Dexmedetomidine Diminishes, but Does Not Prevent, Developmental Effects of Sevoflurane in Neonatal Rats

Abstract

BACKGROUND: Sevoflurane (SEVO) increases neuronal excitation in neonatal rodent brains through alteration of gamma aminobutyric acid (GABA)(A) receptor signaling and increases corticosterone release. These actions may contribute to mechanisms that initiate the anesthetic’s long-term neuroendocrine and neurobehavioral effects. Dexmedetomidine (DEX), a non-GABAergic α2-adrenergic receptor agonist, is likely to counteract SEVO-induced neuronal excitation. We investigated how DEX pretreatment may alter the neurodevelopmental effects induced by SEVO in neonatal rats. METHODS: Postnatal day (P) 5 Sprague-Dawley male rats received DEX (25 µg/kg, intraperitoneal) or vehicle before exposure to 2.1% SEVO for 6 hours (the DEX + SEVO and SEVO groups, respectively). Rats in the DEX-only group received DEX without exposure to SEVO. A subcohort of P5 rats was used for electroencephalographic and serum corticosterone measurements. The remaining rats were sequentially evaluated in the elevated plus maze on P80, prepulse inhibition of the acoustic startle response on P90, Morris water maze (MWM) starting on P100, and for corticosterone responses to physical restraint for 30 minutes on P120, followed by assessment of epigenomic DNA methylation patterns in the hippocampus. RESULTS: Acutely, DEX depressed SEVO-induced electroencephalogram-detectable seizure-like activity (mean ± SEM, SEVO versus DEX + SEVO, 33.1 ± 5.3 vs 3.9 ± 5.3 seconds, P < .001), but it exacerbated corticosterone release (SEVO versus DEX + SEVO, 169.935 ± 20.995 versus 280.853 ± 40.963 ng/mL, P = .043). DEX diminished, but did not fully abolish, SEVO-induced corticosterone responses to restraint (control: 11625.230 ± 877.513, SEVO: 19363.555 ± 751.325, DEX + SEVO: 15012.216 ± 901.706, DEX-only: 12497.051 ± 999.816; F[3,31] = 16.878, P < .001) and behavioral deficiencies (time spent in the target quadrant of the MWM: control: 31.283% ± 1.722%, SEVO: 21.888% ± 2.187%, DEX + SEVO: 28.617% ± 1.501%, DEX-only: 31.339% ± 3.087%; F[3,67] = 3.944, P = .012) in adulthood. Of the 391 differentially methylated genes in the SEVO group, 303 genes in the DEX + SEVO group had DNA methylation patterns that were not different from those in the control group (ie, they were normal). DEX alone did not cause acute or long-term functional abnormalities. CONCLUSIONS: This study suggests that the ability of DEX to depress SEVO-induced neuronal excitation, despite increasing corticosterone release, is sufficient to weaken mechanisms leading to long-term neuroendocrine/neurobehavioral abnormalities. DEX may prevent changes in DNA methylation in the majority of genes affected by SEVO, epigenetic modifications that could predict abnormalities in a wide range of functions.

Protective Effect of Dexmedetomidine against Hyperoxia-Damaged Cerebellar Neurodevelopment in the Juvenile Rat

“…The neurophysiological mechanisms of dexmedetomidine mimic the activation of the brain stem and normal sleep pathways rather than cortical suppression [ 133 ]. It is possible that DEX modulates excitatory glutamatergic signaling [ 134 ].…”

Anesthesia, the developing brain, and dexmedetomidine for neuroprotection

“…They found that the rats treated with dexmedetomidine before sevoflurane exposure showed lower levels of seizure-like activity and behavioral deficiencies (evaluated by the Morris Water Maze test and acoustic startle response) compared to those without dexmedetomidine treatment. In addition, the DNA methylation patterns in the hippocampus of dexmedetomidine-treated rats were more similar to the control group (i.e., no sevoflurane exposure), whereas rats exposed to sevoflurane without dexmedetomidine pretreatment had noticeably higher levels of DNA methylation ( 71 ). These findings suggest that dexmedetomidine may reduce sevoflurane-induced epigenetic modifications in DNA methylation, thereby attenuating the long-term impairment in neuronal function.…”

“…Expanding upon Zhong et al’s study, Yang et al conducted experiments exposing neonatal rats to sevoflurane with or without pre-treatment with dexmedetomidine ( 71 ). They found that the rats treated with dexmedetomidine before sevoflurane exposure showed lower levels of seizure-like activity and behavioral deficiencies (evaluated by the Morris Water Maze test and acoustic startle response) compared to those without dexmedetomidine treatment.…”

Intergenerational Perioperative Neurocognitive Disorder

“…The analysis of genome-wide DNA methylation patterns in the hippocampus of adult rats neonatally exposed to SEVO identified 407 differentially methylated regions in 391 genes (differentially methylated genes) [ 317 ]. The overrepresentation analysis of the differentially methylated genes yielded multiple enriched gene ontology (GO) terms that covered a wide array of biological processes ranging from nervous system development and function to regulation of stress responses, metabolic processes, vasculature development, and blood circulation [ 317 ]. By acting via mechanisms that involve epigenetic changes and dysregulation of stress response systems, these findings raise the possibility that early life exposure to GAs may predispose to PND, induced by subsequent exposure to surgery and/or GAs in adulthood.…”