Fingolimod alleviates type 2 diabetes associated cognitive decline by regulating autophagy and neuronal apoptosis via AMPK/mTOR pathway.

This study aimed to reveal the role of fingolimod (FTY720) in mice with type 2 diabetes-associated cognitive decline and explore its potential neuroprotective mechanism. Mice were divided into five groups: normal control, normal control + FTY720 (1.0 mg/kg/day), type 2 diabetes mellitus, type 2 diabetes mellitus + low-dose FTY720 (0.5 mg/kg/day), and type 2 diabetes mellitus + high-dose FTY720 (1.0 mg/kg/day). Different doses of FTY720 were administered daily for 8 weeks after the induction of type 2 diabetes using a four-week high-fat diet feeding combined with continuous low-dose intraperitoneal injections of streptozotocin. After 8 weeks of treatment, the body weights and fasting blood glucose levels of mice from the five groups were compared. Morris water maze and new object recognition tests were used to evaluate cognitive function. Pathological changes in the hippocampal CA1 region were observed using haematoxylin-eosin and Nissl staining, and the ultrastructure of the hippocampal neurones was assessed using transmission electron microscopy. The expression levels of autophagy- and apoptosis-related proteins, such as LC3, Beclin-1, P62, Bax, and Bcl-2, in the mice hippocampus were detected by western blotting. Simultaneously, AMPK/mTOR signaling pathway proteins were detected to understand the potential mechanism. FTY720 had no significant effect on the body weight or fasting blood glucose levels in mice with type 2 diabetes. However, both FTY720 doses improved the cognitive function and hippocampal damage. In addition, the results suggested that FTY720 dramatically decreased P62 and Bax levels and increased LC3 II/LC3 I ratio, Beclin-1, and Bcl-2 expression in the hippocampus of type 2 diabetic mice. FTY720 also affected the expression of the AMPK/mTOR signaling pathway. Thus, FTY720 improved cognitive function and hippocampal pathological changes in type 2 diabetic mice without affecting fasting blood glucose levels. Our results show that FTY720 may exert neuroprotective effects in vivo by enhancing hippocampal autophagy and inhibiting apoptosis via the AMPK/mTOR signaling pathway.

Li J ，Yin M ，Wang Z ，Xiong Y ，Fang X ，Fang H ... -  《-》

Tangzhiqing decoction attenuates cognitive dysfunction of mice with type 2 diabetes by regulating AMPK/mTOR autophagy signaling pathway.

Yao W ，Zhang Q ，Zhao Y ，Xu X ，Zhang S ，Wang X ... -  《-》

Liraglutide ameliorates cognitive decline by promoting autophagy via the AMP-activated protein kinase/mammalian target of rapamycin pathway in a streptozotocin-induced mouse model of diabetes.

Diabetic cognitive dysfunction has gained widespread attention for its deleterious impact on individuals with diabetes. However, few clinical interventions are available to prevent the disorder. The glucagon-like peptide-1 analog liraglutide exerts neuroprotective effects in several models of neurodegenerative diseases. We investigated the effect of liraglutide pretreatment on diabetes-induced cognitive decline and explored the underlying mechanisms in vivo and in vitro. Liraglutide pretreatment prevented diabetes-induced cognitive impairment as assessed by the Morris Water Maze test, and alleviated neuronal injuries and ultrastructural damage to synapses in the hippocampal CA1 region. Furthermore, liraglutide promoted autophagy as indicated by enhanced expression of the autophagy markers Microtubule-associated protein 1 light chain 3 (LC3)-II and Beclin 1, decreased expression of p62, and increased formation of autophagic vacuoles and LC3-II aggregates. In vitro, liraglutide treatment elevated phosphorylated (p)-AMP-activated protein kinase (AMPK) levels and reduced p-mammalian target of rapamycin (p-mTOR) expression. Additionally, the AMPK inhibitor Compound C exhibited an inhibitory effect on liraglutide-induced increased LC3-II expression and p62 degradation. Liraglutide exhibits neuroprotective effects against diabetes-induced hippocampal neuronal injuries and cognitive impairment by promoting autophagy via the AMPK/mTOR pathway.

Kong FJ ，Wu JH ，Sun SY ，Ma LL ，Zhou JQ ... -  《-》

[Mechanism of Guben Jiannao Liquid on Alzheimer's disease by regulating autophagy based on LKB1/AMPK/mTOR pathway].

Zhang JF ，Long QH ，Zeng CH ，Chen YM ，Xie ZY ，Cai YQ ，Wang X ... -  《-》

Based on Bioinformatics to Explore the Mechanism of "Tangzhiqing" Decoction Alleviating Type 2 Diabetes-associated Cognitive Dysfunction in Mice by Regulating Hippocampal Neuron Apoptosis and Autophagy.

Diabetic cognitive dysfunction (DCD) is emerging as a chronic complication of diabetes that is gaining increasing international recognition. The traditional Chinese medicine (TCM) formulation, Tangzhiqing decoction (TZQ), has shown the capacity to modulate the memory function of mice with DCD by ameliorating insulin resistance. Nevertheless, the precise mechanism underlying the effects of TZQ remains elusive. The chemical constituents of TZQ were screened using TCMSP databases, and DCDassociated disease targets were retrieved from various databases. Subsequently, core targets were identified through network topology analysis. The core targets underwent analysis using Gene Ontology (GO) functional annotations and enrichment in the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. Models were established through high-fat and high-glucose diet feeding along with intraperitoneal injection of streptozotocin (STZ). TZQ and metformin were administered at varying doses over 8 weeks. The Morris water maze was employed to evaluate the cognitive capabilities of each rat group, while indicators of oxidative stress and insulin were assessed in mice. Neuronal apoptosis in distinct groups of mice's hippocampi was detected using TdT-mediated dUTP Nick-End Labeling (TUNEL), and western blot (WB) analysis was conducted to assess the expression of apoptosis- and autophagy-related proteins, including Bax, Bcl2, Caspase3, Caspase8, Beclin1, ATG7, LC3, p62, and Lamp2, within the hippocampus. TZQ exhibited the capacity to modulate neuronal autophagy, ameliorate endoplasmic reticulum stress, apoptosis, inflammation, and oxidative stress, as well as to regulate synaptic plasticity and conduction. TZQ mitigated cognitive dysfunction in mice, while also regulating hippocampal inflammation and apoptosis. Additionally, it influenced the protein expression of autophagy-related factors such as Bax, Bcl2, Caspase3, Caspase8, Beclin1, ATG7, and LC3. Notably, this modulation significantly reduced neuronal apoptosis in the hippocampus and curbed excessive autophagy. TZQ demonstrated a substantial reduction in neuronal apoptosis within the hippocampus and effectively suppressed excessive autophagy.

Shi Y ，Sheng P ，Zhao Y ，Wang X ，Xu X ，Sun S ... -  《-》