Abstract
DNA oxidative damage can cause telomere attrition or dysfunction that triggers cell senescence and apoptosis. The hypothesis of this study is that folic acid decreases apoptosis in neural stem cells (NSCs) by preventing oxidative stress-induced telomere attrition. Primary cultures of NSCs were incubated for 9days with various concentrations of folic acid (0-40µM) and then incubated for 24h with a combination of folic acid and an oxidant (100-µM hydrogen peroxide, H2O2), antioxidant (10-mM N-acetyl-L-cysteine, NAC), or vehicle. Intracellular folate concentration, apoptosis rate, cell proliferative capacity, telomere length, telomeric DNA oxidative damage, telomerase activity, intracellular reactive oxygen species (ROS) levels, cellular oxidative damage, and intracellular antioxidant enzyme activities were determined. The results showed that folic acid deficiency in NSCs decreased intracellular folate concentration, cell proliferation, telomere length, and telomerase activity but increased apoptosis, telomeric DNA oxidative damage, and intracellular ROS levels. In contrast, folic acid supplementation dose-dependently increased intracellular folate concentration, cell proliferative capacity, telomere length, and telomerase activity but decreased apoptosis, telomeric DNA oxidative damage, and intracellular ROS levels. Exposure to H2O2 aggravated telomere attrition and oxidative damage, whereas NAC alleviated the latter. High doses of folic acid prevented telomere attrition and telomeric DNA oxidative damage by H2O2. In conclusion, inhibition of telomeric DNA oxidative damage and telomere attrition in NSCs may be potential mechanisms of inhibiting NSC apoptosis by folic acid.
Highlights
Oxidative damage contributes to neuronal cell death and to the important public health problems of aberrant aging and neurodegenerative disease [1,2]
The neurospheres were mechanically dissociated and the resulting cells were cultured in Dulbecco’s modified Eagle’s medium (DMEM)/F-12 Ham (F12) medium supplemented with 5% FBS, 2% N2, but without B27, epidermal growth factor (EGF), or basic fibroblast growth factor (bFGF)
The results of the present study showed that folic acid deficiency in Neural stem cells (NSCs) decreased intracellular folate concentration, cell proliferative capacity, telomere length and telomerase activity, but increased apoptosis, telomeric DNA oxidative damage and intracellular reactive oxygen species (ROS) levels
Summary
Oxidative damage contributes to neuronal cell death and to the important public health problems of aberrant aging and neurodegenerative disease [1,2]. Neural stem cells (NSCs) are the main cell types that produce central nervous system, which are essential for the study of neural development, neurodegeneration and nervous system diseases [3]. NSC oxidative damage, remains in a tight connection with the occurrence of central nervous system diseases [2]. Damage to telomeric sequences in stem cells can be repaired by a specialized reverse transcriptase called telomerase [6]. Oxidative stress has been observed to accelerate telomere attrition in primary astrocytes [8] and to be associated with apoptosis in endothelial cells [9]. The role of oxidative stress, telomere attrition and telomerase activity in neurodegeneration is still unclear
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