Anaesthesia exposure to the developing nervous system causes neuroapoptosis and behavioural impairment in vertebrate models. Mechanistic understanding is limited, and target-based approaches are challenging. High-throughput methods may be an important parallel approach to drug-discovery and mechanistic research. The nematode worm Caenorhabditis elegans is an ideal candidate model. A rich subset of its behaviour can be studied, and hundreds of behavioural features can be quantified, then aggregated to yield a ‘signature’. Perturbation of this behavioural signature may provide a tool that can be used to quantify the effects of anaesthetic regimes, and act as an outcome marker for drug screening and molecular target research. Larval C. elegans were exposed to: isoflurane, ketamine, morphine, dexmedetomidine, and lithium (and combinations). Behaviour was recorded, and videos analysed with automated algorithms to extract behavioural features. Anaesthetic exposure during early development leads to persisting behavioural variation (in total, 125 features across exposure combinations). Higher concentrations, and combinations of isoflurane with ketamine, lead to persistent change in a greater number of features. Morphine and dexmedetomidine do not appear to lead to behavioural impairment. Lithium rescues the neurotoxic phenotype produced by isoflurane. Findings correlate well with vertebrate research: impairment is dependent on agent, is concentration-specific, is more likely with combination therapies, and can potentially be rescued by lithium. These results suggest that C. elegans may be an appropriate model with which to pursue phenotypic screens for drugs that mitigate the neurobehavioural impairment. Some possibilities are suggested for how high-throughput platforms might be organised in service of this field.
The potential for long-term neurotoxic effects of anesthetics on the developing human brain has led to intensified research in this area. To date, the human evidence has been inconclusive, but a large body of animal evidence continues to demonstrate cause for concern. On April 14 and 15, 2018 the sixth biennial Pediatric Anesthesia and Neurodevelopmental Assessment (PANDA) study symposium was held at Morgan Stanley Children’s Hospital of New York. This symposium brought together clinicians and researchers and served as a platform to review preclinical and clinical data related to anesthesia and neurotoxicity in developing brains. The program participants included many active investigators in the field of anesthesia neurotoxicity as well as stakeholders from different backgrounds with the common interest of potential anesthetic neurotoxicity in children. The moderated poster session included presentations of preclinical animal research studies. These studies focused on defining the anesthetic-induced neurotoxicity phenotype, understanding the mechanism of injury and discovering potential inhibitors of neurotoxic effects.
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