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. 2023 Apr 25;24(9):7804.
doi: 10.3390/ijms24097804.

Dexmedetomidine Protects Cerebellar Neurons against Hyperoxia-Induced Oxidative Stress and Apoptosis in the Juvenile Rat

Robert Puls  1 , Clarissa von Haefen  2 , Christoph Bührer  1 , Stefanie Endesfelder  1
Affiliations

Dexmedetomidine Protects Cerebellar Neurons against Hyperoxia-Induced Oxidative Stress and Apoptosis in the Juvenile Rat

Robert Puls et al. Int J Mol Sci. .

Abstract

The risk of oxidative stress is unavoidable in preterm infants and increases the risk of neonatal morbidities. Premature infants often require sedation and analgesia, and the commonly used opioids and benzodiazepines are associated with adverse effects. Impairment of cerebellar functions during cognitive development could be a crucial factor in neurodevelopmental disorders of prematurity. Recent studies have focused on dexmedetomidine (DEX), which has been associated with potential neuroprotective properties and is used as an off-label application in neonatal units. Wistar rats (P6) were exposed to 80% hyperoxia for 24 h and received as pretreatment a single dose of DEX (5µg/kg, i.p.). Analyses in the immature rat cerebellum immediately after hyperoxia (P7) and after recovery to room air (P9, P11, and P14) included examinations for cell death and inflammatory and oxidative responses. Acute exposure to high oxygen concentrations caused a significant oxidative stress response, with a return to normal levels by P14. A marked reduction of hyperoxia-mediated damage was demonstrated after DEX pretreatment. DEX produced a much earlier recovery than in controls, confirming a neuroprotective effect of DEX on alterations elicited by oxygen stress on the developing cerebellum.

Keywords: cerebellum; dexmedetomidine; hyperoxia; newborn rat; oxidative stress; postnatal developing brain.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Representative immunofluorescence staining pattern of cerebellar sections with cells staining positive for cleaved caspase 3 (CASP3, red) after 24 h of hyperoxia (80% O2) shown for P7 immediately after hyperoxia and for P9, P11, and P14 with survival at normoxic environmental conditions (21% O2). High oxygen (HY) resulted in increased cell death on postnatal days 7 and 9 compared with controls under normoxia (NO). Pretreatment with DEX (HYD) reduced cell death induced by high oxygen. DEX under control conditions appeared to increase cell death at P11 (NOD). Nuclear staining was performed with DAPI (blue). Scale bar 25 μm.
Figure 2
Figure 2
Representation of quantification of (A) cleaved caspase 3 (CASP3+) positive cells as a ratio to 1000 DAPI+ cells in cerebellar slices as well as from transcripts of cerebellar homogenates of (B) Casp3 and (C) AIF, depicted for P7 immediately after hyperoxia (80% O2) and for P9, P11, and P14 with survival under normoxic environmental conditions (21% O2). Experimental groups are shown for hyperoxia exposure (black bars), hyperoxia with dexmedetomidine (dark gray bars), and dexmedetomidine with normoxia (light gray bars), compared with control animals treated with normoxia and sodium chloride (white bars). Data are normalized to levels in rat pups exposed to normoxia at each time point (control 100%, white bars) and the 100% values are 3.2 (P7), 3.7 (P9), 3.3 (P11), and 1.7 (P14) CASP3+ cells/1000 counted DAPI+ cells per regions of lobules. n = 6/group. * p < 0.05, ** p < 0.01, *** p < 0.001, **** p < 0.0001 (ANOVA, Bonferroni’s post hoc test).
Figure 3
Figure 3
Representation of quantification of (A) TBARS in cerebellar protein homogenates and transcripts of cerebellar homogenates of (B) GCLC, (C) Nrf2, (D) SOD1, (E) SOD2, and (F) SOD3, depicted for P7 immediately after hyperoxia (80% O2) and for P9, P11, and P14 with survival under normoxic environmental conditions (21% O2). Experimental groups are shown for hyperoxia exposure (black bars), hyperoxia with dexmedetomidine (dark gray bars), and dexmedetomidine with normoxia (light gray bars), compared with control animals treated with normoxia and sodium chloride (white bars). Data are normalized to levels in rat pups exposed to normoxia at each time point (control 100%, white bars). n = 6/group. * p < 0.05, ** p < 0.01, *** p < 0.001, **** p < 0.0001 (ANOVA, Bonferroni’s post hoc test).
Figure 4
Figure 4
Representation of quantification of (A) TNFα in cerebellar protein homogenates and transcripts of cerebellar homogenates of (B) TNFα, (C) IL1β, and (D) iNOS depicted for P7 immediately after hyperoxia (80% O2) and for P9, P11, and P14 with survival under normoxic environmental conditions (21% O2). Experimental groups are shown for hyperoxia exposure (black bars), hyperoxia with dexmedetomidine (dark gray bars), and dexmedetomidine with normoxia (light gray bars), compared with control animals treated with normoxia and sodium chloride (white bars). Data are normalized to levels in rat pups exposed to normoxia at each time point (control 100%, white bars). n = 6/group. * p < 0.05, ** p < 0.01, *** p < 0.001, **** p < 0.0001 (ANOVA, Bonferroni’s post hoc test).
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Grants and funding

This research was supported by our employer, the Department of Neonatology, Charité—Universitätsmedizin Berlin, Germany.