Ketamine-Induced Neuronal Cell Death in the Perinatal Rhesus Monkey

Abstract

Ketamine is widely used as a pediatric anesthetic. Studies in developing rodents have indicated that ketamine-induced anesthesia results in brain cell death. Additional studies are needed to determine if ketamine anesthesia results in brain cell death in the nonhuman primate and if so, to begin to define the stage of development and the duration of ketamine anesthesia necessary to produce brain cell death. Rhesus monkeys (N = 3 for each treatment and control group) at three stages of development (122 days of gestation and 5 and 35 postnatal days [PNDs]) were administered ketamine intravenously for 24 h to maintain a surgical anesthetic plane, followed by a 6-h withdrawal period. Similar studies were performed in PND 5 animals with 3 h of ketamine anesthesia. Animals were subsequently perfused and brain tissue processed for analyses. Ketamine (24-h infusion) produced a significant increase in the number of caspase 3-, Fluoro-Jade C- and silver stain-positive cells in the cortex of gestational and PND 5 animals but not in PND 35 animals. Electron microscopy indicated typical nuclear condensation and fragmentation in some neuronal cells, and cell body swelling was observed in others indicating that ketamine-induced neuronal cell death is most likely both apoptotic and necrotic in nature. Ketamine increased N-methyl-D-aspartate (NMDA) receptor NR1 subunit messenger RNA in the frontal cortex where enhanced cell death was apparent. Earlier developmental stages (122 days of gestation and 5 PNDs) appear more sensitive to ketamine-induced neuronal cell death than later in development (35 PNDs). However, a shorter duration of ketamine anesthesia (3 h) did not result in neuronal cell death in the 5-day-old monkey.

Acetyl l-carnitine protects motor neurons and Rohon-Beard sensory neurons against ketamine-induced neurotoxicity in zebrafish embryos

“…Activation of NMDARs is essential for long-term potentiation and spatial learning and memory (Malenka and Bear, 2004), and NMDAR blockade results in impaired synaptic plasticity manifested as adverse effects on learning and memory (Sakimura et al, 1995;Shimizu et al, 2000). It has been shown that higher doses of ketamine can induce neuroapoptosis in rodents (Maxwell et al, 2006;Olney et al, 2002a;Wang et al, 2005) and primates (Haberny et al, 2002;Slikker et al, 2007b;Wang et al, 2006) during early development. In agreement, we have previously reported that ketamine induces motor neuron toxicity in zebrafish embryos .…”

What’s good for the goose, may not be good for the gosling

“…Indeed, in a recent investigation of perinatal Rhesus monkeys, there was no evidence of apoptosis subsequent to a three-hour infusion of ketamine. 15 The final chapter on this subject remains to be written.…”

“…15 A total of 61 patients have been diagnosed with PRIS, with 20 deaths in children and 18 in adults. 16 Although Diprivan® has been approved for use in humans since 1989, PRIS was not reported until 1992.…”

“…D'ailleurs, dans une étude récente menée chez des macaques Rhesus périnataux, il n'y a pas eu d'apoptose après une perfusion de kétamine de trois heures. 15 Cette question n'est donc pas encore résolue.…”

“…15 Au total, le PRIS a été diagnostiqué chez 61 patients, et il y a eu 20 décès chez des enfants et 18 chez des adultes. 16 Bien que l'utilisation du Diprivan® chez des humains soit approuvée depuis 1989, aucun cas de PRIS n'a été rapporté avant 1992.…”