Ketamine-induced neuronal damage and altered N-methyl-D-aspartate receptor function in rat primary forebrain culture.
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 (10 µM) or ketamine plus L-carnitine (an antioxidant; 1-100 µM) for 24h, 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 (50 µM), 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.
Division of Neurotoxicology, National Center for Toxicological Research, Food and Drug Administration, 3900 NCTR Rd., Jefferson, AR 72079-0502, USA.
Fang
F
Liu
Tucker A
TA
Patterson
Natalya
N
Sadovova
Xuan
X
Zhang
Shuliang
S
Liu
Xiaoju
X
Zou
Joseph P
JP
Hanig
Merle G
MG
Paule
William
W
Slikker
Cheng
C
Wang
D000818:Animals; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D020552:Comet Assay; D004797:Enzyme-Linked Immunosorbent Assay; D007150:Immunohistochemistry; D007649:Ketamine / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects*; D010084:Oxidation-Reduction; D016548:Prosencephalon / Q000166:cytology / Q000187:drug effects* / Q000503:physiopathology; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology*
D016194:Receptors, N-Methyl-D-Aspartate; D007649:Ketamine; D002118:Calcium