Ketamine-Induced Neurotoxicity and Changes in Gene Expression in the Developing Rat Brain

Ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, is widely used for analgesia and anesthesia in obstetric and pediatric practice. Recent reports indicate that ketamine causes neuronal cell death in developing rodents and nonhuman primates. The present study assessed the potential dose- and time-dependent neurotoxic effects and associated changes in gene expression after ketamine administration to postnatal day 7 (PND-7) rat pups

Cyclosporine exacerbates ketamine toxicity in zebrafish: Mechanistic studies on drug–drug interaction

Cyclosporine A (CsA) is an immunosuppressive drug commonly used in organ transplant patients to prevent allograft rejections. Ketamine is a pediatric anesthetic that noncompetitively inhibits the calcium-permeable N-methyl-D-aspartic acid receptors. Adverse drug–drug interaction effects between ketamine and CsA have been reported in mammals and humans. However, the mechanism of such drug–drug interaction is unclear. We have previously reported adverse effects of combination drugs, such as verapamil/ketamine and shown the mechanism through intervention by other drugs in zebrafish embryos. Here, we show that ketamine and CsA in combination produce developmental toxicity even leading to lethality in zebrafish larvae when exposure began at 24h post-fertilization (hpf ), whereas CsA did not cause any toxicity on its own. We also demonstrate that acetyl L-carnitine (ALCAR) completely reversed the adverse effects. Both ketamine and CsA are CYP3A4 substrates. Although ketamine and CsA independently altered the expression of the hepatic marker CYP3A65, a zebrafish ortholog of human CYP3A4, both drugs together induced further increase in CYP3A65 expression. In the presence of ALCAR, however, CYP3A65 expression was normalized. ALCAR has been shown to prevent ketamine toxicity in mammal and zebrafish. In conclusion, CsA exacerbated ketamine toxicity and ALCAR reversed the effects. These results, providing evidence for the first time on the reversal of the adverse effects of CsA/ketamine interaction by ALCAR, would prove useful in addressing potential occurrences of such toxicities in humans

Developmental origins of adult diseases and neurotoxicity: Epidemiological and experimental studies

To date, only a small number of commercial chemicals have been tested and documented as developmental neurotoxicants. Moreover, an increasing number of epidemiological, clinical and experimental studies suggest an association between toxicant or drug exposure during the perinatal period and the development of metabolic-related diseases and neurotoxicity later in life. The four speakers in this symposium presented their research results on different neurotoxic chemicals as they relate to the developmental origins of health and adult disease (DOHaD). Philippe Grandjean presented epidemiological data on children exposed to methylmercury and discussed the behavioral outcome measures as they relate to age and stage of brain development. Donald A. Fox presented data that low-to-moderate dose human equivalent gestational lead exposure produced late-onset obesity, and motor and coordination dysfunction only in male mice. Didima de Groot discussed the role of caloric restriction and/or high fat diets during gestation and/or postnatal development in mediating the metabolic and neurotoxic effects of developmental methylmercury exposure in rats. Merle G. Paule addressed the long-term changes in learning, motivation and short-term memory in aged Rhesus monkeys following 24 hour exposure to ketamine during early development. Overall, these presentations addressed fundamental issues in the emerging areas of lifetime neurotoxicity testing, differential vulnerable periods of exposure, nonmonotonic dose-response effects and neurotoxic risk assessment

Anesthetic-Induced Oxidative Stress and Potential Protection

Prolonged exposure of developing mammals to general anesthetics affects the N-methyl-D-aspartate (NMDA)–type glutamate or γ-aminobutyric acid (GABA) receptor systems and enhances neuronal toxicity. Stimulation of immature neurons by NMDA antagonists or GABA agonists is thought to increase overall nervous system excitability and may contribute to abnormal neuronal cell death during development. Although the precise mechanisms by which NMDA antagonists or GABA agonists cause neuronal cell death are still not completely understood, up-regulation of the NMDA receptor subunit NR1 may be an initiative factor in neuronal cell death. It is increasingly apparent that mitochondria lie at the center of the cell death regulation process. Evidence for the role of oxidative stress in anesthetic-induced neurotoxicity has been generated in studies that apply oxidative stress blockers. Prevention of neuronal death by catalase and superoxide dismutase in vitro, or by M40403 (superoxide dismutase mimetic) in vivo, supports the contention that the involvement of reactive oxygen species (ROS) and the nature of neuronal cell death in rodents is mainly apoptotic. However, more evidence is necessary to in order verify the role of the NMDA receptor subunit NR1 and ROS in anesthetic-induced neurodegeneration

Role of neural stem cell activity in postweaning development of the sexually dimorphic nucleus of the preoptic area in rats.

The sexually dimorphic nucleus of the preoptic area (SDN-POA) has received increased attention due to its apparent sensitivity to estrogen-like compounds found in food and food containers. The mechanisms that regulate SDN-POA volume remain unclear as is the extent of postweaning development of the SDN-POA. Here we demonstrate that the female Sprague-Dawley SDN-POA volume increased from weaning to adulthood, although this increase was not statistically significant as it was in males. The number of cells positive for Ki67, a marker of cell proliferation, in both the SDN-POA and the hypothalamus was significantly higher at weaning than at adulthood in male rats. In contrast, the number of Ki67-positive cells was significantly higher in the hypothalamus but not in the SDN-POA (p>0.05) at weaning than at adulthood in female rats. A subset of the Ki67-positive cells in the SDN-POA displayed the morphology of dividing cells. Nestin-immunoreactivity delineated a potential macroscopic neural stem cell niche in the rostral end of the 3rd ventricle. In conclusion, stem cells may partially account for the sexually dimorphic postweaning development of the SDN-POA

Current and Future Needs for Developmental Toxicity Testing

A review is presented of the use of developmental toxicity testing in the United States and international regulatory assessment of human health risks associated with exposures to pharmaceuticals (human and veterinary), chemicals (agricultural, industrial, and environmental), food additives, cosmetics, and consumer products. Developmental toxicology data are used for prioritization and screening of pharmaceuticals and chemicals, for evaluating and labeling of pharmaceuticals, and for characterizing hazards and risk of exposures to industrial and environmental chemicals. The in vivo study designs utilized in hazard characterization and dose-response assessment for developmental outcomes have not changed substantially over the past 30 years and have served the process well. Now there are opportunities to incorporate new technologies and approaches to testing into the existing assessment paradigm, or to apply innovative approaches to various aspects of risk assessment. Developmental toxicology testing can be enhanced by the refinement or replacement of traditional in vivo protocols, including through the use of in vitro assays, studies conducted in alternative nonmammalian species, the application of new technologies, and the use of in silico models. Potential benefits to the current regulatory process include the ability to screen large numbers of chemicals quickly, with the commitment of fewer resources than traditional toxicology studies, and to refine the risk assessment process through an enhanced understanding of the mechanisms of developmental toxicity and their relevance to potential human risk. As the testing paradigm evolves, the ability to use developmental toxicology data to meet diverse critical regulatory needs must be retained