Useinovic Nemanja, Newson Adre, Near Michelle, Maksimovic Stefan, Volvovitz Benjamin, Quillinan Nidia, Jevtovic-Todorovic Vesna
Department of Anesthesiology, University of Colorado Anschutz Medical Campus, Aurora, CO, United States.
Neuronal Injury and Plasticity Program, University of Colorado Anschutz Medical Campus, Aurora, CO, United States.
Exp Biol Med (Maywood). 2025 May 16;250:10549. doi: 10.3389/ebm.2025.10549. eCollection 2025.
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.
尽管在动物研究中有充分的文献记载，在突触发生的关键阶段早期接触全身麻醉剂会干扰正常的大脑发育，最终导致认知和情感障碍，但手术干预和/或潜在的全身炎症是否以及如何影响全身麻醉剂的有害作用尚不清楚。一些新出现的证据表明，在接触常用全身麻醉剂之前的无菌性全身炎症会加剧麻醉诱导的神经细胞凋亡并激活炎性小体途径，同时导致认知情感行为受损。为了更好地理解其潜在机制，我们在此关注受损神经元与小胶质细胞之间的多细胞相互作用，因为小胶质细胞是大脑中对压力做出反应的常驻巨噬细胞。我们使用幼鼠（出生后第7天）和最常用的吸入麻醉剂七氟醚，研究小胶质细胞在七氟醚诱导的炎症传播性发育神经毒性中的作用。我们发现，七氟醚暴露会导致幼鼠海马下托出现显著的神经细胞凋亡，在由脂多糖（LPS）注射或创伤（胫骨骨折）引起的全身炎症情况下，这种神经细胞凋亡会加剧。这种加剧不仅体现在神经细胞凋亡的强度上，还体现在其持续时间和发生时间上。我们进一步报告称，七氟醚诱导的神经细胞凋亡会触发小胶质细胞的激活，小胶质细胞进而释放促炎细胞因子MCP-1并上调内皮细胞粘附分子ICAM-1。这导致T淋巴细胞浸润到海马下托，这一事件进一步使小胶质细胞激活持续存在，以试图控制神经细胞凋亡，小胶质细胞耗竭会导致七氟醚诱导的发育性神经细胞凋亡显著恶化这一事实表明了这一点。我们的工作使我们离让动物实验结果与临床情况更相关、从而更具转化性又近了一步。考虑到在没有任何病理过程的情况下接触麻醉极其罕见，这一点至关重要。
