(R,S)-Ketamine metabolites (R,S)-norketamine and (2S,6S)-hydroxynorketamine increase the mammalian target of rapamycin function
This rodent study (2014) argues that a full analysis of (R,S)-ketamine's metabolites is required to understand ketamine's anti-depressive and analgesic effects.
Authors
- Paul, R. K.
- Singh, N. S.
- Khadeer, M.
Published
Abstract
Background
Subanesthetic doses of (R,S)-ketamine are used in the treatment of neuropathic pain and depression. In the rat, the antidepressant effects of (R,S)-ketamine are associated with increased activity and function of mammalian target of rapamycin (mTOR); however, (R,S)-ketamine is extensively metabolized and the contribution of its metabolites to increased mTOR signaling is unknown.
Methods
Rats (n = 3 per time point) were given (R,S)-ketamine, (R,S)-norketamine, and (2S,6S)-hydroxynorketamine and their effect on the mTOR pathway determined after 20, 30, and 60 min. PC-12 pheochromocytoma cells (n = 3 per experiment) were treated with escalating concentrations of each compound and the impact on the mTOR pathway was determined.
Results
The phosphorylation of mTOR and its downstream targets was significantly increased in rat prefrontal cortex tissue by more than ~2.5-, ~25-, and ~2-fold, respectively, in response to a 60-min postadministration of (R,S)-ketamine, (R,S)-norketamine, and (2S,6S)-hydroxynorketamine (P < 0.05, ANOVA analysis). In PC-12 pheochromocytoma cells, the test compounds activated the mTOR pathway in a concentration-dependent manner, which resulted in a significantly higher expression of serine racemase with ~2-fold increases at 0.05 nM (2S,6S)-hydroxynorketamine, 10 nM (R,S)-norketamine, and 1,000 nM (R,S)-ketamine. The potency of the effect reflected antagonistic activity of the test compounds at the α7-nicotinic acetylcholine receptor.
Conclusions
The data demonstrate that (R,S)-norketamine and (2S,6S)-hydroxynorketamine have potent pharmacological activity both in vitro and in vivo and contribute to the molecular effects produced by subanesthetic doses of (R,S)-ketamine. The results suggest that the determination of the mechanisms underlying the antidepressant and analgesic effects of (R,S)-ketamine requires a full study of the parent compound and its metabolites.
Research Summary of '(R,S)-Ketamine metabolites (R,S)-norketamine and (2S,6S)-hydroxynorketamine increase the mammalian target of rapamycin function'
Introduction
Earlier research has shown that subanesthetic doses of (R,S)-ketamine produce rapid antidepressant effects in rodents that are associated with increased phosphorylation of the mammalian target of rapamycin (mTOR) and downstream signalling proteins (pERK1/2, pAkt, p4E-BP1, pp70S6K) and with increased synaptogenesis in the prefrontal cortex. Ketamine is, however, rapidly and extensively metabolised to multiple products including (R,S)-norketamine and diastereomeric hydroxynorketamines such as (2S,6S;2R,6R)-hydroxynorketamine; the contribution of these metabolites to the mTOR-linked molecular effects attributed to the parent drug has been unclear. Paul and colleagues set out to determine whether (R,S)-norketamine and the specific isomer (2S,6S)-hydroxynorketamine have pharmacological activity on the mTOR signalling pathway in vitro and in vivo. The study aimed to measure brain concentrations and mTOR pathway phosphorylation after administration of the parent compound and selected metabolites in male Wistar rats, and to assess concentration-dependent effects on mTOR signalling and serine racemase (m-SR) expression in PC-12 cells. This approach was intended to clarify whether metabolites contribute to molecular events linked to ketamine’s antidepressant and analgesic actions.
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Study Details
- Study Typeindividual
- Journal
- Compound
- Topics
- APA Citation
Paul, R. K., Singh, N. S., Khadeer, M., Moaddel, R., Sanghvi, M., Green, C. E., O’Loughlin, K., Torjman, M. C., Bernier, M., & Wainer, I. W. (2014). (R,S)-Ketamine metabolites (R,S)-norketamine and (2S,6S)-hydroxynorketamine increase the mammalian target of rapamycin function. Anesthesiology, 121(1), 149-159. https://doi.org/10.1097/ALN.0000000000000285
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