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

Authors

Xiaohan Wang, Bingchuan Xie, Xiaoyang Yuan, Jiaying Rong, Xiaojing Lv, Qingying Ma, Li Shen, Bing Han

Published in

Metabolic brain disease. Volume 41. Issue 1. Jul 23, 2026. Epub Jul 23, 2026.

Abstract

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.

PMID:
42489766
Bibliographic data and abstract were imported from PubMed on 23 Jul 2026.

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