Research articleCeftriaxone pretreatment reduces the propensity of postpartum depression following stroke during pregnancy in rats
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).
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Cited by (3)
Postpartum depression in rats causes poor maternal care and neurochemical alterations on dams and long-lasting impairment in sociability on the offspring
2023, Behavioural Brain ResearchCitation Excerpt :Thus, we have evaluated the effects of the maternal separation model on brain amino acid levels, specifically glutamate, GABA and glycine. There are few studies in the literature that correlated alterations in the glutamatergic system with postpartum depression, either in women or with animal models, and most of these studies show decreased levels of brain glutamate or lower expression of genes involved in the glutamatergic system [38,84,104,108]. Our results showed only an increased level of glutamate in the striatum of MS dams, which differed from the literature, suggesting that this result possibly occurred by chance, and therefore had no relation to the maternal separation model.