Shawn David O'Connor1, Omar Hoseá Cabrera2, Joseph D Dougherty2,3, Sukrit Singh4, Brant Stephen Swiney2, Patricia Salinas-Contreras4, Nuri Bradford Farber2, Kevin Kiyoshi Noguchi2. 1. a Edward Mallinckrodt Department of Pediatrics , Division of Newborn Medicine, Washington University in St. Louis School of Medicine, St. Louis Children's Hospital , St. Louis , MO , USA. 2. b Department of Psychiatry , Washington University in St. Louis School of Medicine , St. Louis , MO , USA. 3. c Department of Genetics , Washington University in St. Louis School of Medicine , St. Louis , MO , USA , and. 4. d Division of Biology and Biomedical Sciences, Department of Genetics , Washington University in St. Louis School of Medicine , St. Louis , MO , USA.
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.
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.
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