organotellurium compound ammonium trichloro(dioxoethylene-0,0') tellurate enhances neuronal survival and improves functional outcome in an ischemic stroke model in mice

• Published in: Journal of neurochemistry 2007-08, Vol.102 (4), p.1232-1241
• Main Authors: Okun, Eitan, Arumugam, Thiruma V, Tang, Sung-Chun, Gleichmann, Marc, Albeck, Michael, Sredni, Benjamin, Mattson, Mark P
• Format: Article
• Language: English
• Subjects: Ageing, cell death; Analysis of Variance; Animals; Animals, Newborn; Apoptosis; Biochemistry; Biological and medical sciences; Brain damage; calcium; Calcium - metabolism; caspase; Caspases - metabolism; Cell physiology; Cell Survival - drug effects; Cells, Cultured; Disease Models, Animal; Dose-Response Relationship, Drug; Ethylenes - therapeutic use; excitotoxicity; Fundamental and applied biological sciences. Psychology; Glucose - deficiency; hydroxynonenal; Hypoxia - drug therapy; Infarction, Middle Cerebral Artery - drug therapy; Infarction, Middle Cerebral Artery - pathology; Infarction, Middle Cerebral Artery - physiopathology; Male; Medical sciences; Mice; Mice, Inbred C57BL; Molecular and cellular biology; Neurology; Neurons - drug effects; Neuroprotective Agents - therapeutic use; Neurosciences; Rats; Rodents; Stroke; tellurium; Time Factors; Vascular diseases and vascular malformations of the nervous system
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/j.1471-4159.2007.04615.x

Ammonium trichloro(dioxoethylene-0,0') tellurate (AS101) is a non-toxic organotellurium compound with pleiotropic activities. It was recently shown to induce production of the neurotrophic factor glial cell line-derived neurotrophic factor and to rescue neuronal-like PC-12 cells from neurotrophic factor deprivation-induced apoptosis. In this study, we show that AS101 improves functional outcome and reduces brain damage in a mouse model of focal ischemic stroke. Both pre-stroke and post-stroke intraperitoneal treatments with AS101 reduced infarct size and edema and improved the neurological function of the animals. AS101 treatments reduced both apoptotic and inflammatory caspase activities, and also inhibited protein tyrosine nitration suggesting that AS101 suppresses oxidative stress. Studies of cultured neurons showed that AS101 confers protection against apoptosis induced by either glucose deprivation or the lipid peroxidation product 4-hydroxynonenal. Moreover, AS101 treatment reduced glutamate-induced intracellular calcium elevation, a major contributor to neuronal death in stroke. As AS101 has an excellent safety profile in humans, our pre-clinical data suggest a potential therapeutic benefit of AS101 in patients suffering from stroke and other neurodegenerative conditions.