Neuroprotection by the PARP inhibitor PJ34 modulates cerebral and circulating RAGE levels in rats exposed to focal brain ischemia

Rosaria Greco, Cristina Tassorelli, Antonina Stefania Mangione, Giovanna Levandis, Michelangelo Certo, Giuseppe Nappi, Giacinto Bagetta, Fabio Blandini, Diana Amantea

Research output: Contribution to journalArticlepeer-review

Abstract

The receptor for advanced glycation end products (RAGE) has a potential role as a damage-sensing molecule; however, to date, its involvement in the pathophysiology of stroke and its modulation following neuroprotective treatment are not completely understood. We have previously demonstrated that expression of distinct RAGE isoforms, recognized by different antibodies, is differentially modulated in the brain of rats subjected to focal cerebral ischemia. Here, we focus on the full-length membrane-bound RAGE isoform, showing that its expression is significantly elevated in the striatum, whereas it is reduced in the cortex of rats subjected to transient middle cerebral artery occlusion (MCAo). Notably, the reduction of cortical levels of full-length RAGE detected 24 h after reperfusion is abolished by systemic administration of a neuroprotective dose of the poly(ADP-ribose) polymerase (PARP) inhibitor, N-(6-oxo-5,6-dihydrophenanthridin-2-yl)-N,N-dimethylacetamide (PJ34). More interestingly, a significant reduction of plasma soluble RAGE (sRAGE) occurs 24 h after reperfusion and this effect is reverted by a neuroprotective dose of PJ34. Soluble forms of RAGE, generated either by alternative splicing or by proteolysis of the full-length form, effectively bind advanced glycation end products, thereby competing with the cell surface full-length RAGE, thus providing a 'decoy' function that may counteract the adverse effects of receptor signaling in neurons and may possibly exert cytoprotective effects. Thus, our data confirm the important role of RAGE in ischemic cerebral damage and, more interestingly, suggest the potential use of sRAGE as a blood biomarker of stroke severity and of neuroprotective treatment efficacy.

Original languageEnglish
Pages (from-to)91-97
Number of pages7
JournalEuropean Journal of Pharmacology
Volume744
DOIs
Publication statusPublished - Feb 24 2015

Keywords

  • Cerebral ischemia
  • Full-length
  • MCAo
  • PARP inhibition
  • RAGE
  • sRAGE

ASJC Scopus subject areas

  • Pharmacology
  • Medicine(all)

Fingerprint Dive into the research topics of 'Neuroprotection by the PARP inhibitor PJ34 modulates cerebral and circulating RAGE levels in rats exposed to focal brain ischemia'. Together they form a unique fingerprint.

Cite this