{Reference Type}: Journal Article
{Title}: 3-Methyladenine attenuates neuroinflammation and improves cognitive function in sepsis-associated encephalopathy by inhibiting autophagy.
{Author}: Zhu T;Yao Y;Ding J;Zhang C;Xia N;Tao Y;Zhang W;Qi H;Gong L;Jiang P;
{Journal}: Int Immunopharmacol
{Volume}: 139
{Issue}: 0
{Year}: 2024 Sep 30
{Factor}: 5.714
{DOI}: 10.1016/j.intimp.2024.112744
{Abstract}: <B>OBJECTIVE: </B>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.<BR><B>METHODS: </B>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.<BR><B>RESULTS: </B>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.<BR><B>CONCLUSIONS: </B>3-MA reduced neuroglial activation and neuronal damage, attenuated neuroinflammation, and improved cognitive deficits during recovery period by inhibiting autophagy in SAE.