Pentoxifylline targets TLR4/MyD88/NF-κB signaling to ameliorate neuroinflammation and metabolic dysfunction in a rat model of chronic hypoperfusion-induced vascular cognitive impairment.

Vascular cognitive impairment (VCI) driven by chronic cerebral hypoperfusion lacks disease-modifying therapy. We tested whether pentoxifylline (PTX), a methylxanthine phosphodiesterase inhibitor with dual hemorheological and anti-inflammatory properties, attenuates VCI-like cognitive and inflammatory abnormalities in a rat model. Three-month-old male Sprague-Dawley rats underwent bilateral common carotid artery occlusion (BCCAO) or sham surgery. PTX (60 mg kg⁻1 day⁻1, gavage) or vehicle was administered for 28 days starting 24 h post-operation. Spatial cognition was assessed with the Morris water maze; neuronal injury, microglial activation, and glucose metabolism were evaluated by histology, immunofluorescence, 1⁸F-FDG PET/CT, and western blotting. Systemic and hippocampal cytokines were quantified by multiplex immunoassay; TLR4/MyD88/NF-κB signaling was profiled by RNA-seq and western blotting. BCCAO induced progressive cognitive deficits without sustained weight loss, paralleled by CA1 neuronal damage, microglial proliferation, and marked elevations of IL-1β, IL-2, IL-17, and TNF-α in plasma and hippocampus. PTX shortened escape latency, restored probe-trial platform crossings, preserved neuronal morphology, suppressed microglial Iba-1⁺/Ki67⁺ expansion, and reduced all four cytokines. Mechanistically, PTX down-regulated TLR4, MyD88, and NF-κB p65 mRNA and protein, reduced nuclear translocation of NF-κB p65, and partially reversed frontal and hippocampal glucose hypometabolism. Peripheral IL-1β and IL-17 levels correlated positively with cognitive impairment. Pentoxifylline concurrently mitigates hypoperfusion-associated neuroinflammation, neuronal injury, and glucose hypometabolism via inhibition of the TLR4/MyD88/NF-κB axis, supporting PTX as a readily translatable candidate for early VCI intervention.