Dexmedetomidine protects against glucocorticoid induced progenitor cell apoptosis in neonatal mouse cerebellum

Shawn David O’Connor, Omar Hoseá Cabrera, Joseph D. Dougherty, Sukrit Singh, Brant Stephen Swiney, Patricia Salinas-Contreras, Nuri Bradford Farber, Kevin Kiyoshi Noguchi

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

Objectives: Glucocorticoids (GCs) are used to improve respiratory mechanics in preterm infants despite clinical evidence linking neonatal GC therapy to cerebellar pathology. In developing mouse cerebellum, the GC dexamethasone (DEX) causes rapid GC-induced neural progenitor cell apoptosis (GINA). Focusing on pharmacological neuroprotection strategies, we investigated whether dexmedetomidine (DMT) protects against GINA. Methods: Neonatal mice were pretreated with DMT prior to DEX challenge. Additionally, we tested clonidine and yohimbine in vivo to determine mechanism of DMT neuroprotection. For in vitro studies, cerebellar neural progenitor cells were pretreated with DMT before DEX challenge. Results: In vivo, DMT attenuated GINA at 1 μg/kg and above, p < 0.0001. Clonidine significantly attenuated GINA, p < 0.0001, while yohimbine reversed DMT neuroprotection, p < 0.0001, suggesting DMT neuroprotection is likely mediated via adrenergic signaling. In vitro, DMT neuroprotection was achieved at 10 μM and above, p < 0.001, indicating DMT rescue is cell autonomous. Conclusions: DMT affords dose-dependent neuroprotection from GINA at clinically relevant doses, an effect that is cell autonomous and likely mediated by α2 adrenergic receptor agonism. DMT co-administration with GCs may be an effective strategy to protect the neonatal brain from GINA while retaining the beneficial effects of GCs on respiratory mechanics.

Original languageEnglish
Pages (from-to)2156-2162
Number of pages7
JournalJournal of Maternal-Fetal and Neonatal Medicine
Volume30
Issue number18
DOIs
StatePublished - Sep 17 2017

Keywords

  • Dexmedetomidine
  • cerebellum
  • dexamethasone
  • glucocorticoid
  • neural progenitor cell
  • neuroprotection

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