Scopolamine-induced Delirium Promotes Neuroinflammation and Neuropsychiatric Disorder in Mice

Abstract

BackgroundPostoperative delirium is a common neuropsychiatric syndrome resulting in a high postsurgical mortality rate and decline in postdischarge function. Extensive research has been performed on both human and animal delirium models due to their clinical significance, focusing on systemic inflammation and consequent neuroinflammation playing a key in the pathogenesis of postoperative cognitive dysfunctions. Since animal models are widely utilized for pathophysiological study of neuropsychiatric disorders, this study aimed at examining the validity of the scopolamine-induced delirium mice model with respect to the neuroinflammatory hypothesis of delirium. MethodsMale C57BL/6 mice were treated with intraperitoneal scopolamine (2 mg/kg). Neurobehavioural tests were performed to evaluate the changes in cognitive functions, including learning and memory, and the level of anxiety after surgery or scopolamine treatment. The levels of pro-inflammatory cytokines (IL-1ꞵ, IL-18, and TNF-α) and inflammasome components (NLRP3, ASC, and caspase-1) in different brain regions were measured. Gene expression profiles were also examined using whole-genome RNA sequencing analyses to compare gene expression patterns of different mice models.Results Scopolamine treatment showed significant increase in the level of anxiety and impairments in memory and cognitive function associated with increased level of pro-inflammatory cytokines and NLRP3 inflammasome components. Genetic analysis confirmed the different expression patterns of the genes involved in immune response and inflammation and those related with the development of the nervous system in both surgery and scopolamine-induced mice models. Conclusions The scopolamine-induced delirium mice model successfully showed that analogous neuropsychiatric changes coincide with the neuroinflammatory hypothesis for pathogenesis of delirium.

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“…In the present study, scopolamine-treated mice showed a significant increase in COX-2 activity which was reduced by pretreatment with the S2 extract. The NLRP3 inflammasome, an intracellular sensor that detects a broad range of microbial motifs, increases the levels of pro-inflammatory cytokines such as IL-1β in the brain [ 33 ], promotes the aggregation of innate immune cells, such as microglia, initiates the downstream inflammatory cascade, and accelerates the pathological progression of neurodegenerative diseases [ 34 ]. Its activation has been used as a marker for mobilizing immune defense mechanisms in various inflammatory diseases and the development of neurodegenerative disorders.…”