Anesthesia-induced developmental neurotoxicity in the setting of systemic inflammation: the role of microglia
Although it is well documented in animal research that an early exposure to general anesthetics during critical stages of synaptogenesis disturbs normal brain development ultimately leading to cognitive and affective impairments, it is less clear whether and how surgical interventions and/or underly...
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Frontiers Media S.A.
2025-05-01
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| Series: | Experimental Biology and Medicine |
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| Online Access: | https://www.ebm-journal.org/articles/10.3389/ebm.2025.10549/full |
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| author | Nemanja Useinovic Adre Newson Michelle Near Stefan Maksimovic Benjamin Volvovitz Nidia Quillinan Nidia Quillinan Vesna Jevtovic-Todorovic |
| author_facet | Nemanja Useinovic Adre Newson Michelle Near Stefan Maksimovic Benjamin Volvovitz Nidia Quillinan Nidia Quillinan Vesna Jevtovic-Todorovic |
| author_sort | Nemanja Useinovic |
| collection | DOAJ |
| description | Although it is well documented in animal research that an early exposure to general anesthetics during critical stages of synaptogenesis disturbs normal brain development ultimately leading to cognitive and affective impairments, it is less clear whether and how surgical interventions and/or underlying systemic inflammation impact the detrimental effects of general anesthetics. Some emerging evidence suggests that aseptic systemic inflammation preceding exposure to the commonly used general anesthetics worsens anesthesia-induced neuroapoptosis and activates inflammasome pathways while resulting in impaired cognitive-affective behaviors. To improve our understanding of the underlying mechanisms, here we focused on multicellular interactions between damaged neurons and microglia since microglia is the resident macrophages within the brain that respond to stress. Using infant rats (post-natal day 7) and most commonly used inhaled anesthetic, sevoflurane, we examine microglia role in sevoflurane-induced inflammation-propagated developmental neurotoxicity. We show that sevoflurane exposure leads to a significant neuroapoptosis in young rat pup hippocampal subiculum, a neuroapoptosis that is worsened in the setting of systemic inflammation caused by either lipopolysaccharide (LPS) injection or trauma (tibial fracture). The worsening is not only shown in terms of the intensity of neuroapoptosis but in its duration and onset. We further report that sevoflurane-induced neuroapoptosis triggers activation of microglia, which in turn releases proinflammatory cytokine MCP-1 and upregulates endothelial cell adhesion molecule, ICAM-1. This leads to T-lymphocyte infiltration in the hippocampal subiculum, an event that further perpetuates microglia activation in an attempt to control neuroapoptosis which is suggested by the fact that microglia depletion leads to a significant worsening of sevoflurane-induced developmental neuroapoptosis. Our work gets us a step closer to making our animal work more relevant to the clinical setting and hence more translational. This is vitally important considering that exposure to anesthesia is exceedingly rare in the absence of any kind of a pathological process. |
| format | Article |
| id | doaj-art-ced0a32a9f6f4cc49a898b453a3a855b |
| institution | DOAJ |
| issn | 1535-3699 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Experimental Biology and Medicine |
| spelling | doaj-art-ced0a32a9f6f4cc49a898b453a3a855b2025-08-20T03:10:27ZengFrontiers Media S.A.Experimental Biology and Medicine1535-36992025-05-0125010.3389/ebm.2025.1054910549Anesthesia-induced developmental neurotoxicity in the setting of systemic inflammation: the role of microgliaNemanja Useinovic0Adre Newson1Michelle Near2Stefan Maksimovic3Benjamin Volvovitz4Nidia Quillinan5Nidia Quillinan6Vesna Jevtovic-Todorovic7Department of Anesthesiology, University of Colorado Anschutz Medical Campus, Aurora, CO, United StatesDepartment of Anesthesiology, University of Colorado Anschutz Medical Campus, Aurora, CO, United StatesDepartment of Anesthesiology, University of Colorado Anschutz Medical Campus, Aurora, CO, United StatesDepartment of Anesthesiology, University of Colorado Anschutz Medical Campus, Aurora, CO, United StatesDepartment of Anesthesiology, University of Colorado Anschutz Medical Campus, Aurora, CO, United StatesDepartment of Anesthesiology, University of Colorado Anschutz Medical Campus, Aurora, CO, United StatesNeuronal Injury and Plasticity Program, University of Colorado Anschutz Medical Campus, Aurora, CO, United StatesDepartment of Anesthesiology, University of Colorado Anschutz Medical Campus, Aurora, CO, United StatesAlthough it is well documented in animal research that an early exposure to general anesthetics during critical stages of synaptogenesis disturbs normal brain development ultimately leading to cognitive and affective impairments, it is less clear whether and how surgical interventions and/or underlying systemic inflammation impact the detrimental effects of general anesthetics. Some emerging evidence suggests that aseptic systemic inflammation preceding exposure to the commonly used general anesthetics worsens anesthesia-induced neuroapoptosis and activates inflammasome pathways while resulting in impaired cognitive-affective behaviors. To improve our understanding of the underlying mechanisms, here we focused on multicellular interactions between damaged neurons and microglia since microglia is the resident macrophages within the brain that respond to stress. Using infant rats (post-natal day 7) and most commonly used inhaled anesthetic, sevoflurane, we examine microglia role in sevoflurane-induced inflammation-propagated developmental neurotoxicity. We show that sevoflurane exposure leads to a significant neuroapoptosis in young rat pup hippocampal subiculum, a neuroapoptosis that is worsened in the setting of systemic inflammation caused by either lipopolysaccharide (LPS) injection or trauma (tibial fracture). The worsening is not only shown in terms of the intensity of neuroapoptosis but in its duration and onset. We further report that sevoflurane-induced neuroapoptosis triggers activation of microglia, which in turn releases proinflammatory cytokine MCP-1 and upregulates endothelial cell adhesion molecule, ICAM-1. This leads to T-lymphocyte infiltration in the hippocampal subiculum, an event that further perpetuates microglia activation in an attempt to control neuroapoptosis which is suggested by the fact that microglia depletion leads to a significant worsening of sevoflurane-induced developmental neuroapoptosis. Our work gets us a step closer to making our animal work more relevant to the clinical setting and hence more translational. This is vitally important considering that exposure to anesthesia is exceedingly rare in the absence of any kind of a pathological process.https://www.ebm-journal.org/articles/10.3389/ebm.2025.10549/fulltibial fractureneonatal ratssevofluranelipopolysaccharidemicroglianeuroinflammation |
| spellingShingle | Nemanja Useinovic Adre Newson Michelle Near Stefan Maksimovic Benjamin Volvovitz Nidia Quillinan Nidia Quillinan Vesna Jevtovic-Todorovic Anesthesia-induced developmental neurotoxicity in the setting of systemic inflammation: the role of microglia Experimental Biology and Medicine tibial fracture neonatal rats sevoflurane lipopolysaccharide microglia neuroinflammation |
| title | Anesthesia-induced developmental neurotoxicity in the setting of systemic inflammation: the role of microglia |
| title_full | Anesthesia-induced developmental neurotoxicity in the setting of systemic inflammation: the role of microglia |
| title_fullStr | Anesthesia-induced developmental neurotoxicity in the setting of systemic inflammation: the role of microglia |
| title_full_unstemmed | Anesthesia-induced developmental neurotoxicity in the setting of systemic inflammation: the role of microglia |
| title_short | Anesthesia-induced developmental neurotoxicity in the setting of systemic inflammation: the role of microglia |
| title_sort | anesthesia induced developmental neurotoxicity in the setting of systemic inflammation the role of microglia |
| topic | tibial fracture neonatal rats sevoflurane lipopolysaccharide microglia neuroinflammation |
| url | https://www.ebm-journal.org/articles/10.3389/ebm.2025.10549/full |
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