Developmental neurotoxicity of ketamine in the developing brain ....................................................................... Chaoxuan Dong

Isoflurane Is More Deleterious to Developing Brain Than Desflurane: The Role of the Akt/GSK3βSignaling Pathway

BioMed Research International ◽

10.1155/2016/7919640 ◽

2016 ◽

Vol 2016 ◽

pp. 1-10 ◽

Cited By ~ 10

Author(s):

Guorong Tao ◽

Qingsheng Xue ◽

Yan Luo ◽

Guohui Li ◽

Yimeng Xia ◽

...

Keyword(s):

Signaling Pathway ◽

Learning And Memory ◽

Pediatric Anesthesia ◽

Developmental Neurotoxicity ◽

Developing Brain ◽

Spatial Learning And Memory ◽

Postnatal Exposure ◽

Multiple Exposures

Demand is increasing for safer inhalational anesthetics for use in pediatric anesthesia. In this regard, researchers have debated whether isoflurane is more toxic to the developing brain than desflurane. In the present study, we compared the effects of postnatal exposure to isoflurane with those of desflurane on long-term cognitive performance and investigated the role of the Akt/GSK3βsignaling pathway. Postnatal day 6 (P6) mice were exposed to either isoflurane or desflurane, after which the phosphorylation levels of Akt/GSK3βand learning and memory were assessed at P8 or P31. The phosphorylation levels of Akt/GSK3βand learning and memory were examined after intervention with lithium. We found that isoflurane, but not desflurane, impaired spatial learning and memory at P31. Accompanied by behavioral change, only isoflurane decreased p-Akt (ser473) and p-GSK3β(ser9) expressions, which led to GSK3βoveractivation. Lithium prevented GSK3βoveractivation and alleviated isoflurane-induced cognitive deficits. These results suggest that isoflurane is more likely to induce developmental neurotoxicity than desflurane in context of multiple exposures and that the Akt/GSK3βsignaling pathway partly participates in this process. GSK3βinhibition might be an effective way to protect against developmental neurotoxicity.

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Systems Toxicology Approach for Assessing Developmental Neurotoxicity in Larval Zebrafish

Frontiers in Genetics ◽

10.3389/fgene.2021.652632 ◽

2021 ◽

Vol 12 ◽

Author(s):

Roman A. Li ◽

Marja Talikka ◽

Sylvain Gubian ◽

Colette vom Berg ◽

Florian Martin ◽

...

Keyword(s):

Adverse Outcomes ◽

Developmental Neurotoxicity ◽

Developing Brain ◽

System Level ◽

Biological Processes ◽

Chemical Toxicity ◽

Systems Toxicology ◽

Mechanisms Of Toxicity ◽

Molecular Events ◽

Chemically Induced

Adverse outcomes that result from chemical toxicity are rarely caused by dysregulation of individual proteins; rather, they are often caused by system-level perturbations in networks of molecular events. To fully understand the mechanisms of toxicity, it is necessary to recognize the interactions of molecules, pathways, and biological processes within these networks. The developing brain is a prime example of an extremely complex network, which makes developmental neurotoxicity one of the most challenging areas in toxicology. We have developed a systems toxicology method that uses a computable biological network to represent molecular interactions in the developing brain of zebrafish larvae. The network is curated from scientific literature and describes interactions between biological processes, signaling pathways, and adverse outcomes associated with neurotoxicity. This allows us to identify important signaling hubs, pathway interactions, and emergent adverse outcomes, providing a more complete understanding of neurotoxicity. Here, we describe the construction of a zebrafish developmental neurotoxicity network and its validation by integration with publicly available neurotoxicity-related transcriptomic datasets. Our network analysis identified consistent regulation of tumor suppressors p53 and retinoblastoma 1 (Rb1) as well as the oncogene Krüppel-like factor (Klf8) in response to chemically induced developmental neurotoxicity. The developed network can be used to interpret transcriptomic data in a neurotoxicological context.

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