Relative Neurotoxicity of Ivermectin and Moxidectin in Mdr1ab (？？) Mice and Effects on Mammalian GABA(A) Channel Activity 英文参考文献.docVIP

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Relative Neurotoxicity of Ivermectin and Moxidectin in Mdr1ab (？？) Mice and Effects on Mammalian GABA(A) Channel Activity 英文参考文献.doc

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Relative Neurotoxicity of Ivermectin and Moxidectin in Mdr1ab (？？) Mice and Effects on Mammalian GABA(A) Channel Activity 英文参考文献

RelativeNeurotoxicityofIvermectinandMoxidectinin Mdr1ab(2/2)MiceandEffectsonMammalianGABA(A) ChannelActivity Ce′cileMe′nez1,2,Jean-Franc?oisSutra1,2,RogerPrichard3,AnneLespine1,2* 1INRA, UMR1331, Toxalim, Research Centre in Food Toxicology, Toulouse, France, 2Universite′ de Toulouse, INP, UMR1331, Toxalim, Toulouse, France, 3Institute of Parasitology,McGillUniversity,Montreal,Canada Abstract Theanthelminticsivermectin(IVM)andmoxidectin(MOX)displaydifferencesintoxicityinseveralhostspecies.Entrance into the brain is restricted by the P-glycoprotein (P-gp) efflux transporter, while toxicity is mediated through the brain GABA(A)receptors.ThisstudycomparedthetoxicityofIVMandMOXinvivoandtheirinteractionwithGABA(A)receptorsin vitro.DrugtoxicitywasassessedinMdr1ab(2/2)miceP-gp-deficientaftersubcutaneousadministrationofincreasingdoses (0.11–2.0and0.23–12.9mmol/kgforIVMandMOXinP-gp-deficientmiceandhalflethaldoses(LD )inwild-typemice). 50 Survivalwasevaluatedover14-days.InMdr1ab(2/2)mice,LD50was0.46and2.3mmol/kgforIVMandMOX,respectively, demonstratingthatMOXwaslesstoxicthanIVM.InP-gp-deficientmice,MOXhadalowerbrain-to-plasmaconcentration ratio and entered into the brain more slowly than IVM. The brain sublethal drug concentrations determined after administrationofdosesclosetoLD50were,inMdr1ab(2/2)andwild-typemice,respectively,270and210pmol/gforIVM and830and740–1380pmol/gforMOX,indicatingthathigherbrainconcentrationsarerequiredforMOXtoxicitythanIVM. In rat a1b2c2 GABA channels expressed in Xenopus oocytes, IVM and MOX were both allosteric activators of the GABA- induced response. The Hill coefficient was 1.5260.45 for IVM and 0.3460.56 for MOX (p,0.001), while the maximum potentiation caused by IVM and MOX relative to GABA alone was 413.7666.1 and 257.4640.6%, respectively (p,0.05), showingthatIVMcausesagreaterpotentiationofGABAactiononthisreceptor.DifferencesintheaccumulationofIVMand MOXinthebrainandintheinteractionofIVMandMOXwithGABA(A)receptorsaccountfordifference