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Vorinostat (SAHA) May Exert Its Antidepressant-Like Effects Through the Modulation of Oxidative Stress Pathways

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Abstract

Suberoylanilide hydroxamic acid (SAHA/Vorinostat), a potent inhibitor of histone deacetylases (HDACs), is known to possess antidepressant properties. However, the exact mechanisms underlying this activity are unknown. In this study, we evaluated the effect of SAHA on the expression of GluN2A, GluN2B (NMDA receptor subunits), (p-)AMPK, and ΔFos proteins which are an integral part of the signal transduction pathways in the brain and also involved in the pathophysiology of depression as well as the mechanism of antidepressant action. We also measured the concentration of malondialdehyde (MDA - a product of lipid peroxidation). The study was carried out in the prefrontal cortex (PFC) and hippocampus (Hp), brain regions implicated in depression. Although SAHA induced changes in the expression of all the proteins and MDA concentration, the effects differed depending on the drug dose, time, and brain structure involved. SAHA reduced MDA concentration and significantly increased p-AMPK protein expression, indicating it may prevent oxidative stress. SAHA also increased the levels of HDAC3 and NMDA subunits (GluN2A and GluN2B), implying it is neuroprotective and may play a crucial role in synaptic plasticity. Moreover, ΔFosB and FosB levels were significantly elevated, suggesting that SAHA may modulate learning and memory processes. Overall, the data indicate that the Hp might play a pivotal role in the mechanism of action of SAHA, hinting at novel mechanisms it play in the antidepressant and neuroprotective effects of SAHA.

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Funding

The study was partially supported by a grant from the National Science Centre (contract UMO-2013/09/D/NZ7/02520 to M. Sowa-Kućma) and funds for statutory activities of: the Maj Institute of Pharmacology, PAS (Krakow, Poland); the Jagiellonian University Medical College (Krakow, Poland) and the Medical College of Rzeszow University (Rzeszów, Poland).

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Authors and Affiliations

  1. Department of Pharmacobiology, Jagiellonian University Medical College, Kraków, Poland

    Paulina Misztak & Gabriel Nowak

  2. Maj Institute of Pharmacology, Polish Academy of Sciences, Laboratory of Trace Elements Neurobiology, Smetna 12, 31-343, Krakow, Poland

    Paulina Misztak, Bernadeta Szewczyk & Gabriel Nowak

  3. Department of Human Physiology, Institute of Medical Sciences, Medical College of Rzeszow University, Kopisto 2a, 35-959, Rzeszow, Poland

    Magdalena Sowa-Kućma

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  1. Paulina Misztak
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  2. Magdalena Sowa-Kućma
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PM designed and carried out all the experiments, analyzed the data, and wrote the first version of the manuscript; BS and GN prepared the last version of the manuscript; and MS-K performed the experiments, worked on the latest version of the manuscript.

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Correspondence to Gabriel Nowak.

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Misztak, P., Sowa-Kućma, M., Szewczyk, B. et al. Vorinostat (SAHA) May Exert Its Antidepressant-Like Effects Through the Modulation of Oxidative Stress Pathways. Neurotox Res 39, 170–181 (2021). https://doi.org/10.1007/s12640-020-00317-7

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  • DOI: https://doi.org/10.1007/s12640-020-00317-7

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