1. 3-Methyladenine attenuates neuroinflammation and improves cognitive function in sepsis-associated encephalopathy by inhibiting autophagy.
- Author
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Zhu T, Yao Y, Ding J, Zhang C, Xia N, Tao Y, Zhang W, Qi H, Gong L, and Jiang P
- Subjects
- Animals, Male, Mice, Disease Models, Animal, Mice, Inbred C57BL, Cytokines metabolism, Hippocampus drug effects, Hippocampus metabolism, Hippocampus pathology, Cognitive Dysfunction drug therapy, Cognitive Dysfunction etiology, Anti-Inflammatory Agents therapeutic use, Anti-Inflammatory Agents pharmacology, Sepsis-Associated Encephalopathy drug therapy, Autophagy drug effects, Adenine analogs & derivatives, Adenine pharmacology, Lipopolysaccharides, Cognition drug effects, Neuroinflammatory Diseases drug therapy, Neuroinflammatory Diseases immunology
- Abstract
Objective: Sepsis-associated encephalopathy (SAE) can lead to severe cerebral dysfunction as well as cognitive dysfunction, resulting in a significant disease burden. 3-Methyladenine (3-MA) has been confirmed to have anti-inflammatory effects on diseases characterized by enhanced autophagy. However, its role in SAE has not been clarified., Methods: An SAE mouse model was generated by intraperitoneal injection of lipopolysaccharide (LPS). Mice were given 5, 20, or 80 mg/kg 3-MA to determine the therapeutic dose. The mice in the different groups were given 20 mg/kg 3-MA or saline, and survival, body temperature, body weight and neurobehavioral scores were measured at different time points. The expression of autophagy-related proteins and inflammatory factors was detected by Western blotting, enzyme linked immunosorbent assay (ELISA) and real-time quantitative polymerase chain reaction (RT-qPCR) 12 h after LPS induction. Glial activation and neuronal injury in the hippocampus were detected by immunofluorescence staining and HE staining. The open Field test, novel object recognition (NOR) test, Y-maze test, and Morris water maze (MWM) test were performed to assess cognitive function., Results: Treatment with 20 or 80 mg/kg 3-MA reduced the increase in hippocampal TNF-α, IL-6, and IL-1β expression in SAE model mice, with 20 mg/kg 3-MA having the greatest therapeutic effect. Treatment with 20 mg/kg 3-MA effectively reduced the expression of hippocampal autophagy-related proteins and mortality, ameliorated hypothermia, decreased body weight and electroencephalography (EEG) performance, and attenuated the activation of neuroglia and neuronal damage. Moreover, it alleviated the cognitive dysfunction 2 weeks after LPS induction., Conclusions: 3-MA reduced neuroglial activation and neuronal damage, attenuated neuroinflammation, and improved cognitive deficits during recovery period by inhibiting autophagy in SAE., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)
- Published
- 2024
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