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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 treatment increases the survival of SOD1 Tg mice and delays disease onset and progressionSOD1 B6SJL-Tg (SOD1G93A) 1 Gur/J male mice (56) were divided into five control and treatment groups. The groups were age and weight matched.Probability of survival with AGS-499 (6 mg/kg, 24 h) treatment (n = 10) started at symptoms onset as compared to untreated or vehicle treated mice (n = 7–10 per group).Probability of survival with different AGS-499 doses administered every 24 or 48 h (n = 9–10 per group) started at disease onset as compared to untreated or vehicle treated mice.Decline in body weight during disease progression.Motor performance was evaluated by the Rotarod test. Analysis was performed by repeated measures (mean ± s.e.m.).Neurological score: 0, no symptoms, 1, trembling of hind legs during tail suspension, 2, part of foot is dragging along cage, 3, one limb is paralysed, 4, two limbs are paralysed, 5, cannot right itself within 30 s after being placed on either side.Disease onset: the age in which the peaks of the body weight and Rotarod performance were recorded, and the average mouse age for each treatment group was calculated and is presented as means ± s.e.m. (Student's t-test p = *10.0004, *20.00002 compared to vehicle).Duration of the early disease phase for each group was calculated from onset to 10% weight loss and the late disease phase from 10% weight loss to the end of stage. The results are means ± s.e.m. (Student's t-test p = *10.002, *20.000,*30.007).
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fig06: AGS treatment increases the survival of SOD1 Tg mice and delays disease onset and progressionSOD1 B6SJL-Tg (SOD1G93A) 1 Gur/J male mice (56) were divided into five control and treatment groups. The groups were age and weight matched.Probability of survival with AGS-499 (6 mg/kg, 24 h) treatment (n = 10) started at symptoms onset as compared to untreated or vehicle treated mice (n = 7–10 per group).Probability of survival with different AGS-499 doses administered every 24 or 48 h (n = 9–10 per group) started at disease onset as compared to untreated or vehicle treated mice.Decline in body weight during disease progression.Motor performance was evaluated by the Rotarod test. Analysis was performed by repeated measures (mean ± s.e.m.).Neurological score: 0, no symptoms, 1, trembling of hind legs during tail suspension, 2, part of foot is dragging along cage, 3, one limb is paralysed, 4, two limbs are paralysed, 5, cannot right itself within 30 s after being placed on either side.Disease onset: the age in which the peaks of the body weight and Rotarod performance were recorded, and the average mouse age for each treatment group was calculated and is presented as means ± s.e.m. (Student's t-test p = *10.0004, *20.00002 compared to vehicle).Duration of the early disease phase for each group was calculated from onset to 10% weight loss and the late disease phase from 10% weight loss to the end of stage. The results are means ± s.e.m. (Student's t-test p = *10.002, *20.000,*30.007).

Mentions: The potential of telomerase activation for the treatment of degenerative and neurodegenerative diseases was previously suggested (Fossel and Flanary, 2009; Fu et al, 2000; Harley, 2005). ALS, a neurodegenerative disease with unknown cause and no cure, is characterized by the death and dysfunction of motor neurons in the cerebral cortex, BS and SC (Boillee et al, 2006a; Nayak et al, 2006). We hypothesized that increasing telomerase expression in the BS and in the SC by AGS treatment may have some neuroprotective effects on the motor neurons. As can be seen in Figs 3C and 4C, AGS treatment indeed increased the expression of TERT protein (Fig 3B) and telomerase activity (Fig 4C) in the BS and SC. Since AGS-499 increased telomerase expression in the relevant regions of the mouse brain and in the SC and decreased the excitotoxicity of NMDA, we hypothesized that AGS administration to SOD1 Tg mice that develop ALS may affect the onset and the progression of the disease. Fifty-six B6SJL-Tg (SOD1G93A) 1Gur/J male mice were divided into five treatment groups, which were age- and weight-matched as described in the ‘Materials and Methods’ section. Injection of AGS-499 to the SOD1 Tg mice significantly increased their lifespan, reduced their weight loss, increased their motor performance, and delayed the onset and progression of the disease in a dose- and time-dependent manner (Fig 6). Treatment of mice with AGS-499 at 6 mg/kg injected every 24 h (Fig 6A) demonstrated the most efficient effect among the different treatment groups (Fig 6B) and led to a significant increase of survival from 123 ± 6.3 days (control and vehicle) to 141 ± 6.7 days [6 mg/kg every 24 h, an increase of 16.4% (p < 0.01) in the lifespan]. Injection of AGS-499 (6 mg/kg) every 48 h or at lower doses (1.5 mg/kg) every 24 h also increased the lifespan of the SOD1 Tg mice to 138 ± 5.1 and 133 ± 6.8 days, respectively, an extension of 12.2% (p < 0.01) and 8.1% (p < 0.09). These results suggest that the AGS compound increased the survival of ALS mice in a dose- and time-dependent manner.


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 treatment increases the survival of SOD1 Tg mice and delays disease onset and progressionSOD1 B6SJL-Tg (SOD1G93A) 1 Gur/J male mice (56) were divided into five control and treatment groups. The groups were age and weight matched.Probability of survival with AGS-499 (6 mg/kg, 24 h) treatment (n = 10) started at symptoms onset as compared to untreated or vehicle treated mice (n = 7–10 per group).Probability of survival with different AGS-499 doses administered every 24 or 48 h (n = 9–10 per group) started at disease onset as compared to untreated or vehicle treated mice.Decline in body weight during disease progression.Motor performance was evaluated by the Rotarod test. Analysis was performed by repeated measures (mean ± s.e.m.).Neurological score: 0, no symptoms, 1, trembling of hind legs during tail suspension, 2, part of foot is dragging along cage, 3, one limb is paralysed, 4, two limbs are paralysed, 5, cannot right itself within 30 s after being placed on either side.Disease onset: the age in which the peaks of the body weight and Rotarod performance were recorded, and the average mouse age for each treatment group was calculated and is presented as means ± s.e.m. (Student's t-test p = *10.0004, *20.00002 compared to vehicle).Duration of the early disease phase for each group was calculated from onset to 10% weight loss and the late disease phase from 10% weight loss to the end of stage. The results are means ± s.e.m. (Student's t-test p = *10.002, *20.000,*30.007).
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fig06: AGS treatment increases the survival of SOD1 Tg mice and delays disease onset and progressionSOD1 B6SJL-Tg (SOD1G93A) 1 Gur/J male mice (56) were divided into five control and treatment groups. The groups were age and weight matched.Probability of survival with AGS-499 (6 mg/kg, 24 h) treatment (n = 10) started at symptoms onset as compared to untreated or vehicle treated mice (n = 7–10 per group).Probability of survival with different AGS-499 doses administered every 24 or 48 h (n = 9–10 per group) started at disease onset as compared to untreated or vehicle treated mice.Decline in body weight during disease progression.Motor performance was evaluated by the Rotarod test. Analysis was performed by repeated measures (mean ± s.e.m.).Neurological score: 0, no symptoms, 1, trembling of hind legs during tail suspension, 2, part of foot is dragging along cage, 3, one limb is paralysed, 4, two limbs are paralysed, 5, cannot right itself within 30 s after being placed on either side.Disease onset: the age in which the peaks of the body weight and Rotarod performance were recorded, and the average mouse age for each treatment group was calculated and is presented as means ± s.e.m. (Student's t-test p = *10.0004, *20.00002 compared to vehicle).Duration of the early disease phase for each group was calculated from onset to 10% weight loss and the late disease phase from 10% weight loss to the end of stage. The results are means ± s.e.m. (Student's t-test p = *10.002, *20.000,*30.007).
Mentions: The potential of telomerase activation for the treatment of degenerative and neurodegenerative diseases was previously suggested (Fossel and Flanary, 2009; Fu et al, 2000; Harley, 2005). ALS, a neurodegenerative disease with unknown cause and no cure, is characterized by the death and dysfunction of motor neurons in the cerebral cortex, BS and SC (Boillee et al, 2006a; Nayak et al, 2006). We hypothesized that increasing telomerase expression in the BS and in the SC by AGS treatment may have some neuroprotective effects on the motor neurons. As can be seen in Figs 3C and 4C, AGS treatment indeed increased the expression of TERT protein (Fig 3B) and telomerase activity (Fig 4C) in the BS and SC. Since AGS-499 increased telomerase expression in the relevant regions of the mouse brain and in the SC and decreased the excitotoxicity of NMDA, we hypothesized that AGS administration to SOD1 Tg mice that develop ALS may affect the onset and the progression of the disease. Fifty-six B6SJL-Tg (SOD1G93A) 1Gur/J male mice were divided into five treatment groups, which were age- and weight-matched as described in the ‘Materials and Methods’ section. Injection of AGS-499 to the SOD1 Tg mice significantly increased their lifespan, reduced their weight loss, increased their motor performance, and delayed the onset and progression of the disease in a dose- and time-dependent manner (Fig 6). Treatment of mice with AGS-499 at 6 mg/kg injected every 24 h (Fig 6A) demonstrated the most efficient effect among the different treatment groups (Fig 6B) and led to a significant increase of survival from 123 ± 6.3 days (control and vehicle) to 141 ± 6.7 days [6 mg/kg every 24 h, an increase of 16.4% (p < 0.01) in the lifespan]. Injection of AGS-499 (6 mg/kg) every 48 h or at lower doses (1.5 mg/kg) every 24 h also increased the lifespan of the SOD1 Tg mice to 138 ± 5.1 and 133 ± 6.8 days, respectively, an extension of 12.2% (p < 0.01) and 8.1% (p < 0.09). These results suggest that the AGS compound increased the survival of ALS mice in a dose- and time-dependent manner.

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