Cytoprotective efficacy and mechanisms of the liposoluble iron chelator 2,2'-dipyridyl in the rat photothrombotic ischemic stroke model.
We examined the efficacy of the liposoluble iron chelator 2,2'-dipyridyl (DP) in reducing histological damage in rats submitted to cerebral ischemia and the mechanisms involved in the potential cytoprotection. For this purpose, DP (20 mg/kg, i.p.) was administered 15 min before and 1 h after induction of cortical photothrombotic vascular occlusion in rat. Histological studies were performed to assess infarct volume (at days 1 and 3 postischemia) and astromicroglial activation (at day 3 postischemia). Damage to endothelial and neuronal cells was evaluated at day 1 postischemia by quantitative measurements of Evans Blue extravasation and N-acetylaspartate levels, respectively. Cerebral blood flow was recorded in the ischemic core by laser-Doppler flowmetry within the 15 min to 2 h period after photothrombosis. At 4-h postischemia, radical oxygen species (ROS) production was evaluated by measuring brain glutathione concentrations. The cortical expression of the proteins heme oxygenase-1 (HO-1) and hypoxia-inducible factor-1alpha (HIF-1alpha) was analyzed by Western blotting at day 1 postischemia. Infarct volume and ischemic damage to endothelial and neuronal cells were significantly reduced by DP treatment. This cytoprotection was associated with a reduction in ROS production, perfusion deficits, and astrocytic activation. DP treatment also resulted in significant changes in HO-1 (+100%) and HIF-1alpha (-50%) protein expression at the level of the ischemic core. These results report the efficacy of the liposoluble iron chelator DP in reducing histological damage induced by permanent focal ischemia.
Demougeot
C
C
Laboratoire de Pharmacodynamie et Physiologie Pharmaceutique (L3P), Faculté de Pharmacie, 7, Bd Jeanne d'Arc, BP 87900, 21079 Dijon Cedex, France.
Van Hoecke
M
M
Bertrand
N
N
Prigent-Tessier
A
A
Mossiat
C
C
Beley
A
A
Marie
C
C
D015082:2,2'-Dipyridyl / Q000737:chemistry / Q000627:therapeutic use*; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000473:pathology; D002545:Brain Ischemia / Q000188:drug therapy* / Q000473:pathology; D002470:Cell Survival / Q000187:drug effects; D002540:Cerebral Cortex / Q000473:pathology; D002544:Cerebral Infarction / Q000473:pathology; D002560:Cerebrovascular Circulation / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D006419:Heme Oxygenase (Decyclizing) / Q000096:biosynthesis; D051547:Heme Oxygenase-1; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007502:Iron Chelating Agents / Q000737:chemistry / Q000627:therapeutic use*; D007834:Lasers; D008297:Male; D009457:Neuroglia / Q000187:drug effects / Q000473:pathology; D009474:Neurons / Q000473:pathology; D009687:Nuclear Proteins / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D020521:Stroke / Q000188:drug therapy* / Q000473:pathology; D013927:Thrombosis / Q000188:drug therapy / Q000473:pathology; D014157:Transcription Factors / Q000378:metabolism
D004268:DNA-Binding Proteins; C497444:Hif1a protein, rat; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007502:Iron Chelating Agents; D009687:Nuclear Proteins; D017382:Reactive Oxygen Species; D014157:Transcription Factors; D015082:2,2'-Dipyridyl; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; D005978:Glutathione