title: Poly(ADP-ribose) accumulation and enhancement of postischemic brain damage in 110-kDa poly(ADP-ribose) glycohydrolase null mice.
abstract: Poly(ADP-ribose) (PAR) is a polymer synthesized by poly(ADP-ribose) polymerases (PARPs) and metabolized into free adenosine diphosphate (ADP)-ribose units by poly(ADP-ribose) glycohydrolase (PARG). Perturbations in PAR synthesis have been shown to play a key role in brain disorders including postischemic brain damage. A single parg gene but two PARG isoforms (110 and 60 kDa) have been detected in mouse cells. Complete suppression of parg gene causes early embryonic lethality, whereas mice selectively lacking the 110 kDa PARG isoform (PARG(110)(-/-)) develop normally. We used PARG(110)(-/-) mice to evaluate the importance of PAR catabolism to postischemic brain damage. Poly(ADP-ribose) contents were higher in the brain tissue of PARG(110)(-/-) than PARG(110)(+/+) mice, both under basal conditions and after PARP activation. Distal middle cerebral artery occlusion caused higher increase of brain PAR levels and larger infarct volumes in PARG(110)(-/-) mice than in wild-type counterparts. Of note, the brain of PARG(110)(-/-) mice showed reduced heat-shock protein (HSP)-70 and increased cyclooxygenase-2 expression under both control and ischemic conditions. No differences were detected in brain expression/activation of procaspase-3, PARP-1, Akt, HSP-25 and interleukin-1beta. Our findings show that PAR accumulation worsens ischemic brain injury, and highlight the therapeutic potential of strategies capable of maintaining PAR homeostasis.
authors.affiliation: Department of Pharmacology, University of Florence, Firenze, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Cozzi
authors.forename: Giulia
authors.initials: G
authors.lastname: Cipriani
authors.forename: Silvia
authors.initials: S
authors.lastname: Fossati
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Faraco
authors.forename: Laura
authors.initials: L
authors.lastname: Formentini
authors.forename: Wookee
authors.initials: W
authors.lastname: Min
authors.forename: Ulrich
authors.initials: U
authors.lastname: Cortes
authors.forename: Zhao-Qi
authors.initials: ZQ
authors.lastname: Wang
authors.forename: Flavio
authors.initials: F
authors.lastname: Moroni
authors.forename: Alberto
authors.initials: A
authors.lastname: Chiarugi
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002545:Brain Ischemia / Q000378:metabolism / Q000473:pathology*; D004789:Enzyme Activation; D006026:Glycoside Hydrolases / Q000235:genetics / Q000378:metabolism*; D006706:Homeostasis; D066298:In Vitro Techniques; D020244:Infarction, Middle Cerebral Artery; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009243:NAD / Q000378:metabolism; D018696:Neuroprotective Agents / Q000378:metabolism; D009498:Neurotoxins / Q000378:metabolism; D000071137:Poly (ADP-Ribose) Polymerase-1; D011064:Poly Adenosine Diphosphate Ribose / Q000378:metabolism*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism
chemical_list: D007527:Isoenzymes; D018696:Neuroprotective Agents; D009498:Neurotoxins; D009243:NAD; D011064:Poly Adenosine Diphosphate Ribose; D000255:Adenosine Triphosphate; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D006026:Glycoside Hydrolases; C022407:poly ADP-ribose glycohydrolase