title: Dexmedetomidine-Induced Neuroapoptosis Is Dependent on Its Cumulative Dose.
abstract: Dexmedetomidine (DEX) has inherent neuroprotective properties that have been attributed to the activation of prosurvival kinases. However, the impact of supraclinical doses of DEX on neuroapoptosis and neuronal viability has not been determined.
  
  
  
  Rat pups and primary neuronal cells were treated with DEX or ketamine (KET) alone or in combination. Neuroapoptosis was measured by cleaved-caspase-3 expression and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) staining in brain sections. Expression of prosurvival kinases was measured by Western blot. We measured the impact of DEX with and without α1-adrenergic receptor blockade on the viability of primary neuronal cell cultures.
  
  
  
  Increasing the cumulative dose of DEX resulted in elevated levels of neuroapoptosis in vivo. Low doses increased, whereas high dose decreased phosphorylation of the prosurvival kinases. KET alone and in combination with DEX produced a greater degree of apoptosis and reductions in expression of these protein kinases than DEX alone. Increasing concentrations of DEX decreased, while coadministration of an α1-adrenergic receptor blocker preserved neuronal viability in vitro.
  
  
  
  Although DEX is neuroprotective at clinical doses, high cumulative doses and concentrations induce neuroapoptosis, in vivo and in vitro, respectively. Because the current dosing schedules used in humans yield plasma levels that are substantially below concentrations that induce neurotoxicity, low-dose DEX should not be neurotoxic and has the potential to be a neuroprotective adjuvant.
authors.affiliation: From the *Department of Anesthesiology, Perioperative and Pain Medicine, Boston Children's Hospital, Boston, Massachusetts; †Department of Anaesthesia, Harvard Medical School, Boston, Massachusetts; and ‡Department of Anesthesiology and Pain Medicine, Chung-Ang University College of Medicine, Seoul, Republic of Korea.
authors.forename: Jia-Ren
authors.initials: JR
authors.lastname: Liu
authors.forename: Koichi
authors.initials: K
authors.lastname: Yuki
authors.forename: Chongwha
authors.initials: C
authors.lastname: Baek
authors.forename: Xiao-Hui
authors.initials: XH
authors.lastname: Han
authors.forename: Sulpicio G
authors.initials: SG
authors.lastname: Soriano
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D020927:Dexmedetomidine / Q000008:administration & dosage* / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006993:Hypnotics and Sedatives / Q000008:administration & dosage / Q000633:toxicity; D009474:Neurons / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D006993:Hypnotics and Sedatives; D020927:Dexmedetomidine