title: Acetyl L-carnitine targets adenosine triphosphate synthase in protecting zebrafish embryos from toxicities induced by verapamil and ketamine: An in vivo assessment.
abstract: Verapamil is a Ca2+channel blocker and is highly prescribed as an anti-anginal, antiarrhythmic and antihypertensive drug. Ketamine, an antagonist of the Ca2+-permeable N-methyl-d-aspartate-type glutamate receptors, is a pediatric anesthetic. Previously we have shown that acetyl l-carnitine (ALCAR) reverses ketamine-induced attenuation of heart rate and neurotoxicity in zebrafish embryos. Here, we used 48 h post-fertilization zebrafish embryos that were exposed to relevant drugs for 2 or 4 h. Heart beat and overall development were monitored in vivo. In 48 h post-fertilization embryos, 2 mm ketamine reduced heart rate in a 2 or 4 h exposure and 0.5 mm ALCAR neutralized this effect. ALCAR could reverse ketamine's effect, possibly through a compensatory mechanism involving extracellular Ca2+entry through L-type Ca2+channels that ALCAR is known to activate. Hence, we used verapamil to block the L-type Ca2+channels. Verapamil was more potent in attenuating heart rate and inducing morphological defects in the embryos compared to ketamine at specific times of exposure. ALCAR reversed cardiotoxicity and developmental toxicity in the embryos exposed to verapamil or verapamil plus ketamine, even in the presence of 3,4,5-trimethoxybenzoic acid 8-(diethylamino)octyl ester, an inhibitor of intracellular Ca2+release suggesting that ALCAR acts via effectors downstream of Ca2+. In fact, ALCAR's protective effect was blunted by oligomycin A, an inhibitor of adenosine triphosphate synthase that acts downstream of Ca2+during adenosine triphosphate generation. We have identified, for the first time, using in vivo studies, a downstream effector of ALCAR that is critical in abrogating ketamine- and verapamil-induced developmental toxicities. Published 2016. This article is a U.S. Government work and is in the public domain in the USA.
authors.affiliation: Division of Neurotoxicology, National Center for Toxicological, Research, U.S. Food and Drug Administration, 3900 NCTR Road, Jefferson, AR, 72079, USA.|Division of Genetic and Molecular Toxicology, National Center for Toxicological Research, U.S. Food and Drug Administration, 3900 NCTR Road, Jefferson, AR, 72079, USA.
authors.forename: Xiaoqing
authors.initials: X
authors.lastname: Guo
authors.affiliation: Division of Neurotoxicology, National Center for Toxicological, Research, U.S. Food and Drug Administration, 3900 NCTR Road, Jefferson, AR, 72079, USA.
authors.forename: Melanie
authors.initials: M
authors.lastname: Dumas
authors.affiliation: Division of Neurotoxicology, National Center for Toxicological, Research, U.S. Food and Drug Administration, 3900 NCTR Road, Jefferson, AR, 72079, USA.
authors.forename: Bonnie L
authors.initials: BL
authors.lastname: Robinson
authors.affiliation: Division of Neurotoxicology, National Center for Toxicological, Research, U.S. Food and Drug Administration, 3900 NCTR Road, Jefferson, AR, 72079, USA.
authors.forename: Syed F
authors.initials: SF
authors.lastname: Ali
authors.affiliation: Division of Neurotoxicology, National Center for Toxicological, Research, U.S. Food and Drug Administration, 3900 NCTR Road, Jefferson, AR, 72079, USA.
authors.forename: Merle G
authors.initials: MG
authors.lastname: Paule
authors.affiliation: Division of Neurotoxicology, National Center for Toxicological, Research, U.S. Food and Drug Administration, 3900 NCTR Road, Jefferson, AR, 72079, USA.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Gu
authors.affiliation: Division of Neurotoxicology, National Center for Toxicological, Research, U.S. Food and Drug Administration, 3900 NCTR Road, Jefferson, AR, 72079, USA.
authors.forename: Jyotshna
authors.initials: J
authors.lastname: Kanungo
mesh_terms: D025181:ATP Synthetase Complexes / Q000378:metabolism*; D000108:Acetylcarnitine / Q000494:pharmacology*; D000818:Animals; D004625:Embryo, Nonmammalian / Q000187:drug effects* / Q000201:enzymology; D047108:Embryonic Development / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D007649:Ketamine / Q000633:toxicity*; D020011:Protective Agents / Q000494:pharmacology*; D014700:Verapamil / Q000633:toxicity*; D015027:Zebrafish / Q000196:embryology
chemical_list: D020011:Protective Agents; D007649:Ketamine; D000108:Acetylcarnitine; D014700:Verapamil; D025181:ATP Synthetase Complexes
keywords: acetyl l-carnitine; developmental toxicity; heart rate; ketamine; verapamil; zebrafish