Promotion of neuroinflammation by the glymphatic system: a new insight into ethanol extracts from Alisma orientale in alleviating obesity-associated cognitive impairment

Background: Obesity is one of the critical risk factors for cognitive dysfunction. The glymphatic system (GS) plays a key role in the pathogenesis of cognitive deficits. Alisma orientale has been shown to have anti-inflammatory and antihyperlipidemic effects, whereas its effects and underlying mechanisms on obesity-associated cognitive impairment (OACI) are unclear. Purpose: This work aims to decipher the mechanism of ethanol extracts from Alisma orientale (EEAO) in restoring cognitive impairment in HFD-induced obese mice through a GS approach. Methods: The restoration of abnormal glucose/lipid metabolism and excess adipose deposition by EEAO were assayed by biochemical analysis and visually displayed by a micro-CT scanner and Oil Red O staining. Biochemical assays and Western blotting (WB) were used to measure cerebral blood flow (CBF), free fatty acid (FFAs) levels and the structural integrity of the blood-brain barrier (BBB). Microglial activation and neuro -inflammation were assessed with immunohistochemistry staining, ELISA and WB. Moreover, GS function was determined by immunofluorescence staining, fluorescence tracer imaging and WB. Finally, the neuropathological features and cognitive functions were detested with immunohistochemistry staining, immunofluorescence and Morris Water Maze. Results: EEAO not only alleviated body weight, cerebral lipid accumulation and serum FFAs in HFD-induced obese mice, but also increased CBF and BBB integrity. EEAO suppressed microglial activation and lipid depo-sition in the hippocampus and reduced the level of inflammatory cytokines including IL-6, IL-113 and TNF-alpha in brain tissue. Interestingly, long-term HFD-induced GS dysfunction was significantly restored after EEAO intervention, and neuropathological lesions and cognitive deficits were also markedly rescued. Conclusion: EEAO rescued the cognitive deficits of OACI by inhibiting neuroinflammation and restoring GS dysfunction, indicating a potential remedy for OACI.