Elsevier

Neuroscience Letters

Volume 632, 6 October 2016, Pages 15-22
Neuroscience Letters

Research article
Ceftriaxone pretreatment reduces the propensity of postpartum depression following stroke during pregnancy in rats

https://doi.org/10.1016/j.neulet.2016.08.036Get rights and content

Highlights

  • Ischemic stroke increases the propensity to develop depression in humans and laboratory animals.

  • We hypothesized that ischemic stroke in pregnancy may increase the risk for the development of postpartum depression (PPD).

  • We found that 15 min bilateral common carotid arteries occlusion during pregnancy enhanced depressive-like behaviors in dams.

  • Ceftriaxone pretreatment prevented loss of glutamate transporter (GLT-1) expression in the medial prefrontal cortex (mPFC).

  • Ceftriaxone pretreatment reduced the propensity for the development of PPD.

Abstract

Objective

Ischemic stroke increases the propensity to develop depression in humans and laboratory animals, and we hypothesized that such an incidence during pregnancy may increase the risk for the development of postpartum depression (PPD).

Materials and methods

To test this hypothesis, we used bilateral common carotid arteries occlusion (BCCAO) to induce transient cerebral ischemia in pregnant rats, and evaluated its effects on subsequent development of PPD in dams. Additionally, we investigated whether ceftriaxone pretreatments before the induction of brain ischemia could alter the propensity of PPD.

Results

We found that 15 min BCCAO during pregnancy enhanced immobility time and reduced the frequency of swimming or climbing behaviors in the forced swim test, and decreased the sucrose preference in dams at postpartum day 21. Such behavioral alterations were associated with lower level of GLT-1 expression in the medial prefrontal cortical regions (mPFC) of PPD dams. Specifically, mPFC GLT-1 expression levels in dams with ischemia history were correlated with sucrose preference levels at postpartum day 21. Finally, ceftriaxone pretreatment (200 mg/kg/day, 5 days) before the 15 min BCCAO prevented the development of PPD, and prevented the reduction of GLT-1 expression in the mPFC.

Conclusions

Taken together, our results suggested that ceftriaxone pretreatment before brain ischemia during pregnancy may reduce the propensity for the development of PPD by preventing the loss of GLT-1 expression in the mPFC.

Introduction

Stroke is a devastating event when it happens during pregnancy. While the overall rate of stroke during pregnancy is very low, recent studies have shown that the stroke incidence has been steadily increasing in recent years [1]. Nearly 50% of strokes during pregnancy are ischemic strokes [2]. However, most pregnant women with ischemic stroke do not receive acute stroke reperfusion therapy, partly due to the high risks of this therapy for fetus. Therefore, preventing the incidence of stroke and mitigating the damage of ischemic stroke during pregnancy is critical for pregnant women who are at high risk of stroke.

Postpartum depression (PPD) is a prevalent disorder, which happens in approximately 20–50% of women [3], with as high as 19% of women developing the depression during the first 3 months postpartum [4]. Women who suffer from PPD often experience feelings of inadequacy and hopelessness, which may last from months to years after the childbirth. Various studies have shown that PPD plays a damaging role in the relationship between mother and infant and can result in suboptimal development of cognition and emotion in child. This, in turn, likely increases the risk of depression in the affected children and young adolescents [5], [6], [7], [8]. Despite the prevalence and consequences of PPD, little is known about the biological mechanisms underlying the pathophysiology of this disorder. Particularly, it is still not very clear about the risk factors that might contribute to the development of PPD. Given that ischemic stroke increases the propensity to develop depression in humans and laboratory animals [9], we postulated that stroke incidence during pregnancy may increase the risk for the development of PPD.

Using magnetic resonance imaging, it was demonstrated that glutamate levels in the medial prefrontal cortical regions (mPFC) are increased in patients with PPD [10]. Furthermore, N-methyl-d-aspartate (NMDA) antagonist ketamine has a rapid onset of antidepressant activity in human patients [11], [12]. These studies suggested that increased glutamatergic neurotransmission in the mPFC may be critical for the development of PPD. Furthermore, glutamatergic neurotransmission in the central nervous system is tightly controlled by glutamate transporters. Specifically, presynaptic glutamate is deposited into the vesicles via vesicular glutamate transporter (VGLUT) in order to be synaptically released via calcium influx induced action potentials. After synaptic release, glutamate can act on both ionotropic and metabotropic glutamate receptors [13]. The neurotransmitter activity is limited in time by the action of glutamate transporters, which are responsible for the glutamate re-uptake from the synaptic cleft [14], [15]. Five members of excitatory amino acid transporters (EAAT) family, EAAT1 through 5, have been found in humans. They play a critical role in removing excessive glutamate from the extracellular space and preventing the potential damage from excitotoxicity [14], [16], [17], [18].

Brain anoxia or ischemia can trigger robust release of glutamate causing the death of neurons, leading to mental or physical disorders [19], [20], [21]. Ceftriaxone treatment can enhance the expression of EAATs in the mPFC in laboratory animals [22], [23], [24]. Based on these facts, we hypothesized that brain ischemia during pregnancy may increase the risk of PPD via the reduction of mPFC GLT-1 expression, and upregulation of mPFC GLT-1 expression using ceftriaxone may prevent such deleterious effects of brain ischemia during pregnancy on the subsequent development of PPD. Therefore, in the present study, we used bilateral common carotid arteries occlusion (BCCAO) to induce transient cerebral ischemia in pregnant rats and evaluated its effects on the subsequent development of PPD. In addition, in order to increase mPFC GLT-1 expression, we pretreated the pregnant rats with ceftriaxone before the BCCAO procedure, and investigated whether ceftriaxone pretreatments could alter the propensity of PPD after brain ischemia during pregnancy. Finally, we investigated the postpartum expression of glutamate transporter 1 (GLT-1) in the mPFC in rats, and confirmed the effects of ceftriaxone treatments on GLT-1 expression in the same brain region.

Section snippets

Animals

Female Sprague-Dawley rats (n = 50 on gestational day GD3) at 10–12 weeks old and weighing 200–250 g and non-pregnant, age and weight matching female Sprague-Dawley rats (n = 20) were supplied from Shanghai Laboratory Animal Center. Upon arrival, rats were housed individually. The room for housing the animals in the Animal Center was equipped with lights providing a 12-h light/dark cycle (light on 7:00–19:00) and was controlled for temperature (23 ± 1 °C). Rats were given food and water ad libitum

Effects of brain ischemia during pregnancy and ceftriaxone treatment on delivery time and pups status

We found that brain ischemia during pregnancy or ceftriaxone treatment or a combination of both did not produce a significant increase in preterm delivery in rats. All the rats with 5 min or 15 min of brain ischemia at GD 11 had term delivery of live pups similar to sham control rats. Furthermore, ceftriaxone treatment during GD 6–10 did not induce any premature delivery of pups. Indeed, in all experimental groups all the pups were delivered alive.

Brain ischemia during pregnancy increased subsequent development of PPD

Depressive-like behavior of the dams was assessed

Discussion

The present study was designed to investigate the effects of brain ischemia during pregnancy on the subsequent development of postpartum depressive-like behaviors. We found that 15 min of BCCAO during pregnancy enhanced immobility time, reduced the frequency of swimming or climbing behaviors in the forced swim test, and decreased the sucrose preference in dams at postpartum day 21, as compared with sham control rats. Additionally, 15 min BCCAO did not alter immobility time, the frequency of

Conclusions

In summary, our study is the first to demonstrate that transient brain ischemia during pregnancy can increase the risk for the development of postpartum depression in rats. Such a phenomenon was correlated with the loss of GLT-1 expression in the mPFC in postpartum dams. Furthermore, ceftriaxone treatments prior to the induction of brain ischemia can prevent the loss of GLT-1 expression in the mPFC and reduce the propensity to develop postpartum depression. Taken together, our results indicated

Conflict of interests

The authors declare no conflicts of interest.

Acknowledgement

This study was supported by Basic Medical Research Initiative Program in the Second Hospital of Jilin University (grant number: JH-BMRI-2008195).

References (62)

  • G. Zhen et al.

    Optimized protocol to reduce variable outcomes for the bilateral common carotid artery occlusion model in mice

    J. Neurosci. Methods

    (2007)
  • N.A. Batra

    Proton magnetic resonance spectroscopy measurement of brain glutamate levels in premenstrual dysphoric disorder

    Biol. Psychiatry

    (2008)
  • M. Bloch et al.

    Endocrine factors in the etiology of postpartum depression

    Compr. Psychiatry

    (2003)
  • S.S. Smith

    Estrogen administration increases neuronal responses to excitatory amino acids as a long-term effect

    Brain Res.

    (1989)
  • T. Bruhn

    Ischemia induced changes in expression of the astrocyte glutamate transporter GLT1 in hippocampus of the rat

    Neurochem. Int.

    (2000)
  • P. Ketheeswaranathan

    Changes in glutamate transporter expression in mouse forebrain areas following focal ischemia

    Brain Res.

    (2011)
  • E.J. Nestler

    Neurobiology of depression

    Neuron

    (2002)
  • P. Willner et al.

    The neurobiology of depression and antidepressant action

    Neurosci. Biobehav. Rev.

    (2013)
  • E.L. Moses-Kolko

    Rapid habituation of ventral striatal response to reward receipt in postpartum depression

    Biol. Psychiatry

    (2011)
  • H. Schmoll

    Kindling status in sprague-dawley rats induced by pentylenetetrazole: involvement of a critical development period

    Am. J. Pathol.

    (2003)
  • S.H. Wang

    Hippocampal neurogenesis and behavioural studies on adult ischemic rat response to chronic mild stress

    Behav. Brain Res.

    (2008)
  • S.H. Wang

    Involvement of serotonin neurotransmission in hippocampal neurogenesis and behavioral responses in a rat model of post-stroke depression

    Pharmacol. Biochem. Behav.

    (2010)
  • E.V. Kuklina

    Trends in pregnancy hospitalizations that included a stroke in the United States from 1994 to 2007: reasons for concern?

    Stroke

    (2011)
  • J. Tate et al.

    Pregnancy and stroke risk in women

    Womens Health (Lond. Engl.)

    (2011)
  • L.J. Miller

    Postpartum depression

    JAMA

    (2002)
  • N.I. Gavin

    Perinatal depression: a systematic review of prevalence and incidence

    Obstet. Gynecol.

    (2005)
  • S.H. Goodman

    Social and emotional competence in children of depressed mothers

    Child Dev.

    (1993)
  • A. Rahman

    Impact of maternal depression on infant nutritional status and illness: a cohort study

    Arch. Gen. Psychiatry

    (2004)
  • D.W. Desmond

    Ischemic stroke and depression

    J. Int. Neuropsychol. Soc.

    (2003)
  • A.M. McEwen

    Increased glutamate levels in the medial prefrontal cortex in patients with postpartum depression

    Neuropsychopharmacology

    (2012)
  • C.A. Zarate

    A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression

    Arch. Gen. Psychiatry

    (2006)
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