Aerobic exercise improves the high-fat diet/streptozotocin-induced depression-like behaviors by reducing hippocampal neuroinflammation through suppressing the BTK/NF-κB signaling pathway.

BACKGROUND

Aerobic exercise can help reduce depression symptoms by alleviating hippocampal neuron injury and neuroinflammation. However, the specific mechanisms by which aerobic exercise inhibits neuroinflammation in individuals with diabetes-related depression are not fully understood.

METHODS

This study subjected high-fat diet/streptozotocin (HFD/STZ)-induced type 2 diabetic mice to five weeks of moderate-intensity aerobic treadmill training. Two publicly available GEO datasets were then analyzed to identify differentially expressed genes (DEGs) in the hippocampus of type 2 diabetic rodent models. Subsequently, we conducted a comprehensive batch query using the connectivity map (CMap), which led to the identification of Bruton tyrosine kinase (BTK) inhibitors as the most promising candidates for therapeutic intervention.

RESULTS

In high glucose/palmitate (HG/PA)-treated BV2 microglial cells, the BTK inhibitor acalabrutinib inactivated nuclear factor kappa B (NF-κB) and attenuated microglial activation. Systemic administration of acalabrutinib two weeks after the onset of diabetes inactivated the BTK/NF-κB signaling pathway, reduced microglial activation and neuroinflammation in the hippocampus, and led to an improvement in depression-like behaviors in type 2 diabetic mice. Additionally, aerobic exercise was found to inactivate the BTK/NF-κB pathway in the hippocampus of type 2 diabetic mice. The results showed that exercise training decreased depression-like behaviors and reduced microglial activation and neuroinflammation in the hippocampus, effects that were largely blocked by systemic administration of an NF-κB activator.

CONCLUSIONS

Overall, the findings indicate that aerobic exercise could alleviate type 2 diabetes-associated depression by reducing microglial activation and neuroinflammation in the hippocampus, primarily through suppression of the BTK/NF-κB pathway. BTK is identified as a druggable target for the treatment of type 2 diabetes-associated depression.