Dexmedetomidine protects against glucocorticoid induced progenitor cell apoptosis in neonatal mouse cerebellum.
OBJECTIVE
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.
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.
Shawn David
SD
O'Connor
b Department of Psychiatry , Washington University in St. Louis School of Medicine , St. Louis , MO , USA.
Omar Hoseá
http://orcid.org/0000-0002-9501-6720
OH
Cabrera
b Department of Psychiatry , Washington University in St. Louis School of Medicine , St. Louis , MO , USA.|c Department of Genetics , Washington University in St. Louis School of Medicine , St. Louis , MO , USA , and.
Joseph D
JD
Dougherty
d Division of Biology and Biomedical Sciences, Department of Genetics , Washington University in St. Louis School of Medicine , St. Louis , MO , USA.
Sukrit
S
Singh
b Department of Psychiatry , Washington University in St. Louis School of Medicine , St. Louis , MO , USA.
Brant Stephen
BS
Swiney
d Division of Biology and Biomedical Sciences, Department of Genetics , Washington University in St. Louis School of Medicine , St. Louis , MO , USA.
Patricia
P
Salinas-Contreras
b Department of Psychiatry , Washington University in St. Louis School of Medicine , St. Louis , MO , USA.
Nuri Bradford
NB
Farber
b Department of Psychiatry , Washington University in St. Louis School of Medicine , St. Louis , MO , USA.
Kevin Kiyoshi
KK
Noguchi
D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects*; D018929:Cell Culture Techniques; D002531:Cerebellum / Q000187:drug effects*; D020927:Dexmedetomidine / Q000494:pharmacology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005938:Glucocorticoids / Q000009:adverse effects*; D051379:Mice; D008813:Mice, Inbred ICR; D018696:Neuroprotective Agents / Q000494:pharmacology*; D011897:Random Allocation; D012119:Respiration / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D013234:Stem Cells / Q000187:drug effects
D005938:Glucocorticoids; D018696:Neuroprotective Agents; D020927:Dexmedetomidine
Dexmedetomidine; cerebellum; dexamethasone; glucocorticoid; neural progenitor cell; neuroprotection
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