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