Protective effects of 7-nitroindazole on ketamine-induced neurotoxicity in rat forebrain culture.
Ketamine, a non-competitive N-methyl-d-aspartate (NMDA) receptor antagonist, is used as a pediatric anesthetic for surgical procedures. Recent data suggest that anesthetic drugs may cause neurodegeneration during development. The purpose of this study was to determine the dose and temporal response of ketamine using newborn rat forebrain cultures and also to determine if co-administration of 7-nitroindazole, a nitric oxide synthase (NOS) inhibitor, could protect or reverse ketamine-induced cell death. Neural cells collected from the rat forebrain were incubated for 24h with 1, 10 or 20 microM ketamine alone or with ketamine plus 1, 5, 10 or 20 microM 7-nitroindazole. Ketamine (10 microM) caused an increase in DNA fragmentation and elevated immunoreactivity to nitrotyrosine, a marked reduction in the expression of the neuronal marker polysialic acid neural cell adhesion molecule (PSA-NCAM) and in mitochondrial metabolism, as well as an increased Bax/BCL-XL ratio. No significant effect was observed in the release of lactate dehydrogenase (LDH). Ketamine-induced neurotoxic effects were effectively blocked by 7-nitroindazole (10 microM). These data indicate a role for nitric oxide in the enhanced degeneration induced by ketamine in vitro and also suggest that blocking neuronal nitric oxide synthase (nNOS) may help reduce the risk of ketamine in pediatrics.
Wang
Cheng
C
Division of Neurotoxicology, National Center for Toxicological Research/US Food & Drug Administration, HFT-132 Jefferson, AR, USA. cheng.wang@fda.hhs.gov
Sadovova
Natalya
N
Patterson
Tucker A
TA
Zou
Xiaoju
X
Fu
Xin
X
Hanig
Joseph P
JP
Paule
Merle G
MG
Ali
Syed F
SF
Zhang
Xuan
X
Slikker
William
W
D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D053938:DNA Fragmentation / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D018691:Excitatory Amino Acid Antagonists / Q000633:toxicity*; D005786:Gene Expression Regulation / Q000187:drug effects; D006836:Hydro-Lyases / Q000378:metabolism; D007191:Indazoles / Q000494:pharmacology*; D007649:Ketamine / Q000633:toxicity; D039842:Neural Cell Adhesion Molecule L1 / Q000378:metabolism; D009474:Neurons / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism; D016548:Prosencephalon / Q000166:cytology*; D051381:Rats; D012794:Sialic Acids / Q000378:metabolism; D013778:Tetrazolium Salts; D013844:Thiazoles; D013997:Time Factors; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D051020:bcl-X Protein / Q000378:metabolism
D018691:Excitatory Amino Acid Antagonists; D007191:Indazoles; D039842:Neural Cell Adhesion Molecule L1; D018696:Neuroprotective Agents; D012794:Sialic Acids; D013778:Tetrazolium Salts; D013844:Thiazoles; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; C103469:polysialyl neural cell adhesion molecule; D007649:Ketamine; D052248:Nitric Oxide Synthase Type I; D006836:Hydro-Lyases; C045581:lactate dehydratase; C022616:thiazolyl blue; C080122:7-nitroindazole