Back to Search
Start Over
A novel inhibitor of advanced glycation and endoplasmic reticulum stress reduces infarct volume in rat focal cerebral ischemia
- Source :
-
Brain Research . Dec2007, Vol. 1183, p124-137. 14p. - Publication Year :
- 2007
-
Abstract
- 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. [Copyright &y& Elsevier]
- Subjects :
- *ENDOPLASMIC reticulum
*CEREBRAL ischemia
*LABORATORY rats
*HEME oxygenase
Subjects
Details
- Language :
- English
- ISSN :
- 00068993
- Volume :
- 1183
- Database :
- Academic Search Index
- Journal :
- Brain Research
- Publication Type :
- Academic Journal
- Accession number :
- 27659377
- Full Text :
- https://doi.org/10.1016/j.brainres.2007.07.006