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Objective To observe the therapeutic effect of inosine on diabetic cognitive impairment (DCI) in rats and to explore its mechanism. Methods SD male rats were randomly divided into the control group, model group, and experimental group, respectively. Rats in the model group and experimental group were treated with high-fat diet combined with the intraperitoneal injection of streptozotocin and were screened out by Morris water maze experiment to obtain the DCI models, except rats in the control group. After successful modeling, rats in the experimental group were intraperitoneally injected with 100 mg/kg inosine, and rats in the control group and the model group were intraperitoneally injected with the same volume of normal saline, once a day, for 4 weeks. Morris water maze test was used to detect the cognitive ability of rats. HE staining was used to observe the morphology of hippocampal neurons. ELISA was used to detect the levels of tumor necrosis factor- α (TNF- α), interleukin (IL)-1β, IL-6, malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px) in hippocampus. RT-PCR and Western blotting were used to detect the mRNA and protein expression levels of phosphatidylinositol-3-kinase (PI3K/protein kinaseB (AKT/mammalian target of rapamycin (mTOR) signaling pathway. Results Compared with the control group, the escape latency increased, and the number of crossing the platform decreased in the model group (both P<0. 05). Compared with the model group, the escape latency decreased, and the number of crossing the platform increased in the experimental group (both P<0. 05). In the model group, the hippocampal neurons were loosely arranged and irregularly shaped, and the number was significantly reduced. The hippocampal neurons of the experimental group were relatively neatly arranged and the morphology was regular, and the number increased. Compared with the control group, the levels of TNF-α, IL-1β, IL-6, and MDA in the hippocampus of the model group increased, and the levels of SOD and GSH-Px decreased (all P<0. 05). Compared with the model group, the levels of TNF-α, IL-1β, IL-6, and MDA in the hippocampus of the experimental group decreased, and the levels of SOD and GSH-Px increased (all P<0. 05). The mRNA expression levels of PI3K, AKT, and mTOR and the protein expression levels of PI3K, p-AKT, and p-mTOR were lower in the model group than in the control group (all P< 0. 05). The mRNA expression levels of PI3K, AKT, and mTOR and the protein expression levels of PI3K, p-AKT, and pmTOR in the experimental group were higher than those in the model group (all P<0. 05). Conclusions Inosine can improve the cognition and learning memory in DCI rats, thus alleviating cognitive impairment. The mechanism may be related to activating PI3K/AKT/mTOR signaling pathway and reducing inflammatory response and oxidative stress. [ABSTRACT FROM AUTHOR]

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