A novel inhibitor of advanced glycation and endoplasmic reticulum stress reduces infarct volume in rat focal cerebral ischemia

Shunya Takizawa, Yuko Izuhara, Yasuko Kitao, Osamu Hori, Satoshi Ogawa, Yuko Morita, Shigeharu Takagi, Charles van Ypersele de Strihou, Toshio Miyata

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

We have developed a novel, non-toxic inhibitor of advanced glycation and oxidative stress, TM2002, devoid of effect on blood pressure. In transient focal ischemia, TM2002 significantly decreased infarct volume compared with vehicle (79.5 ± 18.7 vs. 183.3 ± 22.9 mm3, p < 0.01). In permanent focal ischemia, TM2002 (2.79, 5.58, and 11.16 mg/kg twice a day) dose-dependently reduced infarct volume (242.1 ± 32.3, 201.3 ± 15.1, and 171.3 ± 15.2 mm3, respectively), and improved neurological deficits. Reduction of infarct volume is demonstrable, provided that TM2002 was administered within 1.5 h after the occlusion. To unravel TM2002's mechanism of action, we examined its in vitro effect on endoplasmic reticulum (ER) stress, using aortic smooth muscle cells isolated from ORP 150+/- mice and F9 Herp null mutated cells. Cell death induced by ER stress (tunicamycin or hypoxia) was dose-dependently prevented by TM2002. In vivo immunohistochemical study demonstrated a significant reduction of ORP- and TUNEL-positive apoptotic cells, especially in the penumbra. Inhibition of advanced glycation and oxidative stress was confirmed by a significantly reduced number of cells positive for advanced glycation end products and heme oxygenase-1. TM2002 reduced the levels of protein carbonyl formation in ischemic caudate. The efficacy of TM2002 is equivalent to that of a known neuroprotective agent, NXY-059. In conclusion, TM2002 significantly ameliorates ischemic cerebral damage through reduction of ER stress, advanced glycation, and oxidative stress, independently of blood pressure lowering.

Original languageEnglish
Pages (from-to)124-137
Number of pages14
JournalBrain research
Volume1183
Issue number1
DOIs
Publication statusPublished - 2007 Dec 5
Externally publishedYes

Keywords

  • Advanced glycation end product
  • ER stress
  • Heme oxygenase
  • Infarct volume
  • ORP150
  • Transient cerebral ischemia

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Clinical Neurology
  • Developmental Biology

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  • Cite this

    Takizawa, S., Izuhara, Y., Kitao, Y., Hori, O., Ogawa, S., Morita, Y., Takagi, S., van Ypersele de Strihou, C., & Miyata, T. (2007). A novel inhibitor of advanced glycation and endoplasmic reticulum stress reduces infarct volume in rat focal cerebral ischemia. Brain research, 1183(1), 124-137. https://doi.org/10.1016/j.brainres.2007.07.006