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.
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.
Lee
E-Jian
EJ
Department of Surgery, National Cheng Kung University Hospital and Medical School, Tainan, Taiwan. ejian@mail.ncku.edu.tw
Hung
Yu-Chang
YC
Chen
Hung-Yi
HY
Wu
Tian-Shung
TS
Chen
Tsung-Ying
TY
D000818:Animals; D001565:Benzoates / Q000008:administration & dosage / Q000627:therapeutic use*; D001831:Body Temperature / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D020520:Brain Infarction / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D002545:Brain Ischemia / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D002560:Cerebrovascular Circulation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004734:Energy Metabolism / Q000187:drug effects*; D007093:Imidazoles / Q000008:administration & dosage / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D020521:Stroke / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*
D001565:Benzoates; D007093:Imidazoles; D018696:Neuroprotective Agents; C079393:1,3-dihydroxy-4,4,5,5-tetramethyl-2-(4-carboxyphenyl)tetrahydroimidazole; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase