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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 protects mice from NMDA-induced excitotoxicityMice were twice injected with AGS-499 (6 mg/kg), or its vehicle DMSO, 24 and 12 h before inter-peritoneal injection of NMDA (110 mg/kg). Telomerase activity was determined by TRAP assay, in which 2 µg protein from the protein extracts were added to the TRAP specific reaction mixture. Negative control (NG) contained CHAPS buffer instead of the protein extract. IS, internal standard.Mouse survival rate after inter-peritoneal NMDA injection (untreated n = 16, vehicle n = 20, AGS n = 20 *1p = 0.011, *2p = 0.0003 determined by chi test χ2)Seizures and ‘freezing’ in the surviving mice were blind-monitored by nine independent observers, using a neurological score range of 0–5: 0–1, no seizures and freezing episodes and 5, many seizures or freezing episodes (mean ± s.d.; untreated n = 10, vehicle n = 9, AGS n = 17, Student's t-test, *1p = 0.013, *2p = 0.000). Symbols: UT, untreated mice.
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fig05: AGS-499 protects mice from NMDA-induced excitotoxicityMice were twice injected with AGS-499 (6 mg/kg), or its vehicle DMSO, 24 and 12 h before inter-peritoneal injection of NMDA (110 mg/kg). Telomerase activity was determined by TRAP assay, in which 2 µg protein from the protein extracts were added to the TRAP specific reaction mixture. Negative control (NG) contained CHAPS buffer instead of the protein extract. IS, internal standard.Mouse survival rate after inter-peritoneal NMDA injection (untreated n = 16, vehicle n = 20, AGS n = 20 *1p = 0.011, *2p = 0.0003 determined by chi test χ2)Seizures and ‘freezing’ in the surviving mice were blind-monitored by nine independent observers, using a neurological score range of 0–5: 0–1, no seizures and freezing episodes and 5, many seizures or freezing episodes (mean ± s.d.; untreated n = 10, vehicle n = 9, AGS n = 17, Student's t-test, *1p = 0.013, *2p = 0.000). Symbols: UT, untreated mice.

Mentions: Transgenic mice that overexpress TERT were shown to be more resistant to NMDA-induced excitotoxicity (Lee et al, 2008). Since the aforementioned results suggest that the AGS-499 compound increased telomerase expression and activity in the brain, we examined whether AGS-499 treatment may provide protection against NMDA-induced excitotoxicity. AGS-499 was administered s.c. 24 and 12 h prior to i.p. injection of NMDA, and the effect of dual doses of AGS-499 on telomerase in the FB was measured by TRAP assay. The dual dose of AGS-499 significantly increased telomerase activity as demonstrated in Fig 5A. Peripheral injection of NMDA causes epileptic-like seizures that can lead to mortality (Feigenbaum et al, 1989). Pre-treatment of mice with the AGS-499 compound increased the survival rate of the NMDA-injected mice from 64 to 85% (p < 0.05) (Fig 5B). Surprisingly, pretreatment of mice with the vehicle (DMSO), increased the mortality in NMDA-injected mice by 25%. Thus, the AGS compound increased the survival rate by twofold (p < 0.01) as compared to vehicle. In addition, the rate of seizures and behavioural freezing in the surviving mice was blindly monitored by nine independent observers using a neurological score (0–5: 0,1, no seizures and freezing episodes and 5, many seizures or freezing episodes). The results depicted in Fig 5C show that AGS-499 reduced seizures and increased mouse movement in NMDA-injected mice.


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 protects mice from NMDA-induced excitotoxicityMice were twice injected with AGS-499 (6 mg/kg), or its vehicle DMSO, 24 and 12 h before inter-peritoneal injection of NMDA (110 mg/kg). Telomerase activity was determined by TRAP assay, in which 2 µg protein from the protein extracts were added to the TRAP specific reaction mixture. Negative control (NG) contained CHAPS buffer instead of the protein extract. IS, internal standard.Mouse survival rate after inter-peritoneal NMDA injection (untreated n = 16, vehicle n = 20, AGS n = 20 *1p = 0.011, *2p = 0.0003 determined by chi test χ2)Seizures and ‘freezing’ in the surviving mice were blind-monitored by nine independent observers, using a neurological score range of 0–5: 0–1, no seizures and freezing episodes and 5, many seizures or freezing episodes (mean ± s.d.; untreated n = 10, vehicle n = 9, AGS n = 17, Student's t-test, *1p = 0.013, *2p = 0.000). Symbols: UT, untreated mice.
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Related In: Results  -  Collection

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fig05: AGS-499 protects mice from NMDA-induced excitotoxicityMice were twice injected with AGS-499 (6 mg/kg), or its vehicle DMSO, 24 and 12 h before inter-peritoneal injection of NMDA (110 mg/kg). Telomerase activity was determined by TRAP assay, in which 2 µg protein from the protein extracts were added to the TRAP specific reaction mixture. Negative control (NG) contained CHAPS buffer instead of the protein extract. IS, internal standard.Mouse survival rate after inter-peritoneal NMDA injection (untreated n = 16, vehicle n = 20, AGS n = 20 *1p = 0.011, *2p = 0.0003 determined by chi test χ2)Seizures and ‘freezing’ in the surviving mice were blind-monitored by nine independent observers, using a neurological score range of 0–5: 0–1, no seizures and freezing episodes and 5, many seizures or freezing episodes (mean ± s.d.; untreated n = 10, vehicle n = 9, AGS n = 17, Student's t-test, *1p = 0.013, *2p = 0.000). Symbols: UT, untreated mice.
Mentions: Transgenic mice that overexpress TERT were shown to be more resistant to NMDA-induced excitotoxicity (Lee et al, 2008). Since the aforementioned results suggest that the AGS-499 compound increased telomerase expression and activity in the brain, we examined whether AGS-499 treatment may provide protection against NMDA-induced excitotoxicity. AGS-499 was administered s.c. 24 and 12 h prior to i.p. injection of NMDA, and the effect of dual doses of AGS-499 on telomerase in the FB was measured by TRAP assay. The dual dose of AGS-499 significantly increased telomerase activity as demonstrated in Fig 5A. Peripheral injection of NMDA causes epileptic-like seizures that can lead to mortality (Feigenbaum et al, 1989). Pre-treatment of mice with the AGS-499 compound increased the survival rate of the NMDA-injected mice from 64 to 85% (p < 0.05) (Fig 5B). Surprisingly, pretreatment of mice with the vehicle (DMSO), increased the mortality in NMDA-injected mice by 25%. Thus, the AGS compound increased the survival rate by twofold (p < 0.01) as compared to vehicle. In addition, the rate of seizures and behavioural freezing in the surviving mice was blindly monitored by nine independent observers using a neurological score (0–5: 0,1, no seizures and freezing episodes and 5, many seizures or freezing episodes). The results depicted in Fig 5C show that AGS-499 reduced seizures and increased mouse movement in NMDA-injected mice.

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