Andréa T Faccio1, Francisco J Ruperez2, Nagendra S Singh3, Santiago Angulo2, Marina F M Tavares4, Michel Bernier5, Coral Barbas2, Irving W Wainer6. 1. CEMBIO (Centre for Metabolomics and Bioanalysis), Faculty of Pharmacy, Universidad San Pablo CEU, Campus Monteprincipe, Boadilla del Monte, 28668 Madrid, Spain; Institute of Chemistry, University of São Paulo (USP), 05513-970 São Paulo, SP, Brazil. 2. CEMBIO (Centre for Metabolomics and Bioanalysis), Faculty of Pharmacy, Universidad San Pablo CEU, Campus Monteprincipe, Boadilla del Monte, 28668 Madrid, Spain. 3. Laboratory of Clinical Investigation, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA. 4. Institute of Chemistry, University of São Paulo (USP), 05513-970 São Paulo, SP, Brazil. 5. Translational Gerontology Branch, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA. 6. Laboratory of Clinical Investigation, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA; Mitchell Woods Pharmaceuticals, Shelton, CT 06484, USA. Electronic address: iwwainer@mitchellwoods.com.
Abstract
BACKGROUND: Impairment in mitochondrial biogenesis and function plays a key role in depression and anxiety, both of which being associated with changes in fatty acid and phospholipid metabolism. The antidepressant effects of (R,S)-ketamine have been linked to its conversion into (2S,6S;2R,6R)-hydroxynorketamine (HNK); however, the connection between structure and stereochemistry of ketamine and HNK in the mitochondrial homeostatic response has not yet been fully elucidated at a metabolic level. METHODS: We used a multi-platform, non-targeted metabolomics approach to study the change in mitochondrial metabolome of PC-12 cells treated with ketamine and HNK enantiomers. The identified metabolites were grouped into pathways in order to assess global responses. RESULTS: Treatment with (2R,6R)-HNK elicited the significant change in 49 metabolites and associated pathways implicated in fundamental mitochondrial functions such as TCA cycle, branched-chain amino acid biosynthetic pathway, glycoxylate metabolic pathway, and fatty acid β-oxidation. The affected metabolites included glycerate, citrate, leucine, N,N-dimethylglycine, 3-hexenedioic acid, and carnitine and attenuated signals associated with 9 fatty acids and elaidic acid. Important metabolites involved in the purine and pyrimidine pathways were also affected by (2R-6R)-HNK. This global metabolic profile was not as strongly impacted by treatment with (2S,6S)-HNK, (R)- and (S)-ketamine and in some instances opposite effects were observed. CONCLUSIONS: 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.
BACKGROUND: Impairment in mitochondrial biogenesis and function plays a key role in depression and anxiety, both of which being associated with changes in fatty acid and phospholipid metabolism. The antidepressant effects of (R,S)-ketamine have been linked to its conversion into (2S,6S;2R,6R)-hydroxynorketamine (HNK); however, the connection between structure and stereochemistry of ketamine and HNK in the mitochondrial homeostatic response has not yet been fully elucidated at a metabolic level. METHODS: We used a multi-platform, non-targeted metabolomics approach to study the change in mitochondrial metabolome of PC-12 cells treated with ketamine and HNK enantiomers. The identified metabolites were grouped into pathways in order to assess global responses. RESULTS: Treatment with (2R,6R)-HNK elicited the significant change in 49 metabolites and associated pathways implicated in fundamental mitochondrial functions such as TCA cycle, branched-chain amino acid biosynthetic pathway, glycoxylate metabolic pathway, and fatty acid β-oxidation. The affected metabolites included glycerate, citrate, leucine, N,N-dimethylglycine, 3-hexenedioic acid, and carnitine and attenuated signals associated with 9 fatty acids and elaidic acid. Important metabolites involved in the purine and pyrimidine pathways were also affected by (2R-6R)-HNK. This global metabolic profile was not as strongly impacted by treatment with (2S,6S)-HNK, (R)- and (S)-ketamine and in some instances opposite effects were observed. CONCLUSIONS: 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.
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