title: Acetyl L-carnitine protects motor neurons and Rohon-Beard sensory neurons against ketamine-induced neurotoxicity in zebrafish embryos.
abstract: Ketamine, a non-competitive antagonist of N-methyl-D-aspartate (NMDA) type glutamate receptors is commonly used as a pediatric anesthetic. Multiple studies have shown ketamine to be neurotoxic, particularly when administered during the brain growth spurt. Previously, we have shown that ketamine is detrimental to motor neuron development in the zebrafish embryos. Here, using both wild type (WT) and transgenic (hb9:GFP) zebrafish embryos, we demonstrate that ketamine is neurotoxic to both motor and sensory neurons. Drug absorption studies showed that in the WT embryos, ketamine accumulation was approximately 0.4% of the original dose added to the exposure medium. The transgenic embryos express green fluorescent protein (GFP) localized in the motor neurons making them ideal for evaluating motor neuron development and toxicities in vivo. The hb9:GFP zebrafish embryos (28 h post fertilization) treated with 2 mM ketamine for 20 h demonstrated significant reductions in spinal motor neuron numbers, while co-treatment with acetyl L-carnitine proved to be neuroprotective. In whole mount immunohistochemical studies using WT embryos, a similar effect was observed for the primary sensory neurons. In the ketamine-treated WT embryos, the number of primary sensory Rohon-Beard (RB) neurons was significantly reduced compared to that in controls. However, acetyl L-carnitine co-treatment prevented ketamine-induced adverse effects on the RB neurons. These results suggest that acetyl L-carnitine protects both motor and sensory neurons from ketamine-induced neurotoxicity.
authors.affiliation: Division of Neurotoxicology, National Center for Toxicological Research, US Food and Drug Administration, 3900 NCTR Road, Jefferson, AR 72079, USA.
authors.forename: Elvis
authors.initials: E
authors.lastname: Cuevas
authors.forename: William J
authors.initials: WJ
authors.lastname: Trickler
authors.forename: Xiaoqing
authors.initials: X
authors.lastname: Guo
authors.forename: Syed F
authors.initials: SF
authors.lastname: Ali
authors.forename: Merle G
authors.initials: MG
authors.lastname: Paule
authors.forename: Jyotshna
authors.initials: J
authors.lastname: Kanungo
mesh_terms: D000108:Acetylcarnitine / Q000493:pharmacokinetics / Q000494:pharmacology*; D000778:Anesthetics, Dissociative / Q000037:antagonists & inhibitors / Q000633:toxicity; D000818:Animals; D030801:Animals, Genetically Modified; D004305:Dose-Response Relationship, Drug; D004625:Embryo, Nonmammalian; D007649:Ketamine / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D009046:Motor Neurons / Q000187:drug effects*; D055495:Neurogenesis / Q000187:drug effects; D018696:Neuroprotective Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D011984:Sensory Receptor Cells / Q000187:drug effects*; D015027:Zebrafish / Q000196:embryology*
chemical_list: D000778:Anesthetics, Dissociative; D018696:Neuroprotective Agents; D007649:Ketamine; D000108:Acetylcarnitine
keywords: Acetyl l-carnitine; Ketamine; Motor neuron; Rohon-Beard neuron; Transgenic zebrafish
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