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 highdose (10 times HED) does not induce apoptosis in the frontal cortex (layers I, II, and III) of developing brain of cynomolgus monkeys.

Effects of prolonged anesthesia with dexmedetomidine, fentanyl, or remifentanil on the self-renewal of mouse embryonic stem cells

“…These studies suggested that anesthesia might exhibit toxicity towards brain development. In contrast, many investigators have reported that dexmedetomidine, a potent α2-adrenoreceptor agonist with a high affinity for each of the α2-adrenoceptor subtypes (Peng et al, 2013), did not induce neurotoxicity and cellular degeneration in neither neonatal rodents nor primates (Palanisamy, 2012;Koo et al, 2014). Furthermore, remifentanil, a phenylpiperidine analgesic agent with a high affinity to μ-opioid receptors and exhibiting ultra-short-action, has gradually become established in clinical use (Rogliani et al, 2013), and large studies in vivo have validated its safety in neonates as an analgesic (Demirel et al, 2014).…”

Effect of Anesthesia on the Developing Brain: Infant and Fetus

“…The advantages of this model include the ability to carefully monitor hemodynamic changes in the fetus, and the ability to obtain plasma levels of dexmedetomidine, which are technically extremely difficult in neonatal rodent models. Finally, Koo et al [21] studied 20 fetal cynomolgus monkeys at 120 days of gestation. Mothers were exposed to ketamine at high dose for 12 h, or dexmedetomidine at low dose (3 μg/kg loading dose, 3 μg/kg/h for 12 h) or high dose (30 μg/kg loading dose, 30 μg/kg/h for 12 h).…”

A systematic review and narrative synthesis on the histological and neurobehavioral long‐term effects of dexmedetomidine

“…Dexmedetomidine was mostly injected intraperitoneally, intramuscularly, or subcutaneously. In the monkey and ewe studies, it was injected intravenously and in one other study intracerebroventricularly . It was given as a single or repeated bolus with an interval varying between 1 hour and 7 days.…”