Protective effect of acetyl-L-carnitine on propofol-induced toxicity in embryonic neural stem cells.
Propofol is a widely used general anesthetic. A growing body of data suggests that perinatal exposure to general anesthetics can result in long-term deleterious effects on brain function. In the developing brain there is evidence that general anesthetics can cause cell death, synaptic remodeling, and altered brain cell morphology. Acetyl-L-carnitine (L-Ca), an anti-oxidant dietary supplement, has been reported to prevent neuronal damage from a variety of causes. To evaluate the ability of L-Ca to protect against propofol-induced neuronal toxicity, neural stem cells were isolated from gestational day 14 rat fetuses and on the eighth day in culture were exposed for 24h to propofol at 10, 50, 100, 300 and 600 μM, with or without L-Ca (10 μM). Markers of cellular proliferation, mitochondrial health, cell death/damage and oxidative damage were monitored to determine: (1) the effects of propofol on neural stem cell proliferation; (2) the nature of propofol-induced neurotoxicity; (3) the degree of protection afforded by L-Ca; and (4) to provide information regarding possible mechanisms underlying protection. After propofol exposure at a clinically relevant concentration (50 μM), the number of dividing cells was significantly decreased, oxidative DNA damage was increased and a significant dose-dependent reduction in mitochondrial function/health was observed. No significant effect on lactase dehydrogenase (LDH) release was observed at propofol concentrations up to 100 μM. The oxidative damage at 50 μM propofol was blocked by L-Ca. Thus, clinically relevant concentrations of propofol induce dose-dependent adverse effects on rat embryonic neural stem cells by slowing or stopping cell division/proliferation and causing cellular damage. Elevated levels of 8-oxoguanine suggest enhanced oxidative damage [reactive oxygen species (ROS) generation] and L-Ca effectively blocks at least some of the toxicity of propofol, presumably by scavenging oxidative species and/or reducing their production.
Division of Neurotoxicology, National Center for Toxicological Research/Food and Drug Administration, Jefferson, AR 72079, USA. Electronic address: Fang.liu@fda.hhs.gov.
Fang
F
Liu
Department of Anesthesiology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
Shuo W
SW
Rainosek
Toxicologic Pathology Associates, Jefferson, AR 72079, USA.
Natalya
N
Sadovova
Division of Neurotoxicology, National Center for Toxicological Research/Food and Drug Administration, Jefferson, AR 72079, USA.
Charles M
CM
Fogle
Division of Neurotoxicology, National Center for Toxicological Research/Food and Drug Administration, Jefferson, AR 72079, USA.
Tucker A
TA
Patterson
Center for Drug Evaluation and Research/Food and Drug Administration, Silver Spring, MD 20993, USA.
Joseph P
JP
Hanig
Division of Neurotoxicology, National Center for Toxicological Research/Food and Drug Administration, Jefferson, AR 72079, USA.
Merle G
MG
Paule
Office of the Director, National Center for Toxicological Research/Food and Drug Administration, Jefferson, AR 72079, USA.
William
W
Slikker
Division of Neurotoxicology, National Center for Toxicological Research/Food and Drug Administration, Jefferson, AR 72079, USA. Electronic address: Cheng.wang@fda.hhs.gov.
Cheng
C
Wang
D000108:Acetylcarnitine / Q000494:pharmacology*; D018686:Anesthetics, Intravenous / Q000633:toxicity*; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004249:DNA Damage / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D043322:Lactase / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects; D058953:Neural Stem Cells / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D015742:Propofol / Q000633:toxicity*; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D011963:Receptors, GABA-A / Q000378:metabolism
D018686:Anesthetics, Intravenous; D018696:Neuroprotective Agents; D017382:Reactive Oxygen Species; D011963:Receptors, GABA-A; D000108:Acetylcarnitine; D043322:Lactase; D015742:Propofol
Apoptosis; Neural stem cells; Propofol; Protection