title: Neuroprotection by the PARP inhibitor PJ34 modulates cerebral and circulating RAGE levels in rats exposed to focal brain ischemia.
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.
authors.affiliation: Laboratory of Neurophysiology of Integrative Autonomic Systems, Headache Science Centre, "C. Mondino" National Neurological Institute, Pavia, Italy. Electronic address: rosaria.greco@mondino.it.
authors.forename: Rosaria
authors.initials: R
authors.lastname: Greco
authors.affiliation: Laboratory of Neurophysiology of Integrative Autonomic Systems, Headache Science Centre, "C. Mondino" National Neurological Institute, Pavia, Italy; Department of Brain and Behavior, University of Pavia, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Tassorelli
authors.affiliation: Laboratory of Neurophysiology of Integrative Autonomic Systems, Headache Science Centre, "C. Mondino" National Neurological Institute, Pavia, Italy.
authors.forename: Antonina Stefania
authors.initials: AS
authors.lastname: Mangione
authors.affiliation: Laboratory of Functional Neurochemistry, Center for Research in Neurodegenerative Diseases, "C. Mondino" National Neurological Institute, Pavia, Italy.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Levandis
authors.affiliation: Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende (CS), Italy.
authors.forename: Michelangelo
authors.initials: M
authors.lastname: Certo
authors.affiliation: Laboratory of Neurophysiology of Integrative Autonomic Systems, Headache Science Centre, "C. Mondino" National Neurological Institute, Pavia, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Nappi
authors.affiliation: Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende (CS), Italy.
authors.forename: Giacinto
authors.initials: G
authors.lastname: Bagetta
authors.affiliation: Laboratory of Functional Neurochemistry, Center for Research in Neurodegenerative Diseases, "C. Mondino" National Neurological Institute, Pavia, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Blandini
authors.affiliation: Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende (CS), Italy.
authors.forename: Diana
authors.initials: D
authors.lastname: Amantea
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002545:Brain Ischemia / Q000188:drug therapy* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D017127:Glycation End Products, Advanced / Q000378:metabolism; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy / Q000378:metabolism; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010616:Phenanthrenes / Q000494:pharmacology*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D051381:Rats; D017208:Rats, Wistar; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000378:metabolism*; D020521:Stroke / Q000188:drug therapy / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D017127:Glycation End Products, Advanced; C434926:N-(oxo-5,6-dihydrophenanthridin-2-yl)-N,N-dimethylacetamide hydrochloride; D018696:Neuroprotective Agents; D010616:Phenanthrenes; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic
keywords: Cerebral ischemia; Full-length RAGE; MCAo; PARP inhibition; sRAGE