Cytoprotective efficacy and mechanisms of the liposoluble iron chelator 2,2'-dipyridyl in the rat photothrombotic ischemic stroke model.

Abstract

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.

• Authors: C Demougeot, M Van Hoecke, N Bertrand, A Prigent-Tessier, C Mossiat, A Beley, C Marie
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 311 Issue 3 Pg. 1080-7 (Dec 2004) ISSN: 0022-3565 [Print] United States
• PMID: 15280435 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• DNA-Binding Proteins
• Hif1a protein, rat
• Hypoxia-Inducible Factor 1
• Hypoxia-Inducible Factor 1, alpha Subunit
• Iron Chelating Agents
• Nuclear Proteins
• Reactive Oxygen Species
• Transcription Factors
• 2,2'-Dipyridyl
• Heme Oxygenase (Decyclizing)
• Heme Oxygenase-1
• Glutathione

Topics

• 2,2'-Dipyridyl (chemistry, therapeutic use)
• Animals
• Astrocytes (drug effects, pathology)
• Brain Ischemia (drug therapy, pathology)
• Cell Survival (drug effects)
• Cerebral Cortex (pathology)
• Cerebral Infarction (pathology)
• Cerebrovascular Circulation (drug effects)
• DNA-Binding Proteins (metabolism)
• Glutathione (metabolism)
• Heme Oxygenase (Decyclizing) (biosynthesis)
• Heme Oxygenase-1
• Hypoxia-Inducible Factor 1
• Hypoxia-Inducible Factor 1, alpha Subunit
• Iron Chelating Agents (chemistry, therapeutic use)
• Lasers
• Male
• Neuroglia (drug effects, pathology)
• Neurons (pathology)
• Nuclear Proteins (metabolism)
• Rats
• Rats, Wistar
• Reactive Oxygen Species (metabolism)
• Stroke (drug therapy, pathology)
• Thrombosis (drug therapy, pathology)
• Transcription Factors (metabolism)