Novel telomerase-increasing compound in mouse brain delays the onset of amyotrophic lateral sclerosis.
Bottom Line: Hence, we and others hypothesized that increasing telomerase expression by pharmaceutical compounds may protect brain cells from death caused by damaging agents.The survival of telomerase-expressing cells (i.e. motor neurons), but not telomerase-deficient cells, exposed to oxidative stress was increased by AGS-499 treatment, suggesting that the AGS-499 effects are telomerase-mediated.Therefore, a controlled and transient increase in telomerase expression and activity in the brain by AGS-499 may exert neuroprotective effects.
Affiliation: The Shraga Segal Department of Immunology and Microbiology, Ben-Gurion University of the Negev, Beer-Sheva, Israel.Show MeSH
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Mentions: To substantiate the notion that AGS-499 protects cells from oxidative stress by increasing telomerase expression we used TERT-deficient embryonic stem cells (mES Tert−/−) derived from a TERT KO mouse (Liu et al, 2000, 2002). mES Tert−/− cells and their wild type counterparts (Tert+/+) were exposed to various concentrations of H2O2 (unpublished observations) or to 0.2 mM H2O2 for various intervals, and cell survival was examined by the XTT assay. TERT-deficient mES cells (Tert−/−) exhibited a 1.8-fold increased sensitivity to oxidative stress compared to their WT counterparts (Fig 10A). To induce similar oxidative damage in both cell types, Tert−/− cells were treated with 0.2 mM H2O2 for 1 h and Tert+/+ cells were treated for 2 h. After removal of the H2O2-containing medium, fresh medium containing AGS 499 (100 nM) was added for an additional 2 h. H2O2-induced DNA damage (DNA double-strand breaks) in the treated cells was determined by anti-γH2AX (phosphorylated histone) immunolabelling (Burma et al, 2001). Figure 10B depicts the γH2AX foci observed in Tert−/− and Tert+/+ cells treated with vehicle or with AGS-499. The ratio between the number of cells with γH2AX foci and the total number of cells in the slide was calculated for each sample and is shown in Fig 10C. AGS treatment significantly reduced (by twofold) DNA damage induced by oxidative stress in Tert+/+ cells, but had no significant effect on Tert−/− cells, suggesting that the protective activity of AGS-499 depends on TERT.
Affiliation: The Shraga Segal Department of Immunology and Microbiology, Ben-Gurion University of the Negev, Beer-Sheva, Israel.