A novel inhibitor of advanced glycation and endoplasmic reticulum stress reduces infarct volume in rat focal 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 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.
Takizawa
Shunya
S
Division of Neurology, Department of Internal Medicine, Tokai University School of Medicine, Isehara, Kanagawa 259-1193, Japan.
Izuhara
Yuko
Y
Kitao
Yasuko
Y
Hori
Osamu
O
Ogawa
Satoshi
S
Morita
Yuko
Y
Takagi
Shigeharu
S
van Ypersele de Strihou
Charles
C
Miyata
Toshio
T
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D000983:Antipyrine / Q000031:analogs & derivatives / Q000494:pharmacology; D001557:Benzenesulfonates / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D002545:Brain Ischemia / Q000150:complications* / Q000473:pathology; D016923:Cell Death / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D000077553:Edaravone; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000502:physiology*; D005663:Furans / Q000494:pharmacology*; D017127:Glycation End Products, Advanced / Q000037:antagonists & inhibitors*; D007150:Immunohistochemistry; D007202:Indicators and Reagents; D020244:Infarction, Middle Cerebral Artery / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D020767:Intracranial Thrombosis / Q000473:pathology / Q000517:prevention & control; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018696:Neuroprotective Agents; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D011489:Protein Denaturation; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
C527492:1-(5-hydroxy-3-methyl-1-phenyl-1H-pyrazol-4-yl)-6-methyl-1,3-dihydrofuro(3,4-c)pyridine-7-ol; D000975:Antioxidants; D001557:Benzenesulfonates; D005663:Furans; D017127:Glycation End Products, Advanced; D007202:Indicators and Reagents; D018696:Neuroprotective Agents; D011725:Pyridines; C120851:disufenton sodium; D000077553:Edaravone; D000983:Antipyrine