title: Long-lasting neuroprotection and neurological improvement in stroke models with new, potent and brain permeable inhibitors of poly(ADP-ribose) polymerase.
abstract: OBJECTIVE
  Thienyl-isoquinolone (TIQ-A) is a relatively potent PARP inhibitor able to reduce post-ischaemic neuronal death in vitro. Here we have studied, in different stroke models in vivo, the neuroprotective properties of DAMTIQ and HYDAMTIQ, two TIQ-A derivatives able to reach the brain and to inhibit PARP-1 and PARP-2.
  
  
  METHODS
  Studies were carried out in (i) transient (2 h) middle cerebral artery occlusion (tMCAO), (ii) permanent MCAO (pMCAO) and (iii) electrocoagulation of the distal portion of MCA in conjunction with transient (90 min) bilateral carotid occlusion (focal cortical ischaemia).
  
  
  RESULTS
  In male rats with tMCAO, HYDAMTIQ (0.1-10 mg·kg(-1)) injected i.p. three times, starting 4 h after MCAO, reduced infarct volumes by up to 70%, reduced the loss of body weight by up to 60% and attenuated the neurological impairment by up to 40%. In age-matched female rats, HYDAMTIQ also reduced brain damage. Protection, however, was less pronounced than in the male rats. In animals with pMCAO, HYDAMTIQ administered 30 min after MCAO reduced infarct volumes by approximately 40%. In animals with focal cortical ischaemia, HYDAMTIQ treatment decreased post-ischaemic accumulation of PAR (the product of PARP activity) and the presence of OX42-positive inflammatory cells in the ischaemic cortex. It also reduced sensorimotor deficits for up to 90 days after MCAO.
  
  
  CONCLUSIONS
  Our results show that HYDAMTIQ is a potent PARP inhibitor that conferred robust neuroprotection and long-lasting improvement of post-stroke neurological deficits.
authors.affiliation: Department of Preclinical and Clinical Pharmacology, University of Florence, Florence, Italy. flavio.moroni@unifi.it
authors.forename: F
authors.initials: F
authors.lastname: Moroni
authors.forename: A
authors.initials: A
authors.lastname: Cozzi
authors.forename: A
authors.initials: A
authors.lastname: Chiarugi
authors.forename: L
authors.initials: L
authors.lastname: Formentini
authors.forename: E
authors.initials: E
authors.lastname: Camaioni
authors.forename: D E
authors.initials: DE
authors.lastname: Pellegrini-Giampietro
authors.forename: Y
authors.initials: Y
authors.lastname: Chen
authors.forename: S
authors.initials: S
authors.lastname: Liang
authors.forename: M M
authors.initials: MM
authors.lastname: Zaleska
authors.forename: C
authors.initials: C
authors.lastname: Gonzales
authors.forename: A
authors.initials: A
authors.lastname: Wood
authors.forename: R
authors.initials: R
authors.lastname: Pellicciari
mesh_terms: D000818:Animals; D001835:Body Weight / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D005260:Female; D006367:HeLa Cells; D006801:Humans; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism; D007546:Isoquinolines / Q000494:pharmacology; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D018696:Neuroprotective Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D020521:Stroke / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D013876:Thiophenes / Q000494:pharmacology; D014407:Tumor Cells, Cultured
chemical_list: C000595230:2-((dimethylamino)methyl)-9-hydroxythieno(2,3-c)isoquinolin-5(4H)-one; D004791:Enzyme Inhibitors; D007546:Isoquinolines; D018696:Neuroprotective Agents; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D013876:Thiophenes; C475227:thieno(2,3-c)isoquinolin-5-one; C499322:Parp1 protein, rat; C557783:Parp2 protein, rat; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases