Pentoxifylline protects against cerebral ischaemia-reperfusion injury through ferroptosis regulation via the Nrf2/SLC7A11/GPX4 signalling pathway

  • Eur J Pharmacol. 2024 Mar 15:967:176402. doi: 10.1016/j.ejphar.2024.176402.
Pei Li  1 ,  Jun-Min Chen  2 ,  Shi-Hao Ge  2 ,  Mei-Lin Sun  3 ,  Jun-Dong Lu  4 ,  Fan Liu  2 ,  Le-Le Wang  2 ,  Xin Zhang  2 ,  Xiao-Peng Wang  5
Affiliations
  • 1. Department of Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000, Hebei, China; Department of Neurology, Tangshan Gongren Hospital, Tangshan, 063000, Hebei, China.
  • 2. Department of Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000, Hebei, China.
  • 3. Department of Neurology, Xingtai People's Hospital, Xingtai, 054001, Hebei, China.
  • 4. Department of Neurology, Baoding First Central Hospital, Baoding, 071000, Hebei, China.
  • 5. Department of Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000, Hebei, China. Electronic address: [email protected].
PMID: 38331339 DOI: 10.1016/j.ejphar.2024.176402
Abstract

Objective: To investigate whether pentoxifylline (PTX) attenuates cerebral ischaemia-reperfusion injury (IRI) in rats by inhibiting Ferroptosis and to explore the underlying molecular mechanisms.

Methods: Cerebral IRI was induced in male Sprague-Dawley (SD) rats using middle cerebral artery occlusion (MCAO). The effects of PTX on cerebral ischaemia-reperfusion brain samples were detected through neurological deficit score, staining and electron microscopy; levels of Ferroptosis biomarkers from brain samples were detected using kits. Additionally, the expression levels of nuclear factor erythroid 2-related factor 2 (Nrf2), Transferrin Receptor protein 1, divalent metal transporter 1, solute carrier family 7 member 11 (SLC7A11) and Glutathione Peroxidase 4 (GPX4) were determined by immunohistochemistry, real-time quantitative polymerase chain reaction and western blotting.

Results: Pre-treatment with PTX was found to improve neurological function, evidenced by reduced neurological deficit scores, decreased infarct volume and alleviated pathological features post-MCAO. This improvement was accompanied by reduced lipid peroxidation levels and mitigated mitochondrial damage. Notably, PTX's inhibitory effect on Ferroptosis was characterised by enhanced Nrf2 nuclear translocation and regulation of ferroptosis-related proteins. Moreover, inhibition of Nrf2 using ML385 (an Nrf2-specific inhibitor) reversed PTX's neuroprotective effect on MCAO-induced Ferroptosis via the SLC7A11/GPX4 signalling pathway.

Conclusions: Ferroptosis is evident following cerebral ischaemia-reperfusion in rats. Pentoxifylline confers protection against IRI in rats by inhibiting Ferroptosis through the Nrf2/SLC7A11/GPX4 signalling pathway.

Keywords
Cerebral ischaemia-reperfusion; Ferroptosis; GPX4; Nrf2; Pentoxifylline; SLC7A11.
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