title: Neurotoxic effects of dexmedetomidine in fetal cynomolgus monkey brains.
abstract: The neuroprotective effects of dexmedetomidine have been reported by many investigators; however its underlying mechanism to reduce neuronal injury during a prolonged anesthesia remains unclear. In this study, we investigated the neurotoxic effects of dexmedetomidine in fetal monkey brains. In the present study, we compare the neurotoxic effects of dexmedetomidine and ketamine, a general anesthetic with a different mechanism of action, in fetal cynomolgus monkeys. Twenty pregnant monkeys at approximate gestation day 120 were divided into 4 groups: non-treatment controls (Group 1); ketamine at 20 mg/kg intramuscularly followed by a 12-hr infusion at 20-50 mg/kg/hr (Group 2); dexmedetomidine at 3 µg/kg intravenously (i.v.) over 10 min followed by a 12-hr infusion at the human equivalent dose (HED) of 3 µg/kg/hr (Group 3); and dexmedetomidine at 30 µg/kg i.v. over 10 min followed by a 12-hr infusion at 30 µg/kg/hr, 10 times HED (Group 4). Blood samples from both dams and fetuses were measured for concentration of dexmedetomidine. Each fetus was perfusion-fixed, serial sections were cut through the frontal cortex, and stained to detect for apoptosis (activated caspase 3 and TUNEL) and neurodegeneration (silver stain). In utero treatment with ketamine resulted in marked apoptosis and degeneration primarily in layers I and II of the frontal cortex. In contrast, fetal brains from animals treated with dexmedetomidine showed none to minimal neuroapoptotic or neurodegenerative lesions at both low- and high-dose treatments. Plasma levels confirmed systemic exposure of dexmedetomidine in both dams and fetuses. In conclusion, these results demonstrate that dexmedetomidine at both low-dose (HED) and high-dose (10 times HED) does not induce apoptosis in the frontal cortex (layers I, II, and III) of developing brain of cynomolgus monkeys.
authors.affiliation: Preclinical Development, Research & Development, Hospira, Inc., USA.
authors.forename: Edward
authors.initials: E
authors.lastname: Koo
authors.forename: Timi
authors.initials: T
authors.lastname: Oshodi
authors.forename: Carol
authors.initials: C
authors.lastname: Meschter
authors.forename: Alireza
authors.initials: A
authors.lastname: Ebrahimnejad
authors.forename: Gao
authors.initials: G
authors.lastname: Dong
mesh_terms: D058647:Adrenergic alpha-2 Receptor Agonists / Q000008:administration & dosage / Q000097:blood / Q000633:toxicity*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001921:Brain / Q000187:drug effects* / Q000196:embryology* / Q000201:enzymology / Q000473:pathology; D053148:Caspase 3 / Q000378:metabolism; D020927:Dexmedetomidine / Q000008:administration & dosage / Q000097:blood / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006993:Hypnotics and Sedatives / Q000008:administration & dosage / Q000097:blood / Q000633:toxicity*; D007649:Ketamine / Q000008:administration & dosage / Q000097:blood / Q000633:toxicity; D008252:Macaca fascicularis; D008431:Maternal-Fetal Exchange; D019636:Neurodegenerative Diseases / Q000139:chemically induced; D017397:Prefrontal Cortex; D011247:Pregnancy
chemical_list: D058647:Adrenergic alpha-2 Receptor Agonists; D006993:Hypnotics and Sedatives; D020927:Dexmedetomidine; D007649:Ketamine; D053148:Caspase 3