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

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.

• Authors: Shunya Takizawa, Yuko Izuhara, Yasuko Kitao, Osamu Hori, Satoshi Ogawa, Yuko Morita, Shigeharu Takagi, Charles van Ypersele de Strihou, Toshio Miyata
• Journal: Brain research (Brain Res) Vol. 1183 Pg. 124-37 (Dec 05 2007) ISSN: 0006-8993 [Print] Netherlands
• PMID: 17976543 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 1-(5-hydroxy-3-methyl-1-phenyl-1H-pyrazol-4-yl)-6-methyl-1,3-dihydrofuro(3,4-c)pyridine-7-ol
• Antioxidants
• Benzenesulfonates
• Furans
• Glycation End Products, Advanced
• Indicators and Reagents
• Neuroprotective Agents
• Pyridines
• disufenton sodium
• Edaravone
• Antipyrine

Topics

• Animals
• Antioxidants (pharmacology)
• Antipyrine (analogs & derivatives, pharmacology)
• Benzenesulfonates (pharmacology)
• Blood Pressure (drug effects)
• Brain Ischemia (complications, pathology)
• Cell Death (drug effects)
• Dose-Response Relationship, Drug
• Edaravone
• Endoplasmic Reticulum (drug effects, physiology)
• Furans (pharmacology)
• Glycation End Products, Advanced (antagonists & inhibitors)
• Immunohistochemistry
• Indicators and Reagents
• Infarction, Middle Cerebral Artery (etiology, pathology, prevention & control)
• Intracranial Thrombosis (pathology, prevention & control)
• Male
• Mice
• Mice, Knockout
• Neuroprotective Agents
• Oxidation-Reduction
• Oxidative Stress (drug effects, physiology)
• Protein Denaturation
• Pyridines (pharmacology)
• Rats
• Rats, Sprague-Dawley