# Mitochondrial Protection to Prevent Neurobehavioral Changes after Postnatal Anesthesia

> **NIH NIH R01** · WAKE FOREST UNIVERSITY HEALTH SCIENCES · 2022 · $177,581

## Abstract

Project Summary
General anesthetics may act as neurotoxins in the developing mammalian nervous system and cause long-term
neurobehavioral changes after exposure in infancy. Repeated exposure is particularly deleterious to the
developing nervous system, and children who undergo more than one general anesthesia before the age of 4
are at an increased risk for substantial emotional and cognitive changes. It is therefore critical that preventative
treatments be found. Studies in animal models have suggested that persistent anesthetic-induced changes such
as neurotoxicity, gliotoxicity, loss of synapses and changes in mitochondrial structure may lead to long-term
behavioral impairments. Early effects of anesthesia on mitochondria may be key to long-term impairments:
protection of mitochondria from oxidative stress caused by free radical generation from general anesthetics
eliminates subsequent cognitive impairment in adulthood in rodents. We have established a nonhuman primate
model of early anesthetic exposure. In a previous award, we showed that infant rhesus monkeys that received
multiple exposures of to the inhalation anesthetic sevoflurane, commonly used in pediatric anesthesia, showed
long-term changes in socioemotional and cognitive development when tested later in development. In this new
proposal, we will use that model to test the hypothesis that neonatal anesthesia exposure is associated with
long-term changes in synaptic and mitochondrial structure in the primate brain, and that protection of
mitochondria from oxidative stress at the time of anesthesia exposure mitigates or prevents subsequent changes
in cognitive and socioemotional development. Specifically, in Aim 1 of this project, mitochondrial and synaptic
structure in adulthood will be examined at the electron microscopic level in tissue prepared and banked from
those subjects from the previous award. For Aim 2, infant rhesus macaques will be exposed to sevoflurane (3
exposures in the six weeks of life) in the presence of R(+)pramipexole, a mitochondrial protectant, or treated
with vehicle and will be followed behaviorally for 2 years to assess sparing of neurobehavioral changes in the
treated group. We will determine whether R(+)pramipexole treatment also protects against synaptic and
mitochondrial changes in these monkeys. Together, results from these studies can provide a causal link between
anesthetic exposure, mitochondrial dysfunction, and altered emotional and cognitive behavior in monkeys. They
will also provide a first step towards improved anesthetic protocols and preventative treatments that will allow
children to undergo safe surgery while minimizing unintended long-term effects on the brain and behavior.

## Key facts

- **NIH application ID:** 10831114
- **Project number:** 7R01HD099231-04
- **Recipient organization:** WAKE FOREST UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** MARIA C ALVARADO
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $177,581
- **Award type:** 7
- **Project period:** 2020-06-01 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10831114

## Citation

> US National Institutes of Health, RePORTER application 10831114, Mitochondrial Protection to Prevent Neurobehavioral Changes after Postnatal Anesthesia (7R01HD099231-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10831114. Licensed CC0.

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