Neonatal exposure to sevoflurane expands the window of vulnerability to adverse effects of subsequent exposure to sevoflurane and alters hippocampal morphology via decitabine-sensitive mechanisms. (14th September 2020)

• Record Type: Journal Article
• Authors: Lin, Yunan; Lei, Lei; Ju, Ling-Sha; Xu, Ning; Morey, Timothy E.; Gravenstein, Nikolaus; Yang, Jianjun; Martynyuk, Anatoly E.
• Is Part Of: Neuroscience letters. Volume 735(2020)
• Publication Date: 2020-09-14
• Subjects: Neonatal anesthesia -- Sevoflurane -- Seizures -- Hippocampal morphology -- Dnmt -- Kcc2; Neurology -- Periodicals; Neurology -- Periodicals; Research -- Periodicals; Neurologie -- Périodiques; Neuroanatomie -- Périodiques; Neuropharmacologie -- Périodiques; Neurophysiologie -- Périodiques; Neurology; Periodicals; Electronic journals; 617.48
• DOI: 10.1016/j.neulet.2020.135240
• Languages: English
• ISSNs: 0304-3940

Abstract

Highlights: Neonatal exposure to sevoflurane sensitizes to adverse effects of repeated exposure to the anesthetic later in life. Neonatal exposure to sevoflurane induces lasting alterations in hippocampal gene expressions and dendrite morphology. Pretreatment with the DNA methyltransferase inhibitor decitabine diminishes these effects of sevoflurane. Abstract: Background: Deficiencies in neurocognitive function have been found in late childhood or adolescence in patients who had prolonged and/or repeated early-life general anesthesia. Animal studies suggest that anesthetic-induced impairment in the neuron-specific K + -2Cl − ( Kcc2 ) Cl − exporter expression, which regulates developmental maturation of GABA type A receptor (GABAA R) signaling from excitatory to inhibitory, may play a mediating role. We tested whether the DNA methyltransferase (DNMT) inhibitor decitabine ameliorates the anesthetic's adverse effects. Methods: Sprague-Dawley male rats were injected with vehicle or decitabine 30 min before 2.1 % sevoflurane exposure for 5 h on postnatal day 5 (P5). On P19, P20, or P21, electroencephalography-detectable seizures were measured during 1 h of sevoflurane exposure, followed by collection of the trunk blood and brain tissue samples. Other rats were evaluated for changes in hippocampal CA1 dendrite morphology and gene expressions on ≥ P120. Results: Rats in the vehicle plus sevoflurane group responded to sevoflurane exposure on P19, P20 or P21 with electroencephalography-detectable seizures and stress-like corticosterone secretion and had altered hippocampal dendrite morphology in adulthood. These rats had expressions of Kcc2 and Dnmt genes downregulated and upregulated, respectively, in the P19 - P21 cortex and hypothalamus and the ≥ P120 hippocampus. All measured parameters in the sevoflurane-exposed rats that were pretreated with decitabine were not different from those in the control group. Conclusions: Neonatal exposure to sevoflurane sensitizes rats to adverse effects of repeated exposure to the anesthetic. The anesthetic-caused changes in the decitabine-sensitive mechanisms may play a mediating role in the developmental effects of early-life anesthesia.