17β-Estradiol augments antidepressant efficacy of escitalopram in ovariectomized rats: Neuroprotective and serotonin reuptake transporter modulatory effects.
The prevalence or recurrence of depression is seriously increased in women during the transition to and after menopause. The chronic hypo-estrogenic state of menopause may reduce the response to antidepressants; however the influence of estrogen therapy on their efficacy is still controversial. This study aimed at investigating the effects of combining escitalopram with 17β-estradiol on depression and cognitive impairment induced by ovariectomy, an experimental model of human menopause. Young adult female Wistar rats were subjected to either sham operation or ovariectomy. Ovariectomized animals were treated chronically with escitalopram (10mg/kg/day, i.p) alone or with four doses of 17β-estradiol (40μg/kg, s.c) given prior to the behavioral tests. Co-administration of 17β-estradiol improved escitalopram-induced antidepressant effect in forced swimming test verified as more prominent decrease in the immobility time without opposing its memory enhancing effect in Morris water maze. 17β-estradiol augmented the modulatory effects of escitalopram on the hippocampal levels of brain-derived neurotrophic factor and serotonin reuptake transporter as well as tumor necrosis factor-alpha without altering its effects on the gene expressions of serotonin receptor 1A, estrogen receptors alpha and beta, or acetylcholinestearase content. This combined therapy afforded synergistic protective effects on the brain histopathological architecture, particularly, the hippocampus. The antidepressant effect of 17β-estradiol was abolished by pretreatment with estrogen receptor antagonist, tamoxifen (10mg/kg, p.o). In conclusion, 17β-estradiol-induced antidepressant effect was confined to intracellular estrogen receptors activation. Moreover, 17β-estradiol enhanced escitalopram's efficiency in ameliorating menopausal-like depression, via exerting synergistic neuroprotective and serotonin reuptake transporter modulatory effects, without impeding escitalopram-mediated cognitive improvement.
Department of Pharmacology & Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt. Electronic address: weam.wadie@pharma.cu.edu.eg.
Weam W
WW
Ibrahim
Department of Pharmacology & Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt. Electronic address: marwa.safar@pharma.cu.edu.eg.
Marwa M
MM
Safar
Department of Pharmacology & Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt. Electronic address: mahmoud.khattab60@gmail.com.
Mahmoud M
MM
Khattab
Department of Pharmacology & Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt. Electronic address: azza.agha@pharma.cu.edu.eg.
Azza M
AM
Agha
D000110:Acetylcholinesterase / Q000187:drug effects; D000818:Animals; D001522:Behavior, Animal; D019208:Brain-Derived Neurotrophic Factor / Q000187:drug effects*; D015283:Citalopram / Q000008:administration & dosage / Q000494:pharmacology*; D060825:Cognitive Dysfunction / Q000188:drug therapy* / Q000209:etiology; D003863:Depression / Q000188:drug therapy* / Q000209:etiology; D004195:Disease Models, Animal; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D004958:Estradiol / Q000008:administration & dosage / Q000494:pharmacology*; D004965:Estrogen Antagonists / Q000008:administration & dosage / Q000494:pharmacology; D005260:Female; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000494:pharmacology*; D010052:Ovariectomy / Q000009:adverse effects; D016601:RNA-Binding Proteins / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D011960:Receptors, Estrogen / Q000187:drug effects*; D017367:Selective Serotonin Reuptake Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D013629:Tamoxifen / Q000008:administration & dosage / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects*
D000110:Acetylcholinesterase; D019208:Brain-Derived Neurotrophic Factor; D015283:Citalopram; D004958:Estradiol; D004965:Estrogen Antagonists; D018696:Neuroprotective Agents; D016601:RNA-Binding Proteins; D011960:Receptors, Estrogen; D017367:Selective Serotonin Reuptake Inhibitors; D013629:Tamoxifen; D014409:Tumor Necrosis Factor-alpha; C482440:Sert1 protein, rat
Estrogen receptor antagonist; Estrogen receptors; Forced swimming test; Selective serotonin reuptake inhibitor; Serotonin receptor; Serotonin transporter