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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

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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.

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Acknowledgments

This research was supported by grants from the National Cheng Kung University Hospital (NCKUH 90-039 & 91-014) and the National Science Council of Taiwan (NSC 90-2314-B-006-157 & 90-2314-B-006-160).

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Authors and Affiliations

  1. Neurosurgical Service, Department of Surgery, National Cheng Kung University Hospital and Medical School, 138 Sheng-Li Road, Tainan, 70428, Taiwan

    E-Jian Lee & Yu-Chang Hung

  2. Institute of Pharmacy, China Medical University, Taichung, Taiwan

    Hung-Yi Chen

  3. Department of Chemistry, National Cheng Kung University, Tainan, Taiwan

    Tian-Shung Wu

  4. Department of Anaesthesiology, Buddhist Tzu Chi University, Tzu Chi General Hospital, Graduate Institute of Clinical Medicine, Tzu Chi University, 707 Sec. 3, Chung-Yang Rd., Hualien, 970, Taiwan

    Tsung-Ying Chen

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  1. E-Jian Lee
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Correspondence to Tsung-Ying Chen.

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Lee, EJ., Hung, YC., Chen, HY. et al. 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. Neurochem Res 34, 1157–1166 (2009). https://doi.org/10.1007/s11064-008-9892-5

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