Background and aims: Angiotensin II receptor blockers inhibit formation of advanced glycation end products (AGEs) and reduce oxidative stress, and should therefore ameliorate ischemic cerebral damage, but their hypotensive effect limits their clinical use. We have discovered a novel non-toxic inhibitor of advanced glycation and oxidative stress, TM2002, by means of high-throughput screening of the anti-oxidative and AGEs-lowering activities of over 1300 compounds. We here demonstrate its in vivo effectiveness in both transient and permanent focal ischemia models in rats. Methods: TM2002 (5.58 mg/kg twice a day) was administered intravenously in a rat transient focal ischemia model, and we evaluated its effect on infarct volume and neurological function. Brain tissues were examined immunohistochemically for heme oxygenase-1, advanced glycation end products (AGEs), oxygen regulated protein (ORP) 150, heat shock protein (HSP) 70i, HSP60, and TUNEL. Further, in a photothrombotic occlusion model, we evaluated the dose-dependence of the effect of TM2002 on infarct volume and neurological functions, conducted time-window studies of its neuroprotective efficacy, and compared its effect on infarct volume with that of the known neuroprotective agent NXY-059. Results: There was no statistically significant difference in any physiological parameter, including mean arterial blood pressure, between the TM2002- and vehicle-treated groups throughout the experiment. TM2002 significantly reduced infarct volume compared with the vehicle (79.5 ± 52.8 vs. 183.3 ± 68.7 mm3, p < 0.01), and reduced the numbers of cells immunohistochemically positive for heme oxygenase-1, AGEs, ORP150, and TUNEL, especially in the penumbra, as compared with the vehicle-treated group. Further, in the rat photothrombotic occlusion model, TM2002 (2.79, 5.58, and 11.16 mg/kg twice a day) dose-dependently reduced the infarct volume (to 242.1±102.3, 201.3±47.7, and 171.3±48.0 mm3, respectively), and improved the neurological deficits. In this model, TM2002 reduced infarct volume even when administered 1 hour after occlusion, and the efficacy of TM2002 was equivalent to that of NXY-059. Conclusions: Our novel synthetic compound significantly ameliorated ischemic cerebral damage through reduction of ER stress, advanced glycation, and oxidative stress, independently of blood-pressure lowering. Since the efficacy of TM2002 was equivalent to that of NXY-059 in the photothrombotic occlusion model, a clinical trial of TM2002 in stroke patients might be warranted.
|Journal||Journal of Cerebral Blood Flow and Metabolism|
|Issue number||SUPPL. 1|
|Publication status||Published - 2007 Nov 13|
ASJC Scopus subject areas
- Clinical Neurology
- Cardiology and Cardiovascular Medicine