Dexmedetomidine Diminishes, but Does Not Prevent, Developmental Effects of Sevoflurane in Neonatal Rats.
Journal
Anesthesia and analgesia
ISSN: 1526-7598
Titre abrégé: Anesth Analg
Pays: United States
ID NLM: 1310650
Informations de publication
Date de publication:
01 10 2022
01 10 2022
Historique:
pubmed:
28
6
2022
medline:
20
9
2022
entrez:
27
6
2022
Statut:
ppublish
Résumé
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. 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. 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. 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.
Sections du résumé
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.
Identifiants
pubmed: 35759382
doi: 10.1213/ANE.0000000000006125
pii: 00000539-202210000-00031
pmc: PMC9481710
mid: NIHMS1809239
doi:
Substances chimiques
Adrenergic Agonists
0
Anesthetics, Inhalation
0
Sevoflurane
38LVP0K73A
gamma-Aminobutyric Acid
56-12-2
Dexmedetomidine
67VB76HONO
Corticosterone
W980KJ009P
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
877-887Subventions
Organisme : NINDS NIH HHS
ID : R01 NS091542
Pays : United States
Organisme : NICHD NIH HHS
ID : R56 HD102898
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS091542
Pays : United States
Informations de copyright
Copyright © 2022 International Anesthesia Research Society.
Déclaration de conflit d'intérêts
The authors declare no conflicts of interest.
Références
McCann ME, de Graaff JC, Dorris L, et al.; GAS Consortium. Neurodevelopmental outcome at 5 years of age after general anaesthesia or awake-regional anaesthesia in infancy (GAS): an international, multicentre, randomised, controlled equivalence trial. Lancet. 2019;393:664–677.
Banerjee P, Rossi MG, Anghelescu DL, et al. Association between anesthesia exposure and neurocognitive and neuroimaging outcomes in long-term survivors of childhood acute lymphoblastic leukemia. JAMA Oncol. 2019;5:1456–1463.
Walsh BH, Paul RA, Inder TE, Shimony JS, Smyser CD, Rogers CE. Surgery requiring general anesthesia in preterm infants is associated with altered brain volumes at term equivalent age and neurodevelopmental impairment. Pediatr Res. 2021;89:1200–1207.
Peerboom C, Wierenga CJ. The postnatal GABA shift: a developmental perspective. Neurosci Biobehav Rev. 2021;124:179–192.
van Andel DM, Sprengers JJ, Oranje B, Scheepers FE, Jansen FE, Bruining H. Effects of bumetanide on neurodevelopmental impairments in patients with tuberous sclerosis complex: an open-label pilot study. Mol Autism. 2020;11:30.
Edwards DA, Shah HP, Cao W, Gravenstein N, Seubert CN, Martynyuk AE. Bumetanide alleviates epileptogenic and neurotoxic effects of sevoflurane in neonatal rat brain. Anesthesiology. 2010;112:567–575.
Zhang J, Xu C, Puentes DL, Seubert CN, Gravenstein N, Martynyuk AE. Role of steroids in hyperexcitatory adverse and anesthetic effects of sevoflurane in neonatal rats. Neuroendocrinology. 2016;103:440–451.
Li N, Xu N, Lin Y, et al. Roles of testosterone and estradiol in mediation of acute neuroendocrine and electroencephalographic effects of sevoflurane during the sensitive period in rats. Front Endocrinol (Lausanne). 2020;11:545973.
Karst H, Berger S, Turiault M, Tronche F, Schütz G, Joëls M. Mineralocorticoid receptors are indispensable for nongenomic modulation of hippocampal glutamate transmission by corticosterone. Proc Natl Acad Sci U S A. 2005;102:19204–19207.
Xiao X, Zhang H, Wang H, Li Q, Zhang T. Neuroprotective effect of amantadine on corticosterone-induced abnormal glutamatergic synaptic transmission of CA3-CA1 pathway in rat’s hippocampal slices. Synapse. 2017;71:12.
Xu C, Tan S, Zhang J, et al. Anesthesia with sevoflurane in neonatal rats: developmental neuroendocrine abnormalities and alleviating effects of the corticosteroid and Cl(-) importer antagonists. Psychoneuroendocrinology. 2015;60:173–181.
Yang J, Ju L, Jia M, et al. Subsequent maternal separation exacerbates neurobehavioral abnormalities in rats neonatally exposed to sevoflurane anesthesia. Neurosci Lett. 2017;661:137–142.
Weerink MAS, Struys MMRF, Hannivoort LN, Barends CRM, Absalom AR, Colin P. Clinical pharmacokinetics and pharmacodynamics of dexmedetomidine. Clin Pharmacokinet. 2017;56:893–913.
Cruickshank M, Henderson L, MacLennan G, et al. Alpha-2 agonists for sedation of mechanically ventilated adults in intensive care units: a systematic review. Health Technol Assess. 2016;20:v–xx, 1.
Nelson LE, Lu J, Guo T, Saper CB, Franks NP, Maze M. The alpha2-adrenoceptor agonist dexmedetomidine converges on an endogenous sleep-promoting pathway to exert its sedative effects. Anesthesiology. 2003;98:428–436.
Williams JT, Henderson G, North RA. Characterization of alpha 2-adrenoceptors which increase potassium conductance in rat locus coeruleus neurones. Neuroscience. 1985;14:95–101.
Zhou L, Qin SJ, Gao X, et al. Dexmedetomidine prevents post-ischemic LTP via presynaptic and postsynaptic mechanisms. Brain Res. 2015;1622:308–320.
Xu H, Zhao B, She Y, Song X. Dexmedetomidine ameliorates lidocaine-induced spinal neurotoxicity via inhibiting glutamate release and the PKC pathway. Neurotoxicology. 2018;69:77–83.
Ma D, Hossain M, Rajakumaraswamy N, et al. Dexmedetomidine produces its neuroprotective effect via the alpha 2A-adrenoceptor subtype. Eur J Pharmacol. 2004;502:87–97.
Wang K, Wu M, Xu J, et al. Effects of dexmedetomidine on perioperative stress, inflammation, and immune function: systematic review and meta-analysis. Br J Anaesth. 2019;123:777–794.
Perez-Zoghbi JF, Zhu W, Grafe MR, Brambrink AM. Dexmedetomidine-mediated neuroprotection against sevoflurane-induced neurotoxicity extends to several brain regions in neonatal rats. Br J Anaesth. 2017;119:506–516.
Perez-Zoghbi JF, Zhu W, Neudecker V, Grafe MR, Brambrink AM. Neurotoxicity of sub-anesthetic doses of sevoflurane and dexmedetomidine co-administration in neonatal rats. Neurotoxicology. 2020;79:75–83.
Lee JR, Lin EP, Hofacer RD, et al. Alternative technique or mitigating strategy for sevoflurane-induced neurodegeneration: a randomized controlled dose-escalation study of dexmedetomidine in neonatal rats. Br J Anaesth. 2017;119:492–505.
Lee JR, Joseph B, Hofacer RD, et al. Effect of dexmedetomidine on sevoflurane-induced neurodegeneration in neonatal rats. Br J Anaesth. 2021;126:1009–1021.
Goyagi T. Dexmedetomidine reduced sevoflurane-induced neurodegeneration and long-term memory deficits in neonatal rats. Int J Dev Neurosci. 2019;75:19–26.
Dong Y, Hong W, Tang Z, Gao Y, Wu X, Liu H. Dexmedetomidine attenuates neurotoxicity in developing rats induced by sevoflurane through upregulating BDNF-TrkB-CREB and downregulating ProBDNF-P75NRT-RhoA signaling pathway. Mediators Inflamm. 2020;2020:5458061.
Ju LS, Yang JJ, Morey TE, et al. Role of epigenetic mechanisms in transmitting the effects of neonatal sevoflurane exposure to the next generation of male, but not female, rats. Br J Anaesth. 2018;121:406–416.
Sanders RD, Xu J, Shu Y, et al. Dexmedetomidine attenuates isoflurane-induced neurocognitive impairment in neonatal rats. Anesthesiology. 2009;110:1077–1085.
Tan S, Xu C, Zhu W, et al. Endocrine and neurobehavioral abnormalities induced by propofol administered to neonatal rats. Anesthesiology. 2014;121:1010–1017.
Jia M, Liu WX, Yang JJ, et al. Role of histone acetylation in long-term neurobehavioral effects of neonatal exposure to sevoflurane in rats. Neurobiol Dis. 2016;91:209–220.
Ju LS, Yang JJ, Gravenstein N, et al. Role of environmental stressors in determining the developmental outcome of neonatal anesthesia. Psychoneuroendocrinology. 2017;81:96–104.
Yu G. Gene ontology semantic similarity analysis using GOSemSim. Methods Mol Biol. 2020;2117:207–215.
Sayols S. rrvgo: a Bioconductor package to reduce and visualize Gene Ontology terms. 2020. Accessed November 1, 2021. https://ssayols.github.io/rrvgo .
Davis AP, Grondin CJ, Johnson RJ, et al. Comparative Toxicogenomics Database (CTD): update 2021. Nucleic Acids Res. 2021;49:D1138–D1143.
Hernandez-Ferrer C, Gonzalez J. CTDquerier: package for CTDbase data query, visualization and downstream analysis. 2021. Accessed November 1, 2021. https://bioconductor.org/packages/3.11/bioc/html/CTDquerier.html .
Herman JP, Mueller NK, Figueiredo H. Role of GABA and glutamate circuitry in hypothalamo-pituitary-adrenocortical stress integration. Ann N Y Acad Sci. 2004;1018:35–45.
Sarkar J, Wakefield S, MacKenzie G, Moss SJ, Maguire J. Neurosteroidogenesis is required for the physiological response to stress: role of neurosteroid-sensitive GABAA receptors. J Neurosci. 2011;31:18198–18210.
González-Gil A, Villa A, Millán P, Martínez-Fernández L, Illera JC. Effects of dexmedetomidine and ketamine-dexmedetomidine with and without buprenorphine on corticoadrenal function in rabbits. J Am Assoc Lab Anim Sci. 2015;54:299–303.
Wang F, Li C, Shao J, Ma J. Sevoflurane induces inflammation of microglia in hippocampus of neonatal rats by inhibiting Wnt/β-Catenin/CaMKIV pathway. J Pharmacol Sci. 2021;146:105–115.