Abstract
Ketamine exposure disturbed normal neurogenesis in the developing brain and resulted in subsequent neurocognitive deficits. 17β-estradiol provides robust neuroprotection in a variety of brain injury models in animals of both sexes and attenuates neurodegeneration induced by anesthesia agents. In the present study, we aimed to investigate whether 17β-estradiol could attenuate neonatal ketamine exposure-disturbed neurogenesis and behavioral performance. We treated 7-day-old (Postnatal day 7, PND 7) Sprague-Dawley rats and neural stem cells (NSCs) with either normal saline, ketamine, or 17β-estradiol before/after ketamine exposure, respectively. At PND 14, the rats were decapitated to detect neurogenesis in the subventricular zone (SVZ) and subgranular zone (SGZ) of the hippocampus by immunofluorescence staining. The proliferation, neuronal differentiation, and apoptosis of NSCs were assessed by immunohistochemistry method and TUNEL assay, respectively. The protein levels of cleaved caspase-3 in vivo in addition to GSK-3β and p-GSK-3β in vitro were examined by western blotting. Spatial learning and memory abilities were assessed by Morris water maze (MWM) test at PND 42–47. Ketamine exposure decreased cell proliferation in the SVZ and SGZ, inhibited NSC proliferation and neuronal differentiation, promoted NSC apoptosis and led to adult cognitive deficits. Furthermore, ketamine increased cleaved caspase-3 in vivo and decreased the expression of p-GSK-3β in vitro. Treatment with 17β-estradiol could attenuate ketamine-induced changes both in vivo and in vitro. For the first time we showed that 17β-estradiol alleviated ketamine-induced neurogenesis inhibition and cognitive dysfunction in the developing rat brain. Moreover, the protection of 17β-estradiol was associated with GSK-3β.
Highlights
Brain growth spurt (BGS) is critical for the normal development of the central nervous system
There were no differences in the protein expressions of p-glycogen synthase kinase (GSK)-3β [F(2,42) = 43.28; p > 0.05] and cleaved caspase-3 [F(2,24) = 76.59; p > 0.05] between the control group and 17β-estradiol group (Figures 4C,D). These findings suggest that GSK-3β and caspase-3 were involved in ketamine-induced apoptosis and 17β-estradiol elicited protection
We found that treatment with 17β-estradiol decreased neural stem cells (NSCs) apoptosis and increased p-GSK-3β levels, indicating that 17β-estradiol decreased NSC apoptosis by inactivation of GSK3β
Summary
Brain growth spurt (BGS) is critical for the normal development of the central nervous system. Substantial neurogenesis occurs in this period, which is characterized by abundant neural stem cell (NSC) changes including cell proliferation, differentiation, migration, and connection of neural cells (Muramatsu et al, 2007). In rodents, this period lasts from birth to the first 2 weeks of life. Recent studies have shown that ketamine inhibits NSC proliferation and disturbs normal neurogenesis (Scallet et al, 2004; Lu et al, 2017), causes neuroapoptosis and neurodegeneration in the developing brain, which may lead to long-term neurocognitive and memory dysfunctions (Paule et al, 2011; Sabbagh et al, 2012). Some underlying molecular signals such as the PKC/ERK1/2 pathway, reactive oxygen species-mediated mitochondria dysfunction, and glycogen synthase kinase 3β were speculated to be involved in pathophysiological abnormality induced by ketamine exposure (Huang et al, 2012; Bai et al, 2013; Liu et al, 2013), specific adjunctive therapy aiming to mitigate these negative effect of ketamine is still lacking
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