Pentoxifylline Prevents Neuroinflammation and Modifies PTEN/TrkB Signaling in an LPS-Induced Depression Model.

Abstract

Neuroinflammation affects patients with major depressive disorder and is linked to severe, treatment-resistant symptoms, making it a promising therapeutic target for improving depressive symptoms. This study highlighted the neuroprotective role of pentoxifylline (PTX) against lipopolysaccharide (LPS)-induced neuroinflammation and associated behavioral deficits. Mice were injected with LPS (1 mg/kg, i.p) to induce neuroinflammation and treated with PTX (10 mg/kg, i.p). Behavioral and biochemical analyses were performed to evaluate depressive-like behaviors and examine hippocampal protein expression associated with neuroinflammation and synaptic plasticity. LPS administration increased proinflammatory cytokine production (IL-1, IL6, and TNF-α), microglial activation (IBA-1/GFAP), and dysregulation of key synaptic proteins, including BDNF and TrkB, in the hippocampus of mice. Concomitantly, LPS reduced Phosphatase and tensin homolog (PTEN) phosphorylation, potentially contributing to increased neuroinflammation. PTX treatment effectively attenuated LPS-induced effects by suppressing inflammatory responses, restoring BDNF/TrkB signaling, and rescuing synaptic impairments. Mechanistically, PTX treatment increased PTEN phosphorylation and was reversed by the TrkB inhibitor K252a, suggesting that PTX upregulates TrkB/BDNF signaling, leading to increased PTEN phosphorylation and subsequent inhibition of PTEN activity. These findings highlight the potential of PTX as a therapeutic agent for neuroinflammatory conditions, possibly exerting its effects by modulating the PTEN/TrkB/BDNF signaling axis and suggest a novel mechanism of action involving the modulation of the PTEN/TrkB/BDNF signaling pathway.