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

• Published in: Brain research Vol. 1183; pp. 124 - 137
• Main Authors: Takizawa, Shunya, Izuhara, Yuko, Kitao, Yasuko, Hori, Osamu, Ogawa, Satoshi, Morita, Yuko, Takagi, Shigeharu, van Ypersele de Strihou, Charles, Miyata, Toshio
• Format: Journal Article
• Language: English
• Published: London Elsevier B.V 05.12.2007; Amsterdam Elsevier; New York, NY
• Subjects: Advanced glycation end product; Animals; Antioxidants - pharmacology; Antipyrine - analogs & derivatives; Antipyrine - pharmacology; Benzenesulfonates - pharmacology; Biological and medical sciences; Blood Pressure - drug effects; Brain Ischemia - complications; Brain Ischemia - pathology; Cell Death - drug effects; Dose-Response Relationship, Drug; Endoplasmic Reticulum - drug effects; Endoplasmic Reticulum - physiology; ER stress; Furans - pharmacology; Glycation End Products, Advanced - antagonists & inhibitors; Heme oxygenase; Immunohistochemistry; Indicators and Reagents; Infarct volume; Infarction, Middle Cerebral Artery - etiology; Infarction, Middle Cerebral Artery - pathology; Infarction, Middle Cerebral Artery - prevention & control; Intracranial Thrombosis - pathology; Intracranial Thrombosis - prevention & control; Male; Medical sciences; Mice; Mice, Knockout; Neurology; Neuroprotective Agents; ORP150; Oxidation-Reduction; Oxidative Stress - drug effects; Oxidative Stress - physiology; Protein Denaturation; Pyridines - pharmacology; Rats; Rats, Sprague-Dawley; Transient cerebral ischemia; Vascular diseases and vascular malformations of the nervous system; heme oxygenase; TTC; CBF; HO; ER stress; ORP150; AGEs; MCA; aortic smooth muscle cells; SMCs; advanced glycation end products; ER; middle cerebral artery; Advanced glycation end product; ARB; angiotensin converting enzyme inhibitor; angiotensin II receptor blocker; Infarct volume; ACEI; cerebral blood flow; 2% 2,3,5-triphenyltetrazolium chloride; endoplasmic reticulum; Transient cerebral ischemia; Heme oxygenase; Infarct; Rat; Enzyme; Reaction product; Rodentia; Central nervous system; Heme oxygenase (decyclizing); Cardiovascular disease; Glycation; Stress; Encephalon; Vertebrata; Mammalia; Ischemia; Animal; Oxidoreductases; Endoplasmic reticulum
• ISSN: 0006-8993; 1872-6240
• DOI: 10.1016/j.brainres.2007.07.006

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.