Stereochemical and structural effects of (2R,6R)-hydroxynorketamine on the mitochondrial metabolome in PC-12 cells

Faccio, Andréa Tedesco; Ruperez, Francisco J.; Singh, Nagendra; Angulo, Santiago; Tavares, Marina Franco Maggi; Bernier, Michel; Barbas, Coral; Wainer, Irving W.

doi:10.1016/j.bbagen.2018.03.008

Cited by 12 publications

(12 citation statements)

References 80 publications

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“…A number of HNK metabolites have been described, including the (2,4)-, (2,5)-, and Mouse, rat, and dog bioavailability and mouse oral antidepressant efficacy of (2R,6R)-hydroxynorketamine (2,6)-HNKs, (Desta et al, 2012;Moaddel et al, 2010;Woolf and Adams, 1987), with (2R,6R;2S,6S)-HNK being the most prevalent in the plasma of humans (Zarate et al, 2012) and in the plasma and brain of rodents (Can et al, 2016;Moaddel et al, 2016;Zanos et al, 2016) following ketamine administration. Although early studies classified (2R,6R;2S,6S)-HNK as an inactive metabolite due to its lack of anesthetic effects (Leung and Baillie, 1986), more recent studies have established the biological activity of this metabolite (Cavalleri et al, 2018;Chou et al, 2018;Faccio et al, 2018;Ho et al, 2018;Kroin et al, 2018;Moaddel et al, 2013;Paul et al, 2014;Pham et al, 2017;Singh et al, 2016;Wray et al, 2018;Yao et al, 2017;Zanos et al, 2016). Notably, it has been demonstrated that, in mice and rats, intraperitoneal (i.p.)…”

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confidence: 99%

Mouse, rat, and dog bioavailability and mouse oral antidepressant efficacy of (2R,6R)-hydroxynorketamine

et al. 2018

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Background: (R,S)-ketamine has gained attention for its rapid-acting antidepressant actions in patients with treatment-resistant depression. However, widespread use of ketamine is limited by its side effects, abuse potential, and poor oral bioavailability. The ketamine metabolite, (2R,6R)hydroxynorketamine, exerts rapid antidepressant effects, without ketamine's adverse effects and abuse potential, in rodents. Methods: We evaluated the oral bioavailability of (2R,6R)-hydroxynorketamine in three species (mice, rats, and dogs) and also evaluated five candidate prodrug modifications for their capacity to enhance the oral bioavailability of (2R,6R)-hydroxynorketamine in mice. Oral administration of (2R,6R)hydroxynorketamine was assessed for adverse behavioral effects and for antidepressant efficacy in the mouse forced-swim and learned helplessness tests. Results: (2R,6R)-hydroxynorketamine had absolute bioavailability between 46-52% in mice, 42% in rats, and 58% in dogs. Compared to intraperitoneal injection in mice, the relative oral bioavailability of (2R,6R)-hydroxynorketamine was 62%, which was not improved by any of the candidate prodrugs tested. Following oral administration, (2R,6R)-hydroxynorketamine readily penetrated the brain, with brain to plasma ratios between 0.67-1.2 in mice and rats. Oral administration of (2R,6R)-hydroxynorketamine to mice did not alter locomotor activity or precipitate behaviors associated with discomfort, sickness, or stereotypy up to a dose of 450 mg/kg. Oral (2R,6R)-hydroxynorketamine reduced forced-swim test immobility time (15-150 mg/kg) and reversed learned helplessness (50-150 mg/kg) in mice. Conclusions: These results demonstrate that (2R,6R)-hydroxynorketamine has favorable oral bioavailability in three species and exhibits antidepressant efficacy following oral administration in mice.

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confidence: 99%

Mouse, rat, and dog bioavailability and mouse oral antidepressant efficacy of (2R,6R)-hydroxynorketamine

et al. 2018

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“…There is some evidence indicating that HNKs can alter mitochondrial function and energy metabolism, which may contribute to their antidepressant actions; namely, using a metabolomics approach, Faccio et al (2018) demonstrated that a 36-hour exposure of PC12 cells to (2R,6R)-HNK (5 nM) and, to a lesser extent, (2S,6S)-HNK (0.5 nM), (R)-, and (S)ketamine (1 mM) altered the mitochondrial metabolome. Specifically, at the concentrations tested, (2R,6R)-HNK robustly increased markers of glycolysis, including glycerate, fructose-6-phosphate, and glucose-6-phosphate.…”

Section: Effects On Mitochondrial Function and Energy Metabolismmentioning

confidence: 99%

“…There are additional reports demonstrating that (2R,6R)-HNK increases the release of other neurotransmitters, including serotonin and norepinephrine (Ago et al, 2019), and promotes structural plasticity via dendritic outgrowth (Cavalleri et al, 2018;Collo et al, 2018). Recently, (2R,6R)-HNK was also shown to affect other processes, such as inflammatory responses (Ho et al, 2019;Xiong et al, 2019;Rahman et al, 2020) and mitochondrial function (Faccio et al, 2018;Rahman et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

Hydroxynorketamines: Pharmacology and Potential Therapeutic Applications

et al. 2021

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The following authors declare competing financial interests: R.M. and C.A.Z. are listed as co-inventors on a patent for the use of (2R,6R)hydroxynorketamine, (S)-dehydronorketamine, and other stereoisomeric dehydro-and hydroxylated metabolites of (R,S)-ketamine in the treatment of depression and neuropathic pain. P.Z., R.M., P.M., C.T., C.A.Z., and T.G. are listed as co-inventors on a patent application for the use of (2R,6R)-hydroxynorketamine and (2S,6S)-hydroxynorketamine in the treatment of depression, anxiety, anhedonia, suicidal ideation, and post-traumatic stress disorders. R.M., P.M., C.A.Z., and C.T. have assigned their patent rights to the United States government but will share a percentage of any royalties that may be received by the government. P.Z. and T.G. have assigned their patent rights to the University of Maryland Baltimore but will share a percentage of any royalties that may be received by the University of Maryland Baltimore. T.D.G. has received research funding from Allergan and Roche Pharmaceuticals and has served as a consultant for FSV7, LLC, during the preceding 3 years. All other authors declare no competing interests.

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“…5A/B/C/D). The TCA cycle, purine metabolism, and glutamate metabolism were selected as the crucial metabolic pathways according to the number of metabolites contained in metabolic pathways and the relationship between metabolic pathways [34] (Fig. 5E).…”

Section: Ssa and Af Protected Corticosterone-induced Neuroinjury By Rmentioning

confidence: 99%

“…Studies have shown that corticosterone, Aβ 25−35 , and (2R,6R)-Hydroxynorketamine could induce disturbance of cellular metabolic, including purine metabolism, glutamate metabolism, and TCA cycle, etc. in PC12 cell [25][26][27][28]. Meanwhile, metabolomics is an effective tool to elucidate the potential compatibility mechanisms of traditional Chinese medicine [29].…”

Section: Introductionmentioning

confidence: 99%

Synergistic Effect of Saikosaponin a and Albiflorin Against Corticosterone-Induced Neuro-Injury in PC12 Cells via Regulation of TCA Cycle, Purine Metabolism, and Glutamate Metabolism

et al. 2021

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The combination of Radix Bupleuri - Radix Paeoniae alba is one of the most approbated herb pairs in traditional Chinese medicine (TCM) formula for curing depression. Saikosaponin A (SSA) and albiflorin (AF) are major bioactive compounds of Radix Bupleuri and Radix Paeoniae alba respectively, which possess antidepressant effects in pharmacological experiments. However, whether SSA and AF have synergistic neuroprotective effects and the synergistic mechanism is still unknown. The present study employed the corticosterone-induced PC12 cells neuro-injury model to assess the protective effect of SSA and AF, alone and in combination, and the synergistic effect was analyzed using three mathematical models. Meanwhile, the cell metabolomics was used to detect the effects on metabolite regulation of SSA and AF, alone and in combination. According to the results of cell metabolomics, the vital cell transduction pathway related to the crucial cell metabolic pathways were selected. Furthermore, the key metabolites, metabolic enzymes, and cellular markers were verified by ELISA and Western blotting. The results showed that the combination of SSA and AF has a synergistic neuroprotective effect. Besides, the combination could regulate more metabolites (16) than a single agent (12 & 10) and possessed a stronger adjustment effect on metabolites. Correspondingly, the combination regulated more metabolism pathways (7) than alone agents (3 & 5). Furthermore, the TCA cycle, purine metabolism, and glutamate metabolism were selected as crucial metabolism pathways. The results showed that the TCA cycle disorder was regulated by SSA and AF via improving mitochondrial function. The purine metabolism disorder was regulated by SSA via inhibition xanthine oxidase (XOD) activity and the glutamate metabolism disorder was regulated by AF via inhibition glutaminase (GLS) activity. Moreover, the oxidative stress induced by the purine metabolism disorder was attenuated by SSA via a reduction in the ROS level. Additionally, the inflammation induced by the oxidative stress was attenuated by the SSA and AF via inhibition of the NLRP3 protein expression. This study for the first time demonstrated the synergistic neuroprotective effect of SSA and AF, and the synergistic mechanism was involved in metabolic disorders regulation.

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Stereochemical and structural effects of (2R,6R)-hydroxynorketamine on the mitochondrial metabolome in PC-12 cells

Abstract: The present data provide an overall view of the metabolic changes in mitochondrial function produced by (2R,6R)-HNK and related ketamine compounds and offer an insight into the source of the observed variance in antidepressant response elicited by the compounds.

Cited by 12 publications

References 80 publications

Mouse, rat, and dog bioavailability and mouse oral antidepressant efficacy of (2R,6R)-hydroxynorketamine

Mouse, rat, and dog bioavailability and mouse oral antidepressant efficacy of (2R,6R)-hydroxynorketamine

Hydroxynorketamines: Pharmacology and Potential Therapeutic Applications

Synergistic Effect of Saikosaponin a and Albiflorin Against Corticosterone-Induced Neuro-Injury in PC12 Cells via Regulation of TCA Cycle, Purine Metabolism, and Glutamate Metabolism

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Stereochemical and structural effects of (2R,6R)-hydroxynorketamine on the mitochondrial metabolome in PC-12 cells

Abstract: The present data provide an overall view of the metabolic changes in mitochondrial function produced by (2R,6R)-HNK and related ketamine compounds and offer an insight into the source of the observed variance in antidepressant response elicited by the compounds.

Cited by 12 publications

References 80 publications

Mouse, rat, and dog bioavailability and mouse oral antidepressant efficacy of (2R,6R)-hydroxynorketamine

Mouse, rat, and dog bioavailability and mouse oral antidepressant efficacy of (2R,6R)-hydroxynorketamine

Hydroxynorketamines: Pharmacology and Potential Therapeutic Applications

Synergistic Effect of Saikosaponin a and Albiflorin Against Corticosterone-Induced Neuro-Injury in PC12&nbsp;Cells via Regulation of TCA&nbsp;Cycle, Purine Metabolism, and Glutamate Metabolism

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Synergistic Effect of Saikosaponin a and Albiflorin Against Corticosterone-Induced Neuro-Injury in PC12 Cells via Regulation of TCA Cycle, Purine Metabolism, and Glutamate Metabolism