17β-Estradiol augments the neuroprotective effect of agomelatine in depressive- and anxiety-like behaviors in ovariectomized rats

Abstract

Rationale and objective

Estradiol decline has been associated with depression and anxiety in post-menopausal women. Agomelatine (Ago) is an agonist of the melatonergic MT1/MT2 receptors and an antagonist of the serotonergic 5-HT2c receptors. The present study aimed to evaluate the effects of combining Ago with 17β-estradiol (E2) on ovariectomy (OVX)-induced depressive- and anxiety-like behaviors in young adult female rats.

Methods

OVX rats were treated with Ago (40 mg/kg/day, p.o.) for 10 days starting 1 week after surgery alone or combined with two doses of E2 (40 μg/kg/day, s.c.) given before behavioral testing.

Results

Co-administration of E2 enhanced the anti-depressant and anxiolytics effects of Ago as evidenced by decreased immobility time in the forced swimming test, as well as increased time spent in the open arms and number of entries to open arms in the elevated plus-maze. In parallel, Ago increased hippocampal norepinephrine, dopamine, melatonin, and brain-derived neurotrophic factor (BDNF). Meanwhile, Ago-treated rats exhibited reduced hippocampal nuclear factor kappa beta (NF-kB) P65 expression and pro-inflammatory cytokine level. Ago upregulated estrogen receptor (ER α and β) mRNA expression in the hippocampus of OVX rats and elevated serum estradiol levels. Co-administration of E2 with Ago synergistically decreased NF-kB P65 expression and pro-inflammatory cytokines, and increased BDNF levels.

Conclusion

E2 augmented the neuroprotective effect of Ago in OVX rats via its anti-inflammatory and neurotrophic effects. The combined treatment of E2 and Ago should be further investigated as a treatment of choice for depression, anxiety, and sleep disturbances associated with menopause.

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Correspondence to Rabab H. Sayed.

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The protocol of this study complies with the US National Institute of Health (NIH publication No. 85-23, revised 2011) and approved by the Committee of Animal Care and Use of Faculty of Pharmacy, Cairo University (Permit number: PT 2035).

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El-Khatib, Y.A., Sayed, R.H., Sallam, N.A. et al. 17β-Estradiol augments the neuroprotective effect of agomelatine in depressive- and anxiety-like behaviors in ovariectomized rats. Psychopharmacology (2020). https://doi.org/10.1007/s00213-020-05580-2

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Keywords

  • Agomelatine
  • 17β-Estradiol
  • Estrogen receptor
  • Ovariectomy
  • Post-menopausal depression