# Anesthetic neurotoxicity is controlled by ER-stress

> **NIH NIH R01** · SEATTLE CHILDREN'S HOSPITAL · 2020 · $385,800

## Abstract

Project Summary
 Since their discovery volatile anesthetics have been viewed as benign inhibitors of the central nervous
system. However, recent experimental studies have seriously challenged this dogma, causing an astonishing
paradigm shift in the field of anesthesiology, in particular in regard to the care of infants undergoing general
anesthesia. Since more than a million children undergo general anesthesia each year in the U.S., even small
developmental defects from their use during a critical window of vulnerability have potentially large implications
for our current care of children.
 General anesthetics have now been shown to cause neurotoxicity in nematodes, rodents and
primates. Histologic changes in the CNS are accompanied by behavioral defects that persist into adulthood. It
is now established that volatile anesthetics in isolation are capable of inducing neurodegeneration in the
developing nervous systems of multiple organisms. We propose to carry our findings in nematodes into a direct
exploration aiming to prevent anesthetic induced neurotoxicity (AIN) in mammals.
 It remains unclear how great a risk normal anesthetic exposure poses to the newborn human.
Retrospective studies have raised the possibility that significant learning defects may exist in children who
have had multiple anesthetic exposures but other studies have failed to find such an effect. While it is clearly
important to determine the overall significance of AIN in humans, an equally important question is how do
anesthetics cause this toxicity. Using a tractable model (C. elegans), we have identified two intersecting
pathways that mediate AIN. One of these pathways induces a stress pathway leading to activation of the
unfolded protein response in the endoplasmic reticulum (UPRER). The second pathway (known as the daf-2
pathway) induces a protective response to stress and its activation eliminates AIN. Discovering these two
mechanisms led to the identification of signaling molecules, the transcription factor hypoxia inducible factor1
(HIF-1) and the mechanistic target of rapamycin (mTOR), as central in mediating AIN. We can completely
eliminate AIN in the nematode by manipulating these pathways. We propose to discover whether mTOR
and ER-stress mediate AIN in mammals, and to prevent AIN in mice by inhibiting mTOR. We will continue to
exploit the nematode to perform a high throughput screen to discover other molecules capable of eliminating
ER stress, and test their effects on AIN in C. elegans. Our Specific Aims are:
SA1. A. Test the effects of isoflurane on mTOR activation and ER-stress in the mouse.
 B. Test rapamycin in mice for prevention of AIN.
SA2. Perform a high throughput small molecule screen for inhibitors of AIN.

## Key facts

- **NIH application ID:** 9861248
- **Project number:** 5R01GM118514-04
- **Recipient organization:** SEATTLE CHILDREN'S HOSPITAL
- **Principal Investigator:** PHILIP G MORGAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $385,800
- **Award type:** 5
- **Project period:** 2017-03-03 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9861248

## Citation

> US National Institutes of Health, RePORTER application 9861248, Anesthetic neurotoxicity is controlled by ER-stress (5R01GM118514-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9861248. Licensed CC0.

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