ABSTRACT
PURPOSE: Oxidative stress has been reported to cause telomere attrition, which triggers cell apoptosis. Apoptosis of neurocytes may play an essential role in the pathogenesis of neurodegenerative diseases. This study hypothesized that folic acid (FA) supplementation decreased neurocyte apoptosis by alleviating oxidative stress-induced telomere attrition in 25-month-old Sprague Dawley (SD) rats. METHODS: Three-month-old male SD rats were randomly divided into four diet groups by different concentrations of folic acid in equal numbers, with intervention for 22 months. Folate, homocysteine (Hcy), reactive oxygen species (ROS) levels, antioxidant activities, and telomere length in the brain tissues were tested at 11, 18, and 22 months of intervention, and 8-hydroxy-deoxyguanosine (8-OHdG) levels, neurocyte apoptosis and telomere length in the cerebral cortex and hippocampal regions were tested during the 22-month intervention. An automated chemiluminescence system, auto-chemistry analyzer, Q-FISH, qPCR, and TUNEL assay were used in this study. RESULTS: The rats had lower folate concentrations and higher Hcy, ROS, and 8-OHdG concentrations in brain tissue with aging. However, FA supplementation increased folate concentrations and antioxidant activities while decreasing Hcy, ROS, and 8-OHdG levels in rat brain tissue after 11, 18, and 22 months of intervention. Furthermore, FA supplementation alleviated telomere length shortening and inhibited neurocyte apoptosis during the 22-month intervention. CONCLUSION: FA supplementation alleviated oxidative stress-induced telomere attrition and inhibited apoptosis of neurocytes in 25-month-old rats.
Subject(s)
Antioxidants , Folic Acid , Rats , Male , Animals , Folic Acid/pharmacology , Antioxidants/pharmacology , Reactive Oxygen Species , Rats, Sprague-Dawley , Oxidative Stress , Apoptosis , 8-Hydroxy-2'-Deoxyguanosine , TelomereABSTRACT
The brain has high energy demand making it sensitive to changes in energy fuel supply. Aging shrinks brain volume, decreases glucose uptake availability of the brain, and finally, causes cognitive dysfunction. Folic acid supplementation delayed cognitive decline and neurodegeneration. However, whether folic acid affects brain energy metabolism and structural changes is unclear. The study aimed to determine if long-term dietary folic acid supplementation could alleviate age-related cognitive decline by attenuating hippocampus atrophy and promoting brain glucose uptake in Sprague-Dawley (SD) rats. According to folic acid levels in diet, 3-months old male SD rats were randomly divided into four intervention groups for 22 months in equal numbers: folic acid-deficient diet (FA-D) group, folic acid-normal diet (FA-N) group, low folic acid-supplemented diet (FA-L) group, and high folic acid-supplemented diet (FA-H) group. The results showed that serum folate concentrations decreased and serum homocysteine (Hcy) concentrations increased with age, and dietary folic acid supplementation increased serum folate concentrations and decreased Hcy concentrations at 11, 18, and 22 months of intervention. Dietary folic acid supplementation attenuated aging-induced hippocampus atrophy, which was showed by higher fractional anisotropy and lower mean diffusivity in the hippocampus, increased brain 18F-Fluorodeoxyglucose (18F-FDG) uptake, then stimulated neuronal survival, and alleviated age-related cognitive decline in SD rats. In conclusion, long-term dietary folic acid supplementation alleviated age-related cognitive decline by attenuating hippocampus atrophy and promoting brain glucose uptake in SD rats.
Subject(s)
Cognitive Dysfunction , Diet , Rats , Animals , Male , Rats, Sprague-Dawley , Folic Acid/metabolism , Dietary Supplements , Cognitive Dysfunction/prevention & control , Cognitive Dysfunction/metabolism , Aging , Hippocampus/metabolism , Glucose/metabolismABSTRACT
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 9 days with various concentrations of folic acid (0-40 µM) and then incubated for 24 h 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.
Subject(s)
Antioxidants/pharmacology , Apoptosis/drug effects , Folic Acid/pharmacology , Neural Stem Cells/drug effects , Oxidative Stress/drug effects , Telomere/drug effects , Animals , Cell Proliferation/drug effects , Corpus Striatum/drug effects , Corpus Striatum/metabolism , Hippocampus/drug effects , Hippocampus/metabolism , Hydrogen Peroxide/pharmacology , Neural Stem Cells/metabolism , Rats , Rats, Sprague-Dawley , Reactive Oxygen Species/metabolism , Telomere/metabolismABSTRACT
BACKGROUND: The neuroprotective benefits of combined folic acid and docosahexaenoic acid (DHA) on cognitive function in mild cognitive impairment (MCI) patients are suggested but unconfirmed. OBJECTIVE: To explore the effects of 6-month folic acidâ+âDHA on cognitive function in patients with MCI. METHODS: Our randomized controlled trial (trial number ChiCTR-IOR-16008351) was conducted in Tianjin, China. We divided 160 MCI patients agedâ>â60 years into four regimen groups randomly: folic acid (0.8âmg/day)â+âDHA (800âmg/day), folic acid (0.8âmg/day), DHA (800âmg/day), and placebo, for 6 months. Cognitive function and blood amyloid-ß peptide (Aß) biomarker levels were measured at baseline and 6 months. Cognitive function was also measured at 12 months. RESULTS: A total of 138 patients completed this trial. Folic acid improved the full-scale intelligence quotient (FSIQ), arithmetic, and picture complement scores; DHA improved the FSIQ, information, arithmetic, and digit span scores; folic acidâ+âDHA improved the arithmetic (difference 1.67, 95% CI 1.02 to 2.31) and digital span (1.33, 0.24 to 2.43) scores compared to placebo. At 12 months, all scores declined in the intervention groups. Folic acid and folic acidâ+âDHA increased blood folate (folic acidâ+âDHA: 7.70, 3.81 to 11.59) and S-adenosylmethionine (23.93, 1.86 to 46.00) levels and reduced homocysteine levels (-6.51, -10.57 to -2.45) compared to placebo. DHA lower the Aß40 levels (-40.57, -79.79 to -1.35) compared to placebo (pâ<â0.05), and folic acidâ+âDHA reduced the Aß42 (-95.59, -150.76 to -40.43) and Aß40 levels (-45.75, -84.67 to -6.84) more than DHA (pâ<â0.05). CONCLUSION: Folic acid and DHA improve cognitive function and reduce blood Aß production in MCI patients. Combination therapy may be more beneficial in reducing blood Aß-related biomarkers.