Delayed treatment with carboxy-PTIO permits a 4-h therapeutic window of opportunity and prevents against ischemia-induced energy depletion following permanent focal cerebral ischemia in mice.

Abstract

We examined whether a nitric oxide scavenger, 2-(4-carboxyphenyl)-4,4,5,5-tetramethyl-imidazoline-L: -oxyl-3-oxide (carboxy-PTIO), could offer neuroprotective actions and improve cerebral energy metabolism in a model of stroke. Sixty C57BL/10J mice were given either carboxy-PTIO (0.3-1.2 mg/kg) or vehicle intraperitoneally, 0.5 h after permanent middle cerebral artery occlusion, to evaluate the dose-response effects. An additional 70 animals received carboxy-PTIO (0.6 mg/kg) or vehicle, 2-6 h post-ischemia, for establishing the therapeutic window. Subgroups of animals, treated with carboxy-PTIO (0.6 mg/kg) or vehicle, were used for measuring cerebral bioenergetic metabolites (ATP, ADP, AMP, adenosine). Mice treated with carboxy-PTIO (0.6 mg/kg) had dose-specifically reduced brain infarction, significantly by 27-30% (P < 0.05), even when therapy was delayed up to 4 h after the ischemic insult (P < 0.05). Four hour post-ischemia, ATP depleted in the ischemic hemisphere (P < 0.05). Administration with carboxy-PTIO not only improved the recovery of ATP in the ischemic hemisphere (P < 0.05), but also enhanced adenosine content across the ischemic and non-ischemic hemispheres (P < 0.05). The neuroprotection of carboxy-PTIO may be partly attributed to the beneficial effects of improving cerebral energy metabolism.

• Authors: E-Jian Lee, Yu-Chang Hung, Hung-Yi Chen, Tian-Shung Wu, Tsung-Ying Chen
• Journal: Neurochemical research (Neurochem Res) Vol. 34 Issue 6 Pg. 1157-66 (Jun 2009) ISSN: 1573-6903 [Electronic] United States
• PMID: 19083093 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Benzoates
• Imidazoles
• Neuroprotective Agents
• 1,3-dihydroxy-4,4,5,5-tetramethyl-2-(4-carboxyphenyl)tetrahydroimidazole
• Nitric Oxide
• Nitric Oxide Synthase

Topics

• Animals
• Benzoates (administration & dosage, therapeutic use)
• Body Temperature (drug effects)
• Brain (drug effects, metabolism, pathology)
• Brain Infarction (metabolism, pathology, prevention & control)
• Brain Ischemia (metabolism, pathology, prevention & control)
• Cerebrovascular Circulation (drug effects)
• Dose-Response Relationship, Drug
• Energy Metabolism (drug effects)
• Imidazoles (administration & dosage, therapeutic use)
• Male
• Mice
• Mice, Inbred C57BL
• Neuroprotective Agents (administration & dosage, therapeutic use)
• Nitric Oxide (metabolism)
• Nitric Oxide Synthase (antagonists & inhibitors)
• Stroke (metabolism, pathology, prevention & control)