Effects of embryonic cyclosporine exposures on brain development and behavior

Abstract

Cyclosporine, a calcineurin inhibitor, is successfully used as an immunosuppressant in transplant medicine. However, the use of this pharmaceutical during pregnancy is concerning, since calcineurin is thought to play a role in neural development. The risk for human brain development is difficult to evaluate, because of a lack of basic information on the sensitive developmental times and the potentially pleiotropic effects on brain development and behavior. In the present study, we use zebrafish as a model system to examine the effects of embryonic cyclosporine exposures. Early embryonic exposures reduced the size of the eyes and brain. Late embryonic exposures did not affect the size of the eyes or brain, but did lead to substantial behavioral defects at the larval stages. The cyclosporine-exposed larvae displayed a reduced avoidance response to visual stimuli, low swim speeds, increased resting, an increase in thigmotaxis, and changes in the average distance between larvae. Similar results were obtained with the calcineurin inhibitor FK506, suggesting that most, but not all, effects on brain development and behavior are mediated by calcineurin inhibition. Overall, the results show that cyclosporine can induce either structural or functional brain defects, depending on the exposure window. The observed functional brain defects highlight the importance of quantitative behavioral assays when evaluating the risk of developmental exposures.

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

“…The 24 h treatment of the 72 hpf larvae that have a functional liver was intended not only to generate quantifiable moderate toxic endpoints but also to explore whether there was any alteration in the specific drug‐metabolizing CYP enzyme. Exposure of 72 hpf larvae to 10 μ m CsA only has been shown to cause significant behavioral defects but no morphological anomalies (Clift et al, ). Consistent with this report, our current study showed that 10 μ m CsA‐treated larvae developed like control larvae.…”

Effects of embryonic exposure to polychlorinated biphenyls (PCBs) on larval zebrafish behavior

“…Visual, motor and brain defects may have contributed to the pattern of impairments in the PCB-exposed larvae which included attenuated avoidance on the BD assay and elevated freezing and thigmotaxis on the BD/SD assay. One strategy that could prove useful in identifying the source of these functional deficits would be to vary the timing of the PCB-exposure window (Clift et al, 2015). Overall, these findings highlight the potential risks of PCB-exposure to human fetal and neonatal development and the importance of continued monitoring of PCB levels in the environment.…”

Management and treatment of chronic urticaria (CU)

“…[124][125][126][127][128] Use of corticosteroids in the first trimester of pregnancy is not advisable due to the possible increased risk of cleft palate, and ciclosporin use in pregnant women should be considered with extreme caution due to potential adverse embryotoxic and teratogenic effects. 78,129,130 Published evidence on the use of montelukast during pregnancy suggests that there is no increased risk of major malformations above the baseline rate in the general population; however, one study reported a significantly lower birth weight of babies whose mothers had been treated with montelukast. 131 Further clinical studies are required to be able to fully evaluate the efficacy and safety of montelukast in pregnant women.…”