Abstract
Sepsis-associated encephalopathy induces cognitive dysfunction via mechanisms that commonly involve neuroinflammation and synaptic plasticity impairment of the hippocampus. The β2-adrenoceptor (β2-AR) is a G-protein coupled receptor that regulates immune response and synaptic plasticity, whereas its dysfunction has been implicated in various neurodegenerative diseases. Thus, we hypothesized abnormal β2-AR signaling is involved in sepsis-induced cognitive impairment. In the present study, C57BL/6 mice were subjected to cecal ligation and puncture (CLP) to mimic the clinical human sepsis-associated encephalopathy. The levels of hippocampal β2-AR, proinflammatory cytokines tumor necrosis factor (TNF-α), interleukin-1β (IL-1β), IL-6, cAMP-response element binding protein (CREB), brain derived neurotrophic factor (BDNF), post-synaptic density protein 95 (PSD95), and NMDA receptor 2 B subtypes (GluN2B) were determined at 6, 12, 24 h and 7 and 16 days after CLP. For the interventional study, mice were treated with β2-AR agonist clenbuterol in two ways: early treatment (immediately following CLP) and delayed treatment (on the 8th day following CLP). Neurobehavioral performances were assessed by open field and fear conditioning tests. Here, we found that hippocampal β2-AR expression was significantly decreased starting from 12 h and persisted until 16 days following CLP. Besides, sepsis mice also exhibited increasing neuroinflammation, down-regulated CREB/BDNF, decreasing PSD95 and GluN2B expression, and displayed hippocampus-dependent cognitive impairments. Notably, early clenbuterol treatment alleviated sepsis-induced cognitive deficits by polarizing microglia toward an anti-inflammatory phenotype, reducing proinflammatory cytokines including IL-1β, TNF-α, and up-regulating CREB/BDNF, PSD95, and GluN2B. Intriguingly, delayed clenbuterol treatment also improved cognitive impairments by normalization of hippocampal CREB/BDNF, PSD95, and GluN2B. In summary, our results support the beneficial effects of both early and delayed clenbuterol treatment, which suggests that activation of β2-AR has a translational value in sepsis-associated organ dysfunction including cognitive impairments.
Highlights
Sepsis is defined as the host’s reaction to infection and characterized by a systemic inflammatory response with important clinical implications (Singer et al, 2016)
We aimed to investigated whether abnormal β2-AR signaling is involved in sepsis-induced cognitive impairments induced by cecal ligation and perforation (CLP)
When compared with sham group, the expressions of inflammatory mediators sush as IL-1β, TNF-α, and IL-6 in the hippocampus were dramatically increased in CLP group: the level of IL-1β rose significantly at 12, 24 h and 7 days following CLP (F5,12 = 4.948, p = 0.011; Figure 2A); the IL-6 increased at 12 h following CLP (F5,12 = 3.969, p = 0.023; Figure 2A) while the TNF-α increased at 24 h following CLP (F5,12 = 7.330, p = 0.002; Figure 2A)
Summary
Sepsis is defined as the host’s reaction to infection and characterized by a systemic inflammatory response with important clinical implications (Singer et al, 2016). Sepsisassociated encephalopathy (SAE) represents diffuse cerebral dysfunction during sepsis, which frequently develops long-term cognitive impairments, including attention, memory, executive function, and speed of information processing (Gofton and Young, 2012), and some skills do not be improved completely in septic patients after 1 or 2 years of follow-up (Comim et al, 2012), which is associated with poor patient outcomes, such as prolonged hospital stay, reduced quality of life, loss of social dependence, and even increased mortality (Zhang et al, 2014; Pan et al, 2019). There is no specific therapy for sepsis-induced cognitive impairments (Robba et al, 2018), in part because of our limited knowledge of its underlying pathophysiological mechanisms. It has been demonstrated that hippocampus damage strongly destroys various kinds of learning and memory (Zheng et al, 2015)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
