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

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

  • J Neuroimmune Pharmacol. 2025 Apr 3;20(1):31. doi: 10.1007/s11481-025-10193-7.
Tahir Ali # 1 2,  Yanhua Luo # 3,  Chengyou Zheng 3 4,  Shafiq Ur Rahman 5,  Iram Murtaza 6,  Jinxing Feng 7,  Shupeng Li 8 9
Affiliations

Affiliations

  • 1 Institute of Chemical Biology, Shenzhen Bay Laboratory, Shenzhen, China. tali@bs.qau.edu.pk.
  • 2 State Key Laboratory of Chemical Oncogenomics, Guangdong Provincial Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen, Guangdong, PR China, 518055. tali@bs.qau.edu.pk.
  • 3 State Key Laboratory of Chemical Oncogenomics, Guangdong Provincial Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen, Guangdong, PR China, 518055.
  • 4 Department of Neonatology, Shenzhen Children'S Hospital, Shenzhen, China.
  • 5 Department of Pharmacy, Shaheed Benazir Bhutto, University, Dir 18000, Sheringal, KP, Pakistan.
  • 6 Signal Transduction Laboratory, Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, 45320, Pakistan.
  • 7 Department of Neonatology, Shenzhen Children'S Hospital, Shenzhen, China. szfjx2013@hotmail.com.
  • 8 Institute of Chemical Biology, Shenzhen Bay Laboratory, Shenzhen, China. lisp@pku.edu.cn.
  • 9 State Key Laboratory of Chemical Oncogenomics, Guangdong Provincial Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen, Guangdong, PR China, 518055. lisp@pku.edu.cn.
  • # Contributed equally.
PMID: 40175765 DOI: 10.1007/s11481-025-10193-7
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.

Keywords

LPS; Neuroinflammation; PTEN; PTX; TrkB/BDNF.

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