Contemporary Anesthesia Safety Research: New Pathological Mechanism of Fine Motor Deficits in Mice

With the advancement of modern anesthesia techniques, millions of lives rely on successful surgeries each year. However, various clinical studies, including those by the Mayo Anesthesia Safety in Kids (MASK) group, suggest that children who undergo multiple anesthesia exposures may be more susceptible to fine motor control disorders. The underlying mechanisms remain unclear. A new study published in Neurosci. Bull. reveals a novel pathological mechanism associated with fine motor deficits in mice and proposes potential intervention strategies. This research was jointly conducted by several researchers from the State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi Clinical Research Center for Oral Diseases, School of Stomatology, The Fourth Military Medical University, and was accepted on February 17, 2024.

Research Background:

This study focuses on the ERYTHROPOIETIN RECEPTOR (EPOR), a microglial receptor associated with macrophage phagocytic activity, which is significantly downregulated in the medial prefrontal cortex of mice after multiple sevoflurane anesthesia exposures. The key finding is that the inhibited EPO/EPOR signaling axis leads to microglial polarization, excessive excitatory synaptic pruning, and abnormal fine motor control skills in mice after multiple anesthesia exposures. Furthermore, supplementation with the EPO-derived peptide ARA290 via intraperitoneal injection completely reverses these conditions.

Research Method Details:

The researchers randomly grouped newborn mice and applied different treatments to simulate anesthesia exposure and its therapeutic effects. Groups included control, sevoflurane (SEV), and ARA290 treatment groups. Through a series of experiments, such as Golgi staining, transmission electron microscopy observation, Western Blot, and immunofluorescence staining, the researchers analyzed in detail the changes in microglial activity and synaptic pruning. Additionally, RNA sequencing technology was used to analyze differentially expressed genes in the mPFC region of mice after anesthesia exposure, further revealing changes in the EPOR signaling pathway.

Research Results:

The experiments revealed excessive synaptic pruning behavior of microglia after multiple sevoflurane anesthesia exposures, with long-term observation of synaptic and intercellular gap damage. Through intervention treatment, ARA290 effectively reduced microglial activation, decreased abnormal synaptic pruning, and significantly improved fine motor impairment.

Research Significance:

The scientific value of this study lies in proposing new insights into the pathology of early fine motor disorders and providing new therapeutic targets and strategies for treating anesthesia-induced neurotoxicity in the perioperative period. This research not only emphasizes the importance of focusing on the potential impact of anesthesia on children’s brain development in clinical practice but may also change future treatment approaches for related neurodevelopmental disorders.

Research Features:

This study is the first to analyze the impact of a specific receptor (EPOR) on early fine motor disorders from the perspective of microglia, demonstrating notable novelty and innovative experimental design. The validation of ARA290 as a potential drug further indicates that targeting the EPO/EPOR signaling pathway may become a new therapy against anesthesia-induced neurotoxicity.

This research provides new scientific evidence for understanding the potential neurodevelopmental risks of perioperative anesthesia in children and proposes specific research approaches and treatment strategies to prevent or mitigate these risks.