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Ketamine and ketamine metabolites as novel estrogen receptor ligands: Induction of cytochrome P450 and AMPA glutamate receptor gene expression.

ABSTRACT: Major depressive disorder (MDD) is the most common psychiatric illness worldwide, and it displays a striking sex-dependent difference in incidence, with two thirds of MDD patients being women. Ketamine treatment can produce rapid antidepressant effects in MDD patients, effects that are mediated-at least partially-through glutamatergic neurotransmission. Two active metabolites of ketamine, (2R,6R)-hydroxynorketamine (HNK) and (2S,6S)-HNK, also appear to play a key role in ketamine's rapid antidepressant effects through the activation of ?-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptors. In the present study, we demonstrated that estrogen plus ketamine or estrogen plus active ketamine metabolites displayed additive effects on the induction of the expression of AMPA receptor subunits. In parallel, the expression of estrogen receptor alpha (ER?) was also significantly upregulated. Even more striking, radioligand binding assays demonstrated that [3H]-ketamine can directly bind to ER? (KD: 344.5?±?13?nM). Furthermore, ketamine and its (2R,6R)-HNK and (2S,6S)-HNK metabolites displayed similar affinity for ER? (IC50: 2.31?±?0.1, 3.40?±?0.2, and 3.53?±?0.2?µM, respectively) as determined by [3H]-ketamine displacement assays. Finally, induction of AMPA receptors by either estrogens or ketamine and its metabolites was lost when ER? was knocked down or silenced pharmacologically. These results suggest a positive feedback loop by which estrogens can augment the effects of ketamine and its (2R,6R)-HNK and (2S,6S)-HNK metabolites on the ER?-induced transcription of CYP2A6 and CYP2B6, estrogen inducible enzymes that catalyze ketamine's biotransformation to form the two active metabolites. These observations provide novel insight into ketamine's molecular mechanism(s) of action and have potential implications for the treatment of MDD.

SUBMITTER: Ho MF

PROVIDER: S-EPMC5960634 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Ketamine and ketamine metabolites as novel estrogen receptor ligands: Induction of cytochrome P450 and AMPA glutamate receptor gene expression.

Ho Ming-Fen MF Correia Cristina C Ingle James N JN Kaddurah-Daouk Rima R Wang Liewei L Kaufmann Scott H SH Weinshilboum Richard M RM

Biochemical pharmacology 20180403

Major depressive disorder (MDD) is the most common psychiatric illness worldwide, and it displays a striking sex-dependent difference in incidence, with two thirds of MDD patients being women. Ketamine treatment can produce rapid antidepressant effects in MDD patients, effects that are mediated-at least partially-through glutamatergic neurotransmission. Two active metabolites of ketamine, (2R,6R)-hydroxynorketamine (HNK) and (2S,6S)-HNK, also appear to play a key role in ketamine's rapid antidep ...[more]

PMID: 29621538

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Project description:Estradiol-17beta (E(2)beta) and its metabolites, which are sequentially synthesized by cytochrome P450s and catechol-O-methyltransferase to form 2 and 4-hydroxyestradiol (OHE(2)) and 2- and 4-methoxestradiol (ME(2)), are elevated during pregnancy. We investigated whether cytochrome P450s and catechol-O-methyltransferase are expressed in uterine artery endothelial cells (UAECs) and whether E(2)beta and its metabolites modulate cell proliferation via ER-alpha and/or ER-beta and play roles in physiological uterine angiogenesis during pregnancy. Cultured ovine UAECs from pregnant and nonpregnant ewes were treated with 0.1 to 100.0 nmol/L of E(2)beta, 2-OHE(2), 4-OHE(2), 2-ME(2), and 4-ME(2). ER-alpha or ER-beta specificity was tested using ICI 182 780, ER-alpha-specific 1,3-bis(4-hydroxyphenyl)-4-methyl-5-[4-(2-piperidinyleth oxy)phenol]-1H-pyrazole dihydrochloride, ER-beta-specific 4-[2-phenyl-5,7-bis(trifluoromethyl)pyrazolo [1,5-a]pyrim idin-3-yl]phenol antagonists and their respective agonists ER-alpha-specific 4,4',4"-(4-propyl-[1H]-pyrazole-1,3,5-triyl)trisphenol and ER-beta-specific 2,3-bis(4-Hydroxyphenyl)-propionitrile. Angiogenesis was evaluated using 5-bromodeoxyuridine proliferation assay. Using confocal microscopy and Western analyses to determine enzyme location and levels, we observed CYP1A1, CYP1A2, CYP1B1, CYP3A4, and catechol-O-methyltransferase expression in UAECs; however, expressions were similar between nonpregnant UAECs and pregnant UAECs. E(2)beta, 2-OHE(2), 4-OHE(2), and 4-ME(2) treatments concentration-dependently stimulated proliferation in pregnant UAECs but not in nonpregnant UAECs; 2-ME(2) did not stimulate proliferation in either cell type. Proliferative responses of pregnant UAECs to E(2)beta were solely mediated by ER-beta, whereas responses to E(2)beta metabolites were neither ER-alpha nor ER-beta mediated. We demonstrate an important vascular role for E(2)beta, its cytochrome P450- and catechol-O-methyltransferase-derived metabolites, and ER-beta in uterine angiogenesis regulation during pregnancy that may be dysfunctional in preeclampsia and other cardiovascular disorders.

Dataset Information

Ketamine and ketamine metabolites as novel estrogen receptor ligands: Induction of cytochrome P450 and AMPA glutamate receptor gene expression.

Publications

Ketamine and ketamine metabolites as novel estrogen receptor ligands: Induction of cytochrome P450 and AMPA glutamate receptor gene expression.

Similar Datasets

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