TY - JOUR
T1 - Novel telomerase-increasing compound in mouse brain delays the onset of amyotrophic lateral sclerosis
AU - Eitan, Erez
AU - Tichon, Ailon
AU - Gazit, Aviv
AU - Gitler, Daniel
AU - Slavin, Shimon
AU - Priel, Esther
PY - 2012/4/1
Y1 - 2012/4/1
N2 - Telomerase is expressed in the neonatal brain, in distinct regions of adult brain, and was shown to protect developing neurons from apoptosis. Telomerase reactivation by gene manipulation reverses neurodegeneration in aged telomerase-deficient mice. Hence, we and others hypothesized that increasing telomerase expression by pharmaceutical compounds may protect brain cells from death caused by damaging agents. In this study, we demonstrate for the first time that the novel compound AGS-499 increases telomerase activity and expression in the mouse brain and spinal cord (SC). It exerts neuroprotective effects in NMDA-injected CD-1 mice, delays the onset and progression of the amyotrophic lateral sclerosis (ALS) disease in SOD1 transgenic mice, and, after the onset of ALS, it increases the survival of motor neurons in the SC by 60%. 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.
AB - Telomerase is expressed in the neonatal brain, in distinct regions of adult brain, and was shown to protect developing neurons from apoptosis. Telomerase reactivation by gene manipulation reverses neurodegeneration in aged telomerase-deficient mice. Hence, we and others hypothesized that increasing telomerase expression by pharmaceutical compounds may protect brain cells from death caused by damaging agents. In this study, we demonstrate for the first time that the novel compound AGS-499 increases telomerase activity and expression in the mouse brain and spinal cord (SC). It exerts neuroprotective effects in NMDA-injected CD-1 mice, delays the onset and progression of the amyotrophic lateral sclerosis (ALS) disease in SOD1 transgenic mice, and, after the onset of ALS, it increases the survival of motor neurons in the SC by 60%. 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.
KW - ALS
KW - Activator
KW - Brain
KW - Neuroprotector
KW - Telomerase
UR - http://www.scopus.com/inward/record.url?scp=84859383206&partnerID=8YFLogxK
U2 - 10.1002/emmm.201200212
DO - 10.1002/emmm.201200212
M3 - Article
AN - SCOPUS:84859383206
SN - 1757-4676
VL - 4
SP - 313
EP - 329
JO - EMBO Molecular Medicine
JF - EMBO Molecular Medicine
IS - 4
ER -