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Novel telomerase-increasing compound in mouse brain delays the onset of amyotrophic lateral sclerosis.

Eitan E, Tichon A, Gazit A, Gitler D, Slavin S, Priel E - EMBO Mol Med (2012)

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.

View Article: PubMed Central - PubMed

Affiliation: The Shraga Segal Department of Immunology and Microbiology, Ben-Gurion University of the Negev, Beer-Sheva, Israel.

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AGS-499 increases TERT protein in the FB of adult mice in a dose-dependent mannerThe AGS-499 molecule.Mice were injected s.c. with different doses of AGS-499 or its vehicle DMSO. Twelve hours later, whole cell protein extract was prepared from the FB and 30 µg proteins were analysed by Western blot assay using three different anti-TERT antibodies. The results with anti-TERT monoclonal antibody (epitomic) and anti-β-actin antibody are shown.Quantification of the results was performed using densitometric analysis by the EZquant software (mean ± s.e.m.; n = 10), Student's t-test p = *10.019, *20.005, *30.021.Total RNA derived from mouse FB was examined for TERT mRNA by Real Time PCR, normalized to β-actin mRNA and the increase was calculated as fold of the vehicle (mean ± s.e.m.; n = 3, Student's t-test p = *10.016, *20.046). UT, untreated mice.
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fig01: AGS-499 increases TERT protein in the FB of adult mice in a dose-dependent mannerThe AGS-499 molecule.Mice were injected s.c. with different doses of AGS-499 or its vehicle DMSO. Twelve hours later, whole cell protein extract was prepared from the FB and 30 µg proteins were analysed by Western blot assay using three different anti-TERT antibodies. The results with anti-TERT monoclonal antibody (epitomic) and anti-β-actin antibody are shown.Quantification of the results was performed using densitometric analysis by the EZquant software (mean ± s.e.m.; n = 10), Student's t-test p = *10.019, *20.005, *30.021.Total RNA derived from mouse FB was examined for TERT mRNA by Real Time PCR, normalized to β-actin mRNA and the increase was calculated as fold of the vehicle (mean ± s.e.m.; n = 3, Student's t-test p = *10.016, *20.046). UT, untreated mice.

Mentions: Previous studies demonstrated telomerase activity and expression in various adult (8–10 weeks) mouse central nervous system (CNS) regions (Caporaso et al, 2003; Flanary and Streit, 2003; Fu et al, 2000; Lee et al, 2009). We have synthesized novel triaryl compounds that increased telomerase expression in various human cell lines and in vivo in animal models (patents WO 2008/149353, WO 2008/149345, Priel et al) One of these compounds, designated AGS-499 (chemical formula in Fig 1A), was examined for its ability to increase telomerase expression in the mouse brain.


Novel telomerase-increasing compound in mouse brain delays the onset of amyotrophic lateral sclerosis.

Eitan E, Tichon A, Gazit A, Gitler D, Slavin S, Priel E - EMBO Mol Med (2012)

AGS-499 increases TERT protein in the FB of adult mice in a dose-dependent mannerThe AGS-499 molecule.Mice were injected s.c. with different doses of AGS-499 or its vehicle DMSO. Twelve hours later, whole cell protein extract was prepared from the FB and 30 µg proteins were analysed by Western blot assay using three different anti-TERT antibodies. The results with anti-TERT monoclonal antibody (epitomic) and anti-β-actin antibody are shown.Quantification of the results was performed using densitometric analysis by the EZquant software (mean ± s.e.m.; n = 10), Student's t-test p = *10.019, *20.005, *30.021.Total RNA derived from mouse FB was examined for TERT mRNA by Real Time PCR, normalized to β-actin mRNA and the increase was calculated as fold of the vehicle (mean ± s.e.m.; n = 3, Student's t-test p = *10.016, *20.046). UT, untreated mice.
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Related In: Results  -  Collection

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fig01: AGS-499 increases TERT protein in the FB of adult mice in a dose-dependent mannerThe AGS-499 molecule.Mice were injected s.c. with different doses of AGS-499 or its vehicle DMSO. Twelve hours later, whole cell protein extract was prepared from the FB and 30 µg proteins were analysed by Western blot assay using three different anti-TERT antibodies. The results with anti-TERT monoclonal antibody (epitomic) and anti-β-actin antibody are shown.Quantification of the results was performed using densitometric analysis by the EZquant software (mean ± s.e.m.; n = 10), Student's t-test p = *10.019, *20.005, *30.021.Total RNA derived from mouse FB was examined for TERT mRNA by Real Time PCR, normalized to β-actin mRNA and the increase was calculated as fold of the vehicle (mean ± s.e.m.; n = 3, Student's t-test p = *10.016, *20.046). UT, untreated mice.
Mentions: Previous studies demonstrated telomerase activity and expression in various adult (8–10 weeks) mouse central nervous system (CNS) regions (Caporaso et al, 2003; Flanary and Streit, 2003; Fu et al, 2000; Lee et al, 2009). We have synthesized novel triaryl compounds that increased telomerase expression in various human cell lines and in vivo in animal models (patents WO 2008/149353, WO 2008/149345, Priel et al) One of these compounds, designated AGS-499 (chemical formula in Fig 1A), was examined for its ability to increase telomerase expression in the mouse brain.

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.

View Article: PubMed Central - PubMed

Affiliation: The Shraga Segal Department of Immunology and Microbiology, Ben-Gurion University of the Negev, Beer-Sheva, Israel.

Show MeSH
Related in: MedlinePlus