies on Neurosteroids XXV. Influence of a 5.ALPHA.-Reductase Inhibitor, Finasteride, on Rat Brain Neurosteroid Levels and Metabolism

Abstract

Neurosteroids affect neurotransmission through action at the membrane ion-gated receptors and at other neurotransmitter receptors. 3a-Hydroxy-5a-pregnan-20-one (allopregnanolone, AP), a representative neurosteroid, binds to the gaminobutyric acid type A (GABA A ) receptors with a high affinity and positively modulates the action of GABA at these receptors, and hence elicits marked anticonvulsant, antidepressant and anxiolytic effects.1) Under stressful conditions, the brain rapidly synthesizes progesterone (PROG) and subsequently converts it to AP to raise the threshold of brain excitability.2)The two-step metabolism of PROG produces AP through the actions of the enzymes, 5a-reductase (rate-limiting step) and 3a-hydroxysteroid dehydrogenase (3a-HSD). Two distinct 5a-reductase isozymes, types 1 (predominant form in the brain) and 2 (predominant form in the periphery), are found across mammalian species.3) Finasteride [17a-(N-tbutyl)carbamoyl-4-aza-5a-androst-1-en-3-one, FIN] is the 5a-reductase inhibitor that has received clinical approval for the treatment of human benign prostatic hyperplasia and androgenetic alopecia. Both isozymes of the 5a-reductase in the rodent demonstrate comparable inhibition following FIN exposure; FIN can inhibit the 5a-reductase activity in the central nervous system as well as in the periphery.4) Based on this, FIN has also been used to manipulate the brain AP level for characterization of its physiological functions and the mechanism by which it affects the brain functions, and to analyze the exact mechanisms of action of psychotropic agents, whose antidepressant and anxiolytic effects are inferred to occur through an increase in the brain AP synthesis.5,6) Thus, FIN is an indispensable tool in the development of new psychotropic agents targeting neurosteroidogenesis as well as in basic neurosteroid research. On the contrary, the treatment with FIN may induce alternative metabolic pathways, such as 3a-reduction, 20a-reduction and 21-hydroxylation, in the PROG metabolism (Fig. 1), and the generated metabolites may consequently affect the central nervous system and modulate the emotional state. However, there is no report that examines the changes in the brain levels of the PROG and its metabolites following treatment with FIN. Even for AP, a detailed FIN-evoked change in the brain concentration has not been elucidated.Based on this background information, the objectives of this study are to develop liquid chromatography-tandem mass spectrometric (LC-MS/MS) methods that enable the determination of trace amounts of the brain PROG and its down stream conversion products [AP, 3a-dihydroprogesterone (3a-DHP), 20a-dihydroprogesterone (20a-DHP) and 11-deoxycorticosterone (DOC)] (Fig. 1) and to determine the influence of FIN on the brain steroid levels and metabolism in rats under the stressful condition. MATERIALS AND METHODS Materials andReagents AP, 3a-DHP, 3b-DHP and 20a-DHP were obtained from Steraloids (Newport, RI, U.S.A.). PROG and DOC were purchased from Tokyo Kasei Kogyo (Tokyo, Ja...

A Mouse Kindling Model of Perimenstrual Catamenial Epilepsy

“…Seizure exacerbation observed in the present study is caused by reduced neurosteroid levels in the brain. Finasteride blocks the synthesis of neurosteroids such as AP and related 5␣-reduced pregnane analogs that modulate GABA A receptor function (Mukai et al, 2008). Consistent with the time course for finasteride inhibition of neurosteroid synthe- Fig.…”

Estrous Cycle Regulation of Extrasynaptic δ-Containing GABAA Receptor-Mediated Tonic Inhibition and Limbic Epileptogenesis

“…The neurosteroid AP is synthesized de novo within neurons (Reddy, 2009(Reddy, , 2013, and circulating AP levels parallel those of precursor progesterone (Tuveri et al, 2008). Although the dynamics of brain AP during the menstrual cycle are not well studied, it is likely that local synthesis of neurosteroids occurs in key regions of the limbic system, including the hippocampus and amygdala (Agis-Balboa et al, 2006;Ebner et al, 2006;Mukai et al, 2008). GABA A R heterogeneity confers different neurosteroid binding affinities and gating; a1b2g2 and a2b2g2 GABA A Rs are abundant in the hippocampus and have relatively low neurosteroid sensitivity.…”

Finasteride improves motor, EEG, and cellular changes in rat brain in thioacetamide-induced hepatic encephalopathy

“…In addition, FIN was found to inhibit neurosteroid synthesis in the brain, since 5␣-reductase is an enzyme necessary for conversion of progesterone and deoxycorticosterone to the 5␣-pregnane steroids, intermediates that are further reduced to ALLO and THDOC (6,43). On the other hand, the treatment with FIN may induce alternative metabolic pathways in the progesterone metabolism, such as 3␣ reduction, 20␣ reduction, and 21 hydroxylation.…”

“…On the other hand, the treatment with FIN may induce alternative metabolic pathways in the progesterone metabolism, such as 3␣ reduction, 20␣ reduction, and 21 hydroxylation. These effects of FIN on neurosteroid metabolism were found to modulate the emotional state (43), exacerbate lithium-and pilocarpine-induced seizures (34), in-crease formalin-induced pain in rats (42), and alter the ethanol intake pattern in C57BL/6J mice (20). In addition, 5␣-reductase inhibitors exert antipsychotic-like properties in rats and are proposed as a putative novel target in the management of psychotic disorders (11,47).…”