N-acetylcysteine prevents ketamine-induced adverse effects on development, heart rate and monoaminergic neurons in zebrafish

Abstract

N-acetylcysteine, a precursor molecule of glutathione, is an antioxidant. Ketamine, a pediatric anesthetic, has been implicated in cardiotoxicity and neurotoxicity including modulation of monoaminergic systems in mammals and zebrafish. Here, we show that N-acetylcysteine prevents ketamine’s adverse effects on development and monoaminergic neurons in zebrafish embryos. The effects of ketamine and N-acetylcysteine alone or in combination were measured on the heart rate, body length, brain serotonergic neurons and tyrosine hydroxylase-immunoreactive (TH-IR) neurons. In the absence of N-acetylcysteine, a concentration of ketamine that produces an internal embryo exposure level comparable to human anesthetic plasma concentrations significantly reduced heart rate and body length and those effects were prevented by N-acetylcysteine co-treatment. Ketamine also reduced the areas occupied by serotonergic neurons in the brain, whereas N-acetylcysteine co-exposure counteracted this effect. TH-IR neurons in the embryo brain and TH-IR cells in the trunk were significantly reduced with ketamine treatment, but not in the presence of N-acetylcysteine. In our continued search for compounds that can prevent ketamine toxicity, this study using specific endpoints of developmental toxicity, cardiotoxicity and neurotoxicity, demonstrates protective effects of N-acetylcysteine against ketamine’s adverse effects. This is the first study that shows the protective effects of N-acetylcysteine on ketamine-induced developmental defects of monoaminergic neurons as observed in a whole organism.

Ameliorative effects ofN‐acetyl cysteine on diclofenac‐induced renal injury in male rats based on serum biochemical parameters, oxidative biomarkers, and histopathological study

“…Also, in this study, histopathological examinations showed the reduction of mononuclear cells infiltration in treated rats with NAC (Figure ). Previous studies reported that NAC can react with OH radicals and keep tissues from injuries due to the formation of glutathione in the cells and preventing the reduction of antioxidant enzyme activities (Ahmad et al, ; Grisanti et al, ; Robinson, Dumas, Gu, & Kanungo, ). Increased SOD and CAT activities and improved kidney histopathological changes in NAC‐treated group may be resulted from, at least partly, NAC antioxidant activity (Figures and ).…”

Nifedipine toxicity is exacerbated by acetyl l‐carnitine but alleviated by low‐dose ketamine in zebrafish in vivo

“…First, using 2 m m ketamine and 1 m m ALCAR doses, which we have used in many of our previous studies (Guo et al, ; Kanungo et al, , ; Robinson et al, ; Robinson et al, ; Robinson, Dumas, Ali, et al, ; Robinson, Dumas, Gu, et al, ; Robinson, Gu, Ali, Dumas, & Kanungo, ; Trickler et al, ), we discovered that, in the 28 hpf embryos, 2 m m ketamine with 50 μ m nifedipine was less toxic than 50 μ m nifedipine alone. Surprisingly, embryos treated with 50 μ m nifedipine and 2 m m ketamine showed a better body axis than the embryos treated only with 50 μ m nifedipine.…”

“…As our previous studies showed counteracting effects of ALCAR and ketamine (Cuevas et al, ; Guo et al, ; Kanungo et al, ; Robinson et al, ; B. L. Robinson et al, ; B. L. Robinson et al, ), we hypothesized that if ALCAR exacerbates the effect of nifedipine, ketamine would alleviate it. In the presence of 2 m m ketamine in water, which we have used in our previous studies (Guo et al, ; Kanungo et al, ; Kanungo, Cuevas, Ali, & Paule, ; Robinson, Dumas, Gu, et al, ; B. L. Robinson et al, ; Robinson, Dumas, Ali, et al, ; B. L. Robinson et al, ; Trickler et al, ) that gives an internal dose of ~8.4 μ m in the zebrafish embryos (Trickler et al, ), nifedipine toxicity appeared to be milder (Figure ). Nifedipine‐induced axial curvature was no more apparent in ketamine and nifedipine co‐treated embryos (Figure ).…”

“…Data for each group were used to calculate the mean and standard deviation. Body lengths were measured following procedures described in our previous studies (Guo et al, ; Robinson, Dumas, Gu, et al, ). The statistical significance of the effects of the various treatments on hatching rate, survival and body length was determined by one‐way ANOVA (Sigma Stat) using Holm‐Sidak pairwise multiple comparison post‐hoc analysis.…”

“…Effective therapy against CCB toxicity is not well established (Salhanick & Shannon, ), particularly for children (Belson, Gorman, Sullivan, & Geller, ; Euwema & Swanson, ). We have previously shown acetyl l ‐carnitine (ALCAR) to be effective against calcium antagonists (verapamil, cyclosporine A and ketamine) in the zebrafish embryos, in which we were able to delineate a number of mechanisms based on the phenotypes produced upon drug treatments (Cuevas et al, ; Guo et al, ; Kanungo, Cuevas, Ali, & Paule, ; B. Robinson, Dumas, Gu, & Kanungo, ; B. Robinson, Gu, Ali, Dumas, & Kanungo, ; B. L. Robinson et al, ; B. L. Robinson et al, ). In continuation, we explored whether ALCAR can alleviate nifedipine toxicity as it did against toxicities induced by calcium antagonists, such as verapamil, cyclosporine A and ketamine.…”