L-Carnitine rescues ketamine-induced attenuated heart rate and MAPK (ERK) activity in zebrafish embryos.
Ketamine, an antagonist of the N-methyl-D-aspartate (NMDA)-type glutamate receptors, is a pediatric anesthetic. Ketamine has been shown to be neurotoxic and cardiotoxic in mammals. Here, we show that after 2 h of exposure, 5 mM ketamine significantly reduced heart rate in 26 h old zebrafish embryos. In 52 h old embryos, 1 mM ketamine was effective after 2 h and 0.5 mM ketamine at 20 h of exposure. Ketamine also induced significant reductions in activated MAPK (ERK) levels. Treatment of the embryos with the ERK inhibitor, PD 98059, also significantly reduced heart rate whereas the p38/SAPK inhibitor, SB203580, was ineffective. Ketamine is known to inhibit lipolysis and a decrease of ATP content in the heart. Co-treatment with l-carnitine that enhances fatty acid metabolism effectively rescued ketamine-induced attenuated heart rate and ERK activity. These findings demonstrate that l-carnitine counteracts ketamine's negative effects on heart rate and ERK activity in zebrafish embryos.
Division of Neurotoxicology, National Center for Toxicological Research, US Food and Drug Administration, Jefferson, AR 72079, USA. jyotshnabala.kanungo@fda.hhs.gov
Jyotshnabala
J
Kanungo
Elvis
E
Cuevas
Syed F
SF
Ali
Merle G
MG
Paule
D000700:Analgesics / Q000009:adverse effects; D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology*; D002331:Carnitine / Q000494:pharmacology*; D004625:Embryo, Nonmammalian / Q000187:drug effects / Q000502:physiology; D018691:Excitatory Amino Acid Antagonists / Q000009:adverse effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D005419:Flavonoids / Q000494:pharmacology; D006339:Heart Rate / Q000187:drug effects*; D007649:Ketamine / Q000009:adverse effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D014803:Vitamin B Complex; D015027:Zebrafish; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology
D000700:Analgesics; D002316:Cardiotonic Agents; D018691:Excitatory Amino Acid Antagonists; D005419:Flavonoids; D047428:Protein Kinase Inhibitors; D016194:Receptors, N-Methyl-D-Aspartate; D014803:Vitamin B Complex; D007649:Ketamine; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D002331:Carnitine; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one