Abstract
Cognitive dysfunction is one of the most common postoperative complications experienced by older patients after anesthesia and surgery but the cause remains unknown. Immune molecules are essential for many aspects of neural homeostasis, including learning and memory, and an imbalance in immune neuromodulators is implicated in the development of neural dysfunction. Aging alters the control of neuroinflammatory cascades and general anesthetics are immunosuppressants. Therefore, we hypothesized that general anesthesia disturbs neuroimmune signaling in an age-dependent fashion. We tested this hypothesis by examining gene expression of key immune neuromodulators including IL-1β, TNFα, and CCL2 in the hippocampus of young adult (3 mo) and aged (20 mo) mice following isoflurane anesthesia. We show that isoflurane anesthesia increases expression of these signaling molecules in the hippocampus of young adult mice but decreases it in the hippocampus of old mice. Furthermore, anesthetized old mice had an amplified hippocampal neuroimmune response to systemically administered lipopolysaccharide compared to age-matched carrier controls. Together, these data indicate that isoflurane anesthesia disrupts hippocampal neuroimmune mediator gene expression in the old brain and suggests a potential mechanism by which general anesthesia can contribute to disordered neuronal homeostasis and post-anesthesia cognitive disability in older subjects.
Highlights
Data Availability Statement: All relevant data are within the manuscript and its Supporting Information files
Confirming previous studies, we found age-dependent differences in the levels of immune neuromodulators, with expression of interleukin 1β (IL-1β) and CCL2 being 2–4 fold greater in the hippocampus of aged compared to young controls whereas interleukin 10 (IL10) is ~50% lower (Table 2)
We demonstrate that isoflurane anesthesia leads to marked and enduring suppression of IL1β, tumor necrosis factor α (TNFα), and CCL2 expression in the hippocampus, but not frontal cortex, of aged mice, but amplifies the acute hippocampal TNFα and CCL2 responses to peripheral LPS
Summary
MiceThe Harvard/BWH Institutional Animal Care and Use Committee approved the protocol and all experiments were conducted according to regulations set forth by the Harvard Medical School and Brigham and Women’s Hospital Standing Committee on Animals. Young adult (3 mo) and aged (20 mo) male C57BL/6 mice were purchased from Charles River Laboratory (Wilmington, MA) and housed 4 per cage at constant temperature and humidity with a regular light-dark cycle and had access to both food and water ad libitum. Both young adult and aged spontaneously breathing male mice were prospectively randomized to treatment condition and experimental groups were balanced by litter. We chose 3 h to investigate acute recovery and 48 h because we have demonstrated previously that aged rodents have a working memory deficit at this time whereas young adult animals do not [10, 21]
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