# Anesthetic-Induced Neurotoxicity: Molecular Pathways and Genetic Risk Factors

> **NIH NIH R01** · UNIVERSITY OF WISCONSIN-MADISON · 2021 · $349,407

## Abstract

Some individuals undergoing anesthesia and surgery will experience anesthetic-induced neurotoxicity (AiN)
attributable to volatile general anesthetic agents (VGAs). AiN after exposure to VGAs can present with different
phenotypes, including acute neurodegeneration, delirium, lifelong cognitive impairment in children and
accelerated or even de novo neurodegeneration in the aged. Despite controversial clinical trials, the FDA, in
a far-reaching response to recent data, has issued a warning on the use of VGAs in pregnant women and
young children. Furthermore, the American Society of Anesthesiologists' Perioperative Brain Health Initiative
has raised awareness of AiN for the aged brain. As neither the pathophysiology of AiN nor its risk factors are
understood, there are neither prophylactic nor therapeutic measures.
Our underlying hypothesis is that heritable factors determine the threshold for AiN vulnerability while biological
and environmental variables shape its phenotype. We propose to approach AiN with a pharmacogenomic
strategy in the fruit fly Drosophila melanogaster. We will use the ND2360114 strain, which is a model of Leigh
syndrome (a human neurodegenerative disease caused by mutation of NDUFS8, the mammalian ortholog of
ND23). Exposure of ND2360114 flies to VGAs results in four striking phenotypes: (1) young flies are equally
hypersensitive to the behavioral effects of isoflurane and sevoflurane (reproducing the human phenotype), (2)
middle-aged flies incur significant mortality within 24 hours after waking up from isoflurane, (3) genetic and
environmental manipulations profoundly modulate mortality, and (4) phenotypically normal ND2360114/+ flies
become sensitized to AiN from isoflurane at an advanced age thereby. We will use ND2360114 flies as a
sensitized model of AiN with rapid, unambiguous readout. To investigate the modulatory role of genetic
background on AiN, we will use genome-wide association study (GWAS) analysis to identify nucleotide
polymorphisms that modify AiN in ND2360114/+ flies. To determine the scope of heterozygous mutations that
increase the risk of AiN, we will screen candidate mutants in mitochondrial metabolic pathways. To identify
key metabolic regulators of AiN, we will use RNA-seq under experimental conditions that result in different
mortality rates.
These studies are significant because exposure to VGA affects millions of people of all ages every year and
concerns of AiN are widespread. Complications from exposure to anesthesia and surgery have long-lasting
consequences. Considering genetic background when assessing the individual risk of AiN is a step towards
personalized medicine. Understanding its pathophysiology offers a path to informed prevention and treatment.

## Key facts

- **NIH application ID:** 10129974
- **Project number:** 5R01GM134107-02
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** Michael Perouansky
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $349,407
- **Award type:** 5
- **Project period:** 2020-04-01 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10129974

## Citation

> US National Institutes of Health, RePORTER application 10129974, Anesthetic-Induced Neurotoxicity: Molecular Pathways and Genetic Risk Factors (5R01GM134107-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10129974. Licensed CC0.

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