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The role of hippocampal GABAA receptors on anxiolytic effects of Echium amoenum extract in a mice model of restraint stress

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Abstract

Echium amoenum (EA), a popular medicinal plant in Persian medicine, has anxiolytic, antioxidant, sedative, and anti-inflammatory effects. This study examined whether GABA-ergic signaling is involved in the anxiolytic effects of EA in mice. Sixty BALB/c mice (25–30 g) were divided into six groups (n = 10) as follows: the (I) control group received 10 ml/kg normal saline (NS). In the stress groups, the animals underwent 14 consecutive days of restraint stress (RS), and received following treatments simultaneously; (II) RS + NS; (III) RS + Diaz (Diazepam); (IV) RS + EA; (V) RS + Flu (Flumazenil) + EA; (VI) RS + Flu + Diaz. Behavioral tests including the open field test (OFT) and elevated plus maze (EPM) were performed to evaluate anxiety-like behaviors and the effects of the regimens. The plasma level of corticosterone and the hippocampal protein expressions of IL-1β, TNF-α, CREB, and BDNF, as well as p-GABAA/GABAA ratio, were also assessed. The findings revealed that chronic administration of EA alone produced anxiolytic effects in both behavioral tests, while diazepam alone or in combination with Flu failed to decrease the anxiety-like behaviors. Furthermore, the p-GABAA/GABAA and p-CREB/CREB ratios, and protein levels of BDNF were significantly increased in the EA-received group. On the other hand, plasma corticosterone levels and the hippocampal IL-1β and TNF-α levels were significantly decreased by EA. However, pre-treatment with GABAA receptors (GABAA Rs) antagonist, Flu, reversed the anxiolytic and molecular effects of EA in the RS-subjected animals. Our findings confirmed that alternation of GABAAR is involved in the effects of EA against RS-induced anxiety-like behaviors, HPA axis activation, and neuroinflammation.

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Funding

This research was supported by a grant from Neurosciences Research Center, Tabriz University of Medical Sciences (Grant Number: 62571) to SS-E.

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Authors and Affiliations

  1. Neurosciences Research Center, Tabriz University of Medical Sciences, Tabriz, 5166614756, Iran

    Fereshteh Farajdokht, Armin Vosoughi, Javad Mahmoudi & Saeed Sadigh-Eteghad

  2. Department of Physiology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran

    Fereshteh Farajdokht

  3. Cardiovascular Research Center, Tabriz University of Medical Sciences, Tabriz, Iran

    Mojtaba Ziaee

  4. Phytopharmacology Research Center, Maragheh University of Medical Sciences, Maragheh, Iran

    Mojtaba Ziaee

  5. Department of Persian Medicine, Faculty of Persian Medicine, Tabriz University of Medical Sciences, Tabriz, Iran

    Mostafa Araj-Khodaei & Saeed Sadigh-Eteghad

  6. East-Azerbaijan Comprehensive Stroke Program, Tabriz University of Medical Sciences, Tabriz, Iran

    Saeed Sadigh-Eteghad

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  1. Fereshteh Farajdokht
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  2. Armin Vosoughi
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Correspondence to Saeed Sadigh-Eteghad.

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All experiments in this study were approved by the Ethics Committee of Tabriz University of Medical Sciences (Approval No. IR.TBZMED.VCR.REC.1398.047) and followed the guidelines of the National Institute of Health (NIH; Publication No. 85-23, revised 1985).

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Farajdokht, F., Vosoughi, A., Ziaee, M. et al. The role of hippocampal GABAA receptors on anxiolytic effects of Echium amoenum extract in a mice model of restraint stress. Mol Biol Rep 47, 6487–6496 (2020). https://doi.org/10.1007/s11033-020-05699-7

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