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Complexity of Compensatory Effects in Nrf1 Knockdown: Linking Undeveloped Anxiety-Like Behavior to Prevented Mitochondrial Dysfunction and Oxidative Stress

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Abstract

Anxiety-related disorders are complex illnesses that underlying molecular mechanisms need to be understood. Mitochondria stand as an important link between energy metabolism, oxidative stress, and anxiety. The nuclear factor, erythroid-derived 2,-like 1(Nrf1) is a member of the cap “n” collar subfamily of basic region leucine zipper transcription factors and plays the major role in regulating the adaptive response to oxidants and electrophiles within the cell. Here, we injected small interfering RNA (siRNA) targeting Nrf1 in dorsal third ventricle of adult male albino Wistar rats and subsequently examined the effect of this silencing on anxiety-related behavior. We also evaluated apoptotic markers and mitochondrial biogenesis factors, along with electron transport chain activity in three brain regions: hippocampus, amygdala, and prefrontal cortex. Our data revealed that in the group that received Nrf1-siRNA, anxiety-related behavior did not show any significant changes compared to the control group. Caspase-3 did not increase in Nrf1-siRNA-injected rats even though Bax/Bcl2 ratio markedly elevated in Nrf1-knockdown rats in all three mentioned regions compared to control rats. Also, Nrf1 silencing of complex I and II–III did not alter, generally. In addition, Nrf1-knockdown affected mitochondrial biogenesis markers. The level of peroxisome proliferator-activated receptor gamma coactivator-1α and cytochrome-c increased, which indicates a possible role for mitochondrial biogenesis in anxiety.

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Acknowledgments

This work was supported financially by the Iran National Science Foundation (INSF, grant number 91003013).

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Authors and Affiliations

  1. Department of Animal Physiology, Faculty of Biology, Kharazmi University, P.O. Box: 15614, Tehran, Iran

    Solmaz Khalifeh & Shahrbanoo Oryan

  2. Medical Genomics Research Center and School of Advanced Sciences in Medicine, Tehran Medical Sciences Branch, Islamic Azad University, Tehran, Iran

    Solmaz Khalifeh & Mohammad-Reza Zarrindast

  3. Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran

    Fariba Khodagholi, Hadi Digaleh & Nader Maghsoudi

  4. NeuroBiology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran

    Fariba Khodagholi, Hadi Digaleh & Nader Maghsoudi

  5. Department of Physiology, Faculty of Medicine, Hormozgan University of Medical Sciences, Bandar Abbas, Iran

    Fatemeh Shaerzadeh

  6. Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran

    Mohammad-Reza Zarrindast

  7. Institute for Cognitive Science Studies (ICSS), Tehran, Iran

    Mohammad-Reza Zarrindast

  8. School of Cognitive Sciences, Institute for Research in Fundamental Sciences (IPM), Tehran, Iran

    Mohammad-Reza Zarrindast

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  1. Solmaz Khalifeh
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  2. Shahrbanoo Oryan
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  6. Nader Maghsoudi
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Correspondence to Solmaz Khalifeh.

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All procedures involving the care of animals were performed according to the guidelines for animal experimentation issued by the National Institutes of Health Publication (No. 80-23, revised 1996) and the Research and Ethics Committee of Shahid Beheshti University of Medical Sciences.

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Khalifeh, S., Oryan, S., Khodagholi, F. et al. Complexity of Compensatory Effects in Nrf1 Knockdown: Linking Undeveloped Anxiety-Like Behavior to Prevented Mitochondrial Dysfunction and Oxidative Stress. Cell Mol Neurobiol 36, 553–563 (2016). https://doi.org/10.1007/s10571-015-0236-0

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