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

作者：Takizaw Shunya; Izuhara Yuko; Kitao Yasuko; Hori Osamu; Ogawa Satoshi; Morita Yuko; Takagi Shigeharu; de Strihou Charles van Ypersele; Miyata Toshio^*

来源：Brain Research, 2007, 1183: 124-137.

DOI：10.1016/j.brainres.2007.07.006

• advanced glycation end product
• ER stress
• heme oxygenase
• infarct volume
• ORP150
• transient cerebral ischemia

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 mm(3), 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 mm(3), 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.

• 出版日期2007-12-5
• 单位河北医科大学