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Combined Treatment with Low-Dose Ionizing Radiation and Ketamine Induces Adverse Changes in CA1 Neuronal Structure in Male Murine Hippocampi.

ABSTRACT: In children, ketamine sedation is often used during radiological procedures. Combined exposure of ketamine and radiation at doses that alone did not affect learning and memory induced permanent cognitive impairment in mice. The aim of this study was to elucidate the mechanism behind this adverse outcome. Neonatal male NMRI mice were administered ketamine (7.5 mg kg-1) and irradiated (whole-body, 100 mGy or 200 mGy, 137Cs) one hour after ketamine exposure on postnatal day 10. The control mice were injected with saline and sham-irradiated. The hippocampi were analyzed using label-free proteomics, immunoblotting, and Golgi staining of CA1 neurons six months after treatment. Mice co-exposed to ketamine and low-dose radiation showed alterations in hippocampal proteins related to neuronal shaping and synaptic plasticity. The expression of brain-derived neurotrophic factor, activity-regulated cytoskeleton-associated protein, and postsynaptic density protein 95 were significantly altered only after the combined treatment (100 mGy or 200 mGy combined with ketamine, respectively). Increased numbers of basal dendrites and branching were observed only after the co-exposure, thereby constituting a possible reason for the displayed alterations in behavior. These data suggest that the risk of radiation-induced neurotoxic effects in the pediatric population may be underestimated if based only on the radiation dose.

SUBMITTER: Hladik D

PROVIDER: S-EPMC6929167 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Combined Treatment with Low-Dose Ionizing Radiation and Ketamine Induces Adverse Changes in CA1 Neuronal Structure in Male Murine Hippocampi.

Hladik Daniela D Buratovic Sonja S Von Toerne Christine C Azimzadeh Omid O Subedi Prabal P Philipp Jos J Winkler Stefanie S Feuchtinger Annette A Samson Elenore E Hauck Stefanie M SM Stenerlöw Bo B Eriksson Per P Atkinson Michael J MJ Tapio Soile S

International journal of molecular sciences 20191203 23

In children, ketamine sedation is often used during radiological procedures. Combined exposure of ketamine and radiation at doses that alone did not affect learning and memory induced permanent cognitive impairment in mice. The aim of this study was to elucidate the mechanism behind this adverse outcome. Neonatal male NMRI mice were administered ketamine (7.5 mg kg<sup>-1</sup>) and irradiated (whole-body, 100 mGy or 200 mGy, <sup>137</sup>Cs) one hour after ketamine exposure on postnatal day 10 ...[more]

PMID: 31817026

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Project description:Radiotherapy is an effective tool in the treatment of pediatric malignancies but it is associated with adverse side effects, both short- and long-term. One common long-term side effect after cranial radiotherapy is cognitive impairment and this is, at least partly, thought to be caused by reduced hippocampal neurogenesis. Neuroinflammation and a perturbed microenvironment are thought to be important in the dysregulation of neurogenesis seen after irradiation (IR). We investigated the effects of a pre-existing, lipopolysaccharide (LPS)-induced systemic inflammation at the time of IR in both males and females. A single dose of 8 Gy to the brain of postnatal day 14 mice caused an upregulation of cytokines/chemokines (IL-1β, MIP-1β, IL-12, GM-CSF, MIP-1α, IL-17, CCL2 and KC) 6 h after IR, more so in females. Caspase-3 activity, reflecting apoptosis and possibly microglia activation, was elevated 6 h after IR. Females treated with LPS before IR showed a higher caspase-3 activity compared with males. During the chronic phase (3 months post IR), we found that LPS-induced inflammation at the time of IR aggravated the IR-induced injury in both male and female mice, as judged by reduced bromodeoxyuridine incorporation and neurogenesis (doublecortin-positive cells) in the hippocampus. At this late time point, the microglia density was increased by IR, more so in females, indicating long-term effects on the microenvironment. IR increased anxiety-related behavior in vehicle-, but not LPS-, treated animals. However, exploratory behavior was affected by IR in both vehicle- and LPS-treated mice. In conclusion, we found that LPS administration before IR of the young mouse brain aggravated the injury, as judged by reduced hippocampal neurogenesis. This supports the clinical practice to postpone radiotherapy if the patient shows signs of infection. Systemic inflammation is not always obvious, though, for example because of concurrent corticosteroid treatment, so careful monitoring of inflammation is warranted.

Dataset Information

Combined Treatment with Low-Dose Ionizing Radiation and Ketamine Induces Adverse Changes in CA1 Neuronal Structure in Male Murine Hippocampi.

Publications

Combined Treatment with Low-Dose Ionizing Radiation and Ketamine Induces Adverse Changes in CA1 Neuronal Structure in Male Murine Hippocampi.

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