Effect of dexmedetomidine on sevoflurane-induced neurodegeneration in neonatal rats

Lee, Jeong Rim; Joseph, Bernadin; Hofacer, Rylon D.; Upton, Brian A.; Lee, Samuel Y.; Ewing, L.; Zhang, Bingqing; Danzer, Steve C.; Loepke, Andreas W.

doi:10.1016/j.bja.2021.01.033

Cited by 21 publications

(27 citation statements)

References 59 publications

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“…Both groups reported a higher degree of neuronal apoptosis in neonatal rats when subanesthetic doses of SEVO were supplemented with higher doses of DEX. 22,24 These findings, along with our observations of exacerbated stress-like response in the presence of the 2 agents, point to the possibility that the combination of SEVO and DEX may induce acute neurotoxic effects by acting via similar molecular mechanisms. One such mechanism may be alterations in GABA A R signaling, as discussed above.…”

Section: Discussionmentioning

confidence: 53%

“…The dose of DEX was chosen based on data in the literature on DEX-induced modulation of neurodevelopmental effects of neonatal anesthesia in rodents. [21][22][23][24][25][26]28 One subset of P5 rats (n = 10 in the SEVO group and n = 7 in the DEX + SEVO group) was instrumented for EEG recording during a minor 12-to 15-minute surgical procedure performed under isoflurane anesthesia (2.0%-2.5%). The EEG recordings lasted for 1 hour of baseline activity and for another hour during SEVO sedation: 6% SEVO for 3 minutes for anesthesia induction and 2.1% SEVO for 57 minutes for anesthesia maintenance, as previously described [6][7][8] (see Supplemental Digital Content 1, Text 1, http://links.…”

Section: Treatment Groupsmentioning

confidence: 99%

“…However, studies of the effects of DEX on neurotoxic effects of SEVO in neonatal rats have generated somewhat conflicting findings. [21][22][23][24][25][26] Here, we investigated whether DEX can alleviate SEVO-induced neuronal hyperexcitation and corticosterone release at the time of exposure, as well as long-term effects of SEVO.…”

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confidence: 99%

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

Yang

Tong

Brant³

et al. 2022

Anesthesia &Amp; Analgesia

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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.

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Section: Discussionmentioning

confidence: 53%

Section: Treatment Groupsmentioning

confidence: 99%

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

Yang

Tong

Brant³

et al. 2022

Anesthesia &Amp; Analgesia

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“…The supra-clinical dose of Dex was determined using a neuroapoptosis model [26] to determine the anesthetic dosage regimen. Loss of righting re ex response (LORR) was used to estimate the response after the mice were placed in the supine position [20]. LORR grading ranged from 0 to 4: 0 = no response, 1 = delayed attempt to right itself, but failing, 2 = delayed, uncoordinated return to the upright position, 3 = sedated, but righting themselves in a coordinated fashion, or 4 = awake, not remaining supine.…”

Section: Experimental Preparation Proceduresmentioning

confidence: 99%

“…Previous studies have focused on the neuroprotective effects of Dex using different animal models, such as cerebral ischemia models [13], hypoxic models [14], oxygen-glucose-deprivation-induced injury models [15], and in ammatory models [16]. Others have demonstrated the protective properties of Dex against neurotoxicity induced by inhaled anesthetic agents, such as iso urane [17,18] and sevo urane [19][20][21][22][23].…”

Section: Introductionmentioning

confidence: 99%

Neuroprotective effect of dexmedetomidine on autophagy in mice administered intracerebroventricular injections of Aβ25-35

Lee

Han

Cho

et al. 2022

Preprint

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Current evidence suggests that dexmedetomidine (Dex) can be used as an adjuvant to general anesthesia for the elderly with or without neurodegenerative diseases, such as Alzheimer's disease (AD), since it has perioperative analgesic properties and can prevent postoperative delirium. Dysfunction involving the autophagy-lysosomal pathway is thought to underlie the pathological mechanism of AD. Evidence regarding the effects of Dex on neuronal autophagy dysfunction in mice with AD is lacking. Therefore, we hypothesized that administration of Dex could exert neuroprotective effects by ameliorating pathological autophagy dysfunction in mice that received an intracerebroventricular (i.c.v.) injection of amyloid β-protein fragment 25–35 (Aβ25−35) and in an autophagy-deficient cellular model. Low dose Dex treatment reversed decreases in percentage of alternation in the Y-maze test. It restored levels of phosphorylated Ca2+/calmodulin-dependent protein kinase II (p-CaMKII) and postsynaptic density-95 (PSD-95), both memory-related proteins. Dex also protected synapses from Aβ-induced toxicity in mice injected with Aβ25−35. Furthermore, increased expression of the autophagy-related microtubule-associated protein light chain3- II (LC3-II), p62, and lysosome-associated membrane protein2 (LAMP2) in Aβ25−35 mice was reduced after low-dose Dex treatment, ameliorating aberrant autophagic reflux. The present study demonstrated that low-dose Dex treatment ameliorated memory and learning impairments. It’s neuroprotective mechanism was associated with autophagic flux in a murine Aβ25−35 model. These findings suggest that Dex could represent an effective clinical approach for AD patients as a neuroprotective adjuvant in anesthesia.

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Do Anesthetic Drugs Harm Neonates? A Global Perspective

Hansen

Henneberg

Engelhardt

2023

Neonatal Anesthesia

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Effect of dexmedetomidine on sevoflurane-induced neurodegeneration in neonatal rats

Cited by 21 publications

References 59 publications

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

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

Neuroprotective effect of dexmedetomidine on autophagy in mice administered intracerebroventricular injections of Aβ25-35

Do Anesthetic Drugs Harm Neonates? A Global Perspective

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