Epigenetics and energetics in ventral hippocampus mediate rapid antidepressant action: Implications for treatment resistance
Open accessAbstract
Significance: Responsiveness, resistance to, and speed of treatment are major problems for depression. The energetic and epigenetic agent acetyl- l -carnitine (LAC) is known to exert rapid antidepressant-like effects in LAC-deficient Flinders Sensitive Line rats. Here, we identified central metabolic-regulator genes (e.g., insulin and glucose signaling) in ventral dentate gyrus (vDG), a mood-regulatory region, as key factors predisposing to depression and LAC responsiveness. While improving central energy regulation and exerting rapid antidepressant-like effects, LAC corrects systemic metabolic markers of hyperinsulinemia. Also, acute stress during the treatment alters the responsiveness to LAC and induces some resistance to the treatment with a new gene profile, whereby, again, metabolic factors in vDG are key players. These results posit vDG energy regulation as factor to be considered for development of better therapeutics.
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Molecules that affect energy homeostasis, such as acetyl-L-carnitine, affect and hence provide rapid antidepressant-like activity.
“Molecules that affect energy homeostasis, such as the epigenetic molecule acetyl-L-carnitine that is produced during normal metabolism, affect and hence provide rapid antidepressant-like activity.157,158”
From Epigenetic mechanisms of major depression: Targeting neuronal plasticity (2018) · cites this paper as [157]
Acetyl-L-carnitine has rapid anti-depressant-like effects and metabolic functions that rapidly reverse hyperinsulinemia and hyperglycemia in the FS rat which is deficient in LAC.
“Another potential intervention with a natural molecule, based on animal models, is acetyl-L-carnitine (LAC) which has not only rapid anti-depresssant-like effects, as noted above, but also has metabolic functions that rapidly reverses hyperinsulinemia and hyperglycemia in the FS, rat which is deficient in LAC.”
From Neurobiological and Systemic Effects of Chronic Stress (2017) · cites this paper as [67]
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- Authors
- Bigio, B., Mathé, A. A., Sousa, V. C., Zelli, D., Svenningsson, P., McEwen, B. S., & Nasca, C.
- Affiliations
- Rockefeller University (US)
- Karolinska Institutet (SE)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2016-06-27
- Volume
- 113
- Issue
- 28
- Pages
- 7906-7911
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC4948346
- OpenAlex
- W2475256373
- Cited by
- 85
- References
- 41
- Citations by year
- 2026: 1 · 2025: 6 · 2024: 6 · 2023: 3 · 2022: 6 · 2021: 12 · 2020: 8 · 2019: 9 · 2018: 15 · 2017: 14 · 2016: 5
- FWCI
- 11.60
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Hope for Depression Research Foundation (BMS1)
- American Foundation for Suicide Prevention (CN1)
- HHS | NIH | National Center for Advancing Translational Sciences (TR000043)
- Swedish medical research council (AAM1)
- Topics
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Keywords
- acetyl-L-carnitine, depression, antidepressant treatment resistance, ventral hippocampus, epigenetics, Flinders Sensitive Line rats, acute stress, hyperinsulinemia, insulin resistance, leptin receptor, mGluR2, neuropeptide Y, mineralocorticoid receptor, ELOVL7, Npas4, insulin receptor, glucose transporters, gene expression profiling
- MeSH terms
- Acetylcarnitine, Animals, Antidepressive Agents, Depression, Disease Models, Animal, Drug Resistance, Energy Metabolism, Hyperglycemia, Hyperinsulinism, Male, Stress, Psychological, Dentate Gyrus, Gene Expression Profiling, Epigenesis, Genetic, Rats
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