Roflumilast protects against spatial memory impairments and exerts anti-inflammatory effects after transient global cerebral ischemia

J.M. Bonato, E. Meyer, P.S.B. de Mendonca, H. Milani, J. Prickaerts, R.M.W. de Oliveira*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

10 Citations (Web of Science)


Phosphodiesterase 4 (PDE4) inhibitors have been shown to present beneficial effects in cerebral ischemic injury because of their ability to improve cognition and target different phases and mechanisms of cerebral ischemia, including apoptosis, neurogenesis, angiogenesis, and inflammation. The present study investigated whether repeated treatment with the PDE4 inhibitor roflumilast rescued memory loss and attenuated neuroinflammation in rats following transient global cerebral ischemia (TGCI). TGCI caused memory impairments, neuronal loss (reflected by Neuronal nuclei (NeuN) immunoreactivity), and compensatory neurogenesis (reflected by doublecortin (DCX) immunoreactivity) in the hippocampus. Also, increases in the protein expression of the phosphorylated response element-binding protein (pCREB) and inflammatory markers such as the glial fibrillary acidic protein (GFAP) and ionized calcium-binding adaptor molecule 1 (Iba-1), were detected in the hippocampus in TGCI rats. Repeated treatment with roflumilast (0.003 and 0.01 mg/kg) prevented spatial memory deficits without promoting hippocampal protection in ischemic animals. Roflumilast increased the levels of pCREB, arginase-1, interleukin (IL) 4, and IL-10 in the hippocampus 21 days after TGCI. These data suggest a protective effect of roflumilast against functional sequelae of cerebral ischemia, which might be related to its anti-inflammatory properties.
Original languageEnglish
Pages (from-to)1171-1188
Number of pages18
JournalEuropean Journal of Neuroscience
Issue number4
Publication statusPublished - 1 Feb 2021


  • cognitive deficit
  • phosphodiesterase inhibitor
  • roflumilast
  • transient global cerebral ischemia

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