TNF-α Inhibition Modulates CX3CR1, Pyroptosis-related Genes, and BDNF to Alleviate Anxiety-like Behavior in Type 2 Diabetic Rats

Background: Type 2 diabetes is strongly associated with neuroinflammation and neurodegeneration in the hippocampus, yet the underlying mechanisms are not fully understood. This study seeks to address this gap by exploring the role of TNF-α in modulating behavior, fractalkine (CX3CL1) signaling, and pyroptosis-related pathways in the hippocampus of streptozotocin (STZ)-nicotinamide (NA)-induced diabetic rats, thereby providing insights into potential therapeutic targets for diabetes-induced neuroinflammation. Methods: Male Sprague Dawley rats (10-12 weeks old) were assigned to three groups: the etanercept-treated diabetic (DE) group, diabetic control (DC) group, and normal control (NC) group. Type 2 diabetes was induced via intraperitoneal injections of STZ and NA, with fasting blood glucose levels > 200 mg/dL confirming the condition. Etanercept was administered biweekly. Anxiety-like behavior and locomotor activity were evaluated using the open field test. After ten weeks, the rats were sacrificed, and the hippocampal tissues were dissected for immunohistochemical analysis of GFAP, CX3CR1, CX3CL1, BDNF expression, as well as qPCR, to quantify pyroptosis-related gene expression. Results: TNF-α inhibition through etanercept treatment attenuated anxiety-like behavior, reduced GFAP and CX3CR1 expression, and lowered the levels of pyroptosis-related genes (Il-1b, Il-18, Nlrp3) in the hippocampus of diabetic rats, whereas CX3CL1 expression remained unaffected. Additionally, etanercept treatment increased BDNF expression in the hippocampus, suggesting a potential neuroprotective effect. Conclusion: This study suggests that TNF-α inhibition decreases hippocampal GFAP, CX3CR1, and pyroptosis-related gene expression, while enhancing BDNF. These changes may contribute to reduced anxiety-like behavior, highlighting a potential neuroprotective role of TNF-α inhibition in type 2 diabetes. © The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2025.