Abstract
Early life exposure to ketamine caused neurohistopathologic changes and persistent cognitive dysfunction. For this study, a pregnant rat model was developed to investigate neurocognitive effects in the offspring, following ketamine exposure during the second trimester. Pregnant rats on gestational day 14 (equal to midtrimester pregnancy in humans), intravenously received 200 mg/kg ketamine for 3 h. Their behavior was tested (Morris water maze, odor recognition test, and fear conditioning) at postnatal days (P25–30). Furthermore, hippocampal morphology of the offspring (P30) was examined via Nissl staining and hippocampal dendritic spine density was determined via Golgi staining. The hippocampal protein levels of nerve growth factor (NGF), extracellular signal-regulated kinase (ERK), phosphorylated-ERK (p-ERK), cyclic adenosine monophosphate response element-binding (CREB), p-CREB, synaptophysin (SYP), synapsin (SYN), and postsynaptic density-95 (PSD95) were measured via western blot. Additionally, SCH772984 (an ERK inhibitor) was used to evaluate both role and underlying mechanism of the ERK pathway in PC12 cells. We found that ketamine caused long-term neurocognitive dysfunction, reduced the density of the dendritic spin, caused neuronal loss, and down-regulated the expression of NGF, ERK, p-ERK, mitogen, and stress-activated protein kinase (MSK), CREB, p-CREB, SYP, SYN, and PSD95 in the hippocampus. These results suggest that ketamine induced maternal anesthesia during period of the fetal brain development can cause long-term neurocognitive dysfunction in the offspring, which likely happens via inhibition of the NGF-ERK-CREB pathway in the hippocampus. Our results highlight the central role of ERK in neurocognition.
Highlights
A large number of pregnant women are exposed to various types of anesthetics for surgery or diagnosis every year
We found that ketamine caused long-term neurocognitive dysfunction, reduced the density of the dendritic spin, caused neuronal loss, and down-regulated the expression of nerve growth factor (NGF), extracellular signal-regulated kinase (ERK), p-ERK, mitogen, and stress-activated protein kinase (MSK), cyclic adenosine monophosphate response element-binding (CREB), p-CREB, SYP, SYN, and postsynaptic density-95 (PSD95) in the hippocampus
These results suggest that ketamine induced maternal anesthesia during period of the fetal brain development can cause long-term neurocognitive dysfunction in the offspring, which likely happens via inhibition of the NGF-ERK-CREB pathway in the hippocampus
Summary
A large number of pregnant women are exposed to various types of anesthetics for surgery or diagnosis every year. Exposure to isoflurane during pregnancy can impair postnatal spatial memory and learning in the offspring [3]. Neonatal administration of commonly used anesthetic agents has been shown to induce long-term neurocognitive dysfunction in rodents [4]. Ketamine is one of the most commonly used drugs in pediatric clinical anesthesia. Ketamine is frequently consumed by drug addicts in the public, sadly including pregnant women [5]. Ketamine may interfere with hippocampal neurogenesis and long-term neurocognitive function in rats up to seven days after birth [7]. These findings raise concerns about the potential adverse effects of ketamine exposure for fetuses and infants
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