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The Sirtuin 2 Inhibitor AK-7 Leads to an Antidepressant-Like Effect in Mice via Upregulation of CREB1, BDNF, and NTRK2 Pathways

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Abstract

Depression is one of the most important and serious health problems in developing countries which affects millions of people. It is associated with the decrease of the quality of life as well as suicides and mortality. The disease may show recurrent episodes in some patients. Obviously, not all the patients with depression could be treated properly, because some individuals are drug-resistant and the options for the therapy are limited. Therefore, it is crucial to investigate new molecules and pathways that may have possible antidepressant activity. Sirtuin (SIRT), known as a class III histone deacetylase, which is regulated by nicotinamide adenine dinucleotide (NAD +), is one of these molecules. In the current study, we investigated the possible antidepressant-like effect of SIRT2 inhibitor AK-7. For this purpose, behavioral tests were performed in chronic AK-7-treated mice, and the expression levels of BDNF, NGF, NTF3, CREB, NTRK2, ERK1, ERK2, and GAP43 genes were evaluated by qRT-PCR analysis in brain tissues. Protein levels for BDNF, CREB1, and NTRK2 were determined by western blot. Our data showed that AK-7 significantly decreased immobility time and showed antidepressant-like effect. In addition, AK-7 treatment significantly increased mRNA levels of CREB and NTRK2 and protein levels of CREB1, BDNF, and NTRK2. Finally, our results suggest that SIRT2 and AK-7 may have a potential role in the cellular mechanisms of depression.

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Acknowledgements

We would like to thank SUDAM staff (especially Salih Metin Gokyaprak, DVM and Mehmet Kosen) for their full support.

Funding

This study was supported by the Scientific and Research Projects Department at the University of Konya-NE (Project Number 191218013).

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Authors and Affiliations

  1. Department of Medical Biology, Meram Faculty of Medicine, University of Konya-NE, Konya, Turkey

    Ebru Guclu & Hasibe Cingilli Vural

  2. Department of Medical Pharmacology, Meram Faculty of Medicine, University of Konya-NE, 42080, Akyokus, Meram, Konya, Turkey

    Salim Yalcin Inan

Authors
  1. Ebru Guclu
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  2. Salim Yalcin Inan
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Contributions

The main idea of the present study was from Ebru Guclu and Salim Yalcin Inan. Salim Yalcin Inan and Ebru Guclu designed the protocol of the study. Hasibe Cingilli Vural provided budget for this study. While data collection for behavioral experiments has been done by Salim Yalcin Inan and Ebru Guclu, molecular studies have been performed by Ebru Guclu and Hasibe Cingilli Vural. Writing the manuscript has been done by Ebru Guclu and Salim Yalcin Inan. All authors contributed to and have approved the final manuscript before submission.

Corresponding author

Correspondence to Salim Yalcin Inan.

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All procedures conformed to NIH guidelines and were approved by the University of Selcuk Animal Care and Use Committee (Protocol 2019–28).

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Guclu, E., Inan, S.Y. & Vural, H.C. The Sirtuin 2 Inhibitor AK-7 Leads to an Antidepressant-Like Effect in Mice via Upregulation of CREB1, BDNF, and NTRK2 Pathways. Mol Neurobiol 59, 7036–7044 (2022). https://doi.org/10.1007/s12035-022-03026-8

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