The Shraga Segal Department of Immunology and Microbiology, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
EMBO Mol Med. 2012 Apr;4(4):313-29. doi: 10.1002/emmm.201200212. Epub 2012 Feb 20.
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.
端粒酶在新生儿大脑中表达，在成人大脑的特定区域表达，并被证明可以保护发育中的神经元免于凋亡。通过基因操作使端粒酶重新激活可逆转端粒酶缺陷的老年小鼠的神经退行性变。因此，我们和其他人假设，通过药物化合物增加端粒酶的表达可能会保护脑细胞免受损伤剂引起的死亡。在这项研究中，我们首次证明了新型化合物 AGS-499 可增加小鼠大脑和脊髓中的端粒酶活性和表达。它在 NMDA 注射的 CD-1 小鼠中发挥神经保护作用，延迟 SOD1 转基因小鼠中肌萎缩侧索硬化症（ALS）的发病和进展，并且在 ALS 发病后，它使 SC 中的运动神经元的存活率增加了 60％。暴露于氧化应激的端粒酶表达细胞（即运动神经元）而不是端粒酶缺陷细胞的存活通过 AGS-499 处理而增加，这表明 AGS-499 的作用是通过端粒酶介导的。因此，AGS-499 在大脑中可控和短暂地增加端粒酶的表达和活性可能会发挥神经保护作用。
