Ketamine-Induced Neuronal Damage and Altered N-Methyl-d-Aspartate Receptor Function in Rat Primary Forebrain Culture

Abstract

Ketamine, a noncompetitive N-methyl-d-aspartate (NMDA) receptor antagonist, is frequently used in pediatric general anesthesia. Accumulating evidence from animal experiments has demonstrated that ketamine causes neuronal cell death during the brain growth spurt. To elucidate the underlying mechanisms associated with ketamine-induced neuronal toxicity and search for approaches or agents to prevent ketamine's adverse effects on the developing brain, a primary nerve cell culture system was utilized. Neurons harvested from the forebrain of newborn rats were maintained under normal control conditions or exposed to either ketamine (10µM) or ketamine plus l-carnitine (an antioxidant; 1-100µM) for 24 h, followed by a 24-h withdrawal period. Ketamine exposure resulted in elevated NMDA receptor (NR1) expression, increased generation of reactive oxygen species (ROS) as indicated by higher levels of 8-oxoguanine production, and enhanced neuronal damage. Coadministration of l-carnitine significantly diminished ROS generation and provided near complete protection of neurons from ketamine-induced cell death. NMDA receptors regulate channels that are highly permeable to calcium, and calcium imaging data demonstrated that neurons exposed to ketamine had a significantly elevated amplitude of calcium influx and higher intracellular free calcium concentrations ([Ca 2+ ]i) evoked by NMDA (50µM), compared with control neurons. These findings suggest that prolonged ketamine exposure produces an increase in NMDA receptor expression (compensatory upregulation), which allows for a higher/toxic influx of calcium into neurons once ketamine is removed from the system, leading to elevated ROS generation and neuronal cell death. l-Carnitine appears to be a promising agent in preventing or reversing ketamine's toxic effects on neurons at an early developmental stage.

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

“…Recent findings indicate that anesthetics that act as NMDA receptors induce widespread neuronal apoptosis in the immature mammalian brain (Ikonomidou et al, 1999;Liu et al, 2013;Wang et al, 2013;Young et al, 2005;Zhang et al, 2008). Reports also show that exposure of the developing brain to a clinically relevant cocktail of anesthetics that has both NMDA antagonist and GABA mimetic properties results in an extensive pattern of neuroapoptosis, and subsequent cognitive deficits (Olney et al, 2002b).…”

Low-dose Ketamine for Children and Adolescents with Acute Sickle Cell Disease Related Pain: A Single Center Experience

“…Another patient in that same case series complained of dysphoria after the initial ketamine bolus and asked that drug is discontinued [19]. Due to our study design we are not able to comment on the long term effect of ketamine, more specifically neuroapoptosis, which has been recently raised as major concern and potentially results from the exposure of the developing brain to ketamine [28][29][30].…”

Adverse Outcome Pathway on chronic binding of antagonist to N-methyl-D-aspartate receptors (NMDARs) during brain development induces impairment of learning and memory abilities

“…In rat primary forebrain cultures, the intracellular Ca2+ increases after activation of the NMDA receptor and this increase is blocked when the cells are cultured under Ca2+ free conditions, demonstrating that the NMDA-evoked increase in intracellular Ca2+ derives from extracellular and not intracellular sources (Liu et al, 2013).…”