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Neuroprotective Effect of Apigenin on Depressive-Like Behavior: Mechanistic Approach

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Abstract

Apigenin, as a natural flavonoid present in several plants is characterized with potential anticancer, antioxidant, and anti-inflammatory properties. Recent studies proposed that apigenin affects depression disorder through unknown mechanistic pathways. The effects of apigenin’s anti-depressive properties on streptozocin-mediated depression have been investigated through the evaluation of behavioral tests, oxidative stress, cellular energy homeostasis and inflammatory responses. The results demonstrated anti-depressive properties of apigenin in behavioral test including forced swimming and splash tests and oxidative stress biomarkers such as reduced glutathione, lipid peroxidation, total antioxidant power and coenzyme Q10 levels. Apigenin, also, demonstrated its regulatory potency in cellular energy homeostasis and immune system gene expression through inhibiting Nlrp3 and Tlr4 overexpression. Furthermore, failure in energy production as the key factor in various psychiatric disorders was reversed by apigenin modulating effect on AMPK gene expression. Overall, 20 mg/kg of apigenin was recognized as the dose suitable for minimizing the undesirable adverse effects in the STZ-mediated depression model proposed in this study. Our data suggested that apigenin could be able to adjust behavioral dysfunction, biochemical biomarkers and recovered cellular antioxidant level in depressed animals. The surprising results were achieved by raise in COQ10 level, which could regulate the overexpression of the AMPK gene in stressful conditions. The regulatory effect of apigenin in inflammatory signaling pathways such as Nlrp3, and Tlr4 gene expression was studied at the surface part of the hippocampus.

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Abbreviations

AMPK:

AMP-activated protein kinase

ATP:

Adenosine triphosphate

BDNF:

Brain-derived neurotrophic factor

CoQ10 :

Coenzyme Q10

DTNB:

5,5′-Dithiobis (2-nitrobenzoic acid)

FRAP:

Ferric ion reducing antioxidant power

FST:

Forced swimming test

GSH:

Glutathione

HPLC:

High performance liquid chromatography

IL-1β:

Interleukin-1β

icv:

Intracerebroventricular

LPO:

Lipid peroxidation

MPT:

Mitochondrial permeability transition

MDA:

Malondialdehyde

NGF:

Nerve growth factor

NT-3:

Neurotrophin-3

Nrf-2:

Nuclear respiratory factors

OFT:

Open field test

HPA:

Pituitary and adrenal axis

TNF-α:

Tumor necrosis factor

Tlr4:

Toll-like receptor 4

ROS:

Reactive oxygen species

SSRIs:

Selective serotonin reuptake inhibitors

STZ:

Streptozotocin

Sirt 1:

Sirtuin 1

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Funding

This work was supported by the deputy of research of Zanjan University of Medical Sciences (Grant No. A-12-769-27 & 29).

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Author notes

  1. Ali Sharafi and Mir-Jamal Hosseini have contributed equally to this work.

Authors and Affiliations

  1. Zanjan Applied Pharmacology Research Center, Zanjan University of Medical Sciences, Zanjan, Iran

    Soroush Bijani, Rana Dizaji & Mir-Jamal Hosseini

  2. Department of Pharmacology and Toxicology, School of Pharmacy, Zanjan University of Medical Sciences, P.O. Box 45139-56184, Zanjan, Iran

    Soroush Bijani & Mir-Jamal Hosseini

  3. Zanjan Pharmaceutical Biotechnology Research Center, Zanjan University of Medical Sciences, Zanjan, Iran

    Ali Sharafi

  4. Department of Pharmaceutical Biotechnology, School of Pharmacy, Zanjan University of Medical Sciences, P.O. Box 45139-56184, Zanjan, Iran

    Ali Sharafi

Authors
  1. Soroush Bijani
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  2. Rana Dizaji
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  4. Mir-Jamal Hosseini
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Contributions

MJH & AS conceived and designed the experiments and the study protocol; SB performed the experiments; MJH: analyzed the data; MJH & SB interpreted the data; MJH, AS & SB wrote the paper, MJH & AS & SB conducted the critical review of the manuscript.

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Correspondence to Ali Sharafi or Mir-Jamal Hosseini.

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The authors declare that we do not have any commercial or associative interest that represents a conflict of interest in connection with the work submitted.

Ethical Approval

All of animal work were in accordance with the National Institute of Health (NIH) Guidelines for the Care and Use of Laboratory Animals (HHS publication 85–23, 1985), legislation for the protection of animals used for scientific purposes (Directive 2010/63/EU) and our institutional guidelines for animal care and use (Department of Pharmacology, School of Pharmacology, Zanjan University of Medical Sciences, Zanjan, Iran).

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Bijani, S., Dizaji, R., Sharafi, A. et al. Neuroprotective Effect of Apigenin on Depressive-Like Behavior: Mechanistic Approach. Neurochem Res 47, 644–655 (2022). https://doi.org/10.1007/s11064-021-03473-0

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