Strategies to defeat ketamine-induced neonatal brain injury

Abstract

Studies using animal models have shown that general anesthetics such as ketamine trigger widespread and robust apoptosis in the infant rodent brain. Recent clinical evidence suggests that the use of general anesthetics on young children (at ages equivalent to those used in rodent studies) can promote learning deficits as they mature. Thus, there is a growing need to develop strategies to prevent this injury. In this study, we describe a number of independent approaches to address therapeutic intervention. Postnatal day 7 (P7) rats were injected with vehicle (sterile PBS) or the NMDAR antagonist ketamine (20 mg/kg). At 8 hours after, we prepared brains for immunohistochemical detection of the pro-apoptotic enzyme activated caspase-3 (AC3). Focusing on the somatosensory cortex, AC3-positive cells were then counted in a non-biased stereological manner. We found AC3 levels were markedly increased in ketamine-treated animals. In one study, microarray analysis of the somatosensory cortex from ketamine-treated P7 pups revealed that expression of activity dependent neuroprotective protein (ADNP) was enhanced. Thus, we injected P7 animals with the ADNP peptide fragment NAP 15 min before ketamine administration and found we could dose-dependently reverse the injury. In separate studies, pretreatment of P6 animals with 20 mg/kg vitamin D3 or a non-toxic dose of ketamine (5 mg/kg) also prevented ketamine-induced apoptosis at P7. In contrast, pretreatment of P7 animals with aspirin (30 mg/kg) 15 min before ketamine administration actually increased AC3 counts in some regions. These data show that a number of unique approaches can be taken to address anesthesia-induced neurotoxicity in the infant brain, thus providing MDs with a variety of alternative strategies that enhance therapeutic flexibility.

17β-estradiol attenuates ketamine-induced neuroapoptosis and persistent cognitive deficits in the developing brain

“…Thus, the search for adjunctive neuroprotective measures that will prevent or ameliorate the toxicity of ketamine in the developing human brain is highly warranted. Although many strategies, including the use of the activity-dependent neuroprotective protein peptide fragment NAPVSIPQ (NAP) (Turner et al, 2012), vitamin D (Turner et al, 2012), lithium (Straiko et al, 2009), erythropoietin (Shang et al, 2007), L-carnitine (Liu et al, 2013), nicotinamide (Ullah et al, 2012), and clonidine (Ponten et al, 2012), are known to have neuroprotective effects against ketamine-induced apoptosis both in vivo and in vitro, their efficacy and safety need to be further verified for uses targeting the developing brain.…”

Ketamine use in current clinical practice

“…Numerous animal studies in rodents indicate that ketamine induces neurodegeneration in the developing brain in a dose-depended manner, and the data also suggest that limiting exposure limits the potential for neurodegeneration. Some postnatal preclinical studies suggested that ketamine-induced injury in the infant rodent brain was a centrally driven event [24,25] . There are very few studies that have examined the potential functional consequences of the neurodegeneration noted in the animal models, except recent evidence suggests that multiple exposures to anesthetics (including ketamine) and surgery before the age of 2 was a significant independent risk factor for the later development of learning disabilities [26] .…”

In vivo and in vitro ketamine exposure exhibits a dose-dependent induction of activity-dependent neuroprotective protein in rat neurons

“…Ketamine is a non-competitive N-methyl-D-aspartate (NMDA) antagonist that disrupts calcium homeostasis in neurons (Sinner et al, 2005;Slikker et al, 2007). Since calcium signaling has an important role in cytoskeleton stability (Lankford and Letourneau, 1989) as well as neuronal viability (Turner et al, 2007;Ringler et al, 2008), ketamineinduced calcium deregulation may lead to alterations in axonal outgrowth and induction of apoptotic cell death (Wang et al, 2005;Turner et al, 2012;Bai et al, 2013;Dong and Anand, 2013).…”

“…This study investigated the dual role of ketamine, as both a neurotoxin in some animal models (Wang et al, 2005;Slikker et al, 2007;Turner et al, 2012;Bai et al, 2013), and as a neuroprotectant in other animal models Rovnaghi et al, 2008;Turner et al, 2012). Depending on the dosage, ketamine has been demonstrated to be protective as well as destructive to certain brain regions.…”