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

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.

Keywords:

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

Declaration of interest

The authors declare no conflicts of interest.

Funding details

This work was supported by: K.K.N. NIH grants MH083046, HD052664, HD052664S, HD083001 and the Intellectual and Developmental Disabilities Research Center at Washington University in St. Louis (NIH/NICHD U54-HD087011). J.D.D. NIH grants MH109133, HG008687, MH100027 and DA038458. S.S. Washington University HHMI-WU Summer Undergraduate Research Fellowship (SURF) Program.