Acute but not sustained aromatase inhibition displays antidepressant properties

Kokras, Nikolaos; Pastromas, Nikolaos; Porto, Tatiany H.; Kafetzopoulos, Vasilios; Mavridis, Theodoros; Dalla, Christina

doi:10.1017/s1461145714000212

Cited by 19 publications

(23 citation statements)

References 26 publications

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“…Another non-steroidal aromatase inhibitor, letrozole, was used in experiments with gonadally intact rats. The dose of letrozole (1 mg/kg) was chosen based on a previous study of affective behavior in rats ( Kokras et al, 2014 ), as well as a pharmacokinetic study of letrozole-cyclodextrin complex ( Wempe et al, 2007 ).…”

Section: Methodsmentioning

confidence: 99%

Acute inhibition of neurosteroid estrogen synthesis suppresses status epilepticus in an animal model

Sato

Woolley

2016

eLife

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Status epilepticus (SE) is a common neurological emergency for which new treatments are needed. In vitro studies suggest a novel approach to controlling seizures in SE: acute inhibition of estrogen synthesis in the brain. Here, we show in rats that systemic administration of an aromatase (estrogen synthase) inhibitor after seizure onset strongly suppresses both electrographic and behavioral seizures induced by kainic acid (KA). We found that KA-induced SE stimulates synthesis of estradiol (E2) in the hippocampus, a brain region commonly involved in seizures and where E2 is known to acutely promote neural activity. Hippocampal E2 levels were higher in rats experiencing more severe seizures. Consistent with a seizure-promoting effect of hippocampal estrogen synthesis, intra-hippocampal aromatase inhibition also suppressed seizures. These results reveal neurosteroid estrogen synthesis as a previously unknown factor in the escalation of seizures and suggest that acute administration of aromatase inhibitors may be an effective treatment for SE.DOI: http://dx.doi.org/10.7554/eLife.12917.001

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Section: Methodsmentioning

confidence: 99%

Acute inhibition of neurosteroid estrogen synthesis suppresses status epilepticus in an animal model

Sato

Woolley

2016

eLife

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“…However, the precise mechanisms of depression‐associated deficits and how oestrogens impact on these remains unclear and requires further investigation. Finally, although we have focussed on 17β‐oestradiol, other hormones, in particular testosterone and progesterone, have been implicated in depressive‐like behaviours in rodents and warrant further investigation.…”

Section: Discussionmentioning

confidence: 99%

Differential effects of chronic 17β‐oestradiol treatment on rat behaviours relevant to depression

Gogos

McCarthy

Walker

et al. 2018

J Neuroendocrinology

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| INTRODUC TI ONMajor depressive disorder (MDD) is classified as an affective disorder typified by persistent sadness, a loss of interest in previously enjoyable activities and cognitive deficits including impairments in attention, learning and memory. 1 It is widely accepted that MDD is more prevalent in women than in men. 2,3 Although this difference may be related to psychosocial and cultural factors, it is likely that neurobiological sex differences play an important role. In women, the risk of developing a depressive illness appears to increase during key periods of the reproductive lifecycle when levels of oestrogens and progesterone are changing: during puberty, postnatal period, perimenopause and postpartum. 4,5 Strong links between fluctuations in mood and sex hormones have been reported. 6,7 Additionally, the effects that oestrogens have on cognition, particularly learning and memory, are well-established. 8 Popular theory posits that 17β-oestradiol, the most potent of the endogenous oestrogens, may be neuroprotective, and that the absence of this protection as a result of low oestradiol levels may increase vulnerability to psychiatric disturbance. 7,9 The notion that oestradiol is protective against Sex differences are a prominent feature of the pathophysiology of psychiatric disorders, such as major depressive disorder, which affects women at a higher incidence than men. Research suggests that the most potent endogenous oestrogen, 17βoestradiol, may have therapeutic potential in treating depression. However, preclinical studies have produced mixed results, likely as a result of various methodological factors such as treatment duration. The present study aimed to investigate the effects of ovariectomy and chronic 17β-oestradiol treatment via a s.c. silastic implant on behaviours relevant to depression in adult female Sprague-Dawley rats. Rats were assessed in the forced swim test, saccharin preference test and novel object recognition memory test, as well as for possible confounding behaviours, including locomotion and anxiety (open field test) and motivation and anxiety (novelty suppressed feeding test). Treatment effects were verified using body and uterus weight, as well as serum concentrations of 17β-oestradiol, progesterone and testosterone. Compared to ovariectomised rats, chronic 17β-oestradiol treatment enhanced saccharin preference and novel object recognition performance. There were no group differences in passive or active coping behaviour when assayed using the forced swim test. Taken together, these results support an antidepressant-like action of oestrogens but highlight that the beneficial effects of chronic 17β-oestradiol treatment may be related to specific depression-related symptoms, particularly anhedonia and memory. K E Y W O R D Sfemale rats, forced swim test, locomotor, novel object recognition, novelty suppressed feeding, oestrogen, ovariectomy, sucrose preference

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“…Recently, the effects of letrozole on cognition have attracted more attention, but the evidence for its effects on depression is less understood. Both clinical and pre-clinical trials have found opposing effects of letrozole on mood and behavior (Borbélyová et al, 2017;Chang et al, 2015;Kokras et al, 2018Kokras et al, , 2014Meng et al, 2011). Most animal studies to date have used rodents of varying ages, gonadal hormone status, sex, and duration of treatment, resulting in conflicting data that are poorly understood.…”

Section: Introductionmentioning

confidence: 99%

Chronic aromatase inhibition increases ventral hippocampal neurogenesis in middle-aged female mice

Chaiton

Wong

Galea

2019

Psychoneuroendocrinology

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Letrozole, a third-generation aromatase inhibitor, prevents the production of estrogens in the final step in conversion from androgens. Due to its efficacy at suppressing estrogens, letrozole has recently taken favor as a first-line adjuvant treatment for hormone-responsive breast cancer in middle-aged women. Though patient response to letrozole has generally been positive, there is conflicting evidence surrounding its effects on the development of depression. It is possible that the potential adverse effects of letrozole on mood are a result of the impact of hormonal fluctuations on neurogenesis in the hippocampus. Thus, to clarify the effects of letrozole on the hippocampus and behavior, we examined how chronic administration affects hippocampal neurogenesis and depressive-like behavior in middle-aged, intact female mice. Mice were given either letrozole (1mg/kg) or vehicle by injection (i.p.) daily for 3 weeks. Depressive-like behavior was assessed during the last 3 days of treatment using the forced swim test, tail suspension test, and sucrose preference test. The production of new neurons was quantified using the immature neuronal marker doublecortin (DCX), and cell proliferation was quantified using the endogenous marker Ki67. We found that letrozole increased DCX and Ki67 expression and maturation in the dentate gyrus, but had no significant effect on depressive-like behavior. Our findings suggest that a reduction in estrogens in middle-aged females increases hippocampal neurogenesis without any adverse impact on depressive-like behavior; as such, this furthers our understanding of how estrogens modulate neurogenesis, and to the rationale for the utilization of letrozole in the clinical management of breast cancer.

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Acute but not sustained aromatase inhibition displays antidepressant properties

Cited by 19 publications

References 26 publications

Acute inhibition of neurosteroid estrogen synthesis suppresses status epilepticus in an animal model

Acute inhibition of neurosteroid estrogen synthesis suppresses status epilepticus in an animal model

Differential effects of chronic 17β‐oestradiol treatment on rat behaviours relevant to depression

Chronic aromatase inhibition increases ventral hippocampal neurogenesis in middle-aged female mice

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