Abstract
X-linked adrenoleukodystrophy (X-ALD) is an inherited neurometabolic disorder caused by disfunction of the ABCD1 gene, which encodes a peroxisomal protein responsible for the transport of the very long-chain fatty acids from the cytosol into the peroxisome, to undergo β-oxidation. The mainly accumulated saturated fatty acids are hexacosanoic acid (C26:0) and tetracosanoic acid (C24:0) in tissues and body fluids. This peroxisomal disorder occurs in at least 1 out of 20,000 births. Considering that pathophysiology of this disease is not well characterized yet, and glial cells are widely used in studies of protective mechanisms against neuronal oxidative stress, we investigated oxidative damages and inflammatory effects of vesicles containing lecithin and C26:0, as well as the protection conferred by N-acetyl-l-cysteine (NAC), trolox (TRO), and rosuvastatin (RSV) was assessed. It was verified that glial cells exposed to C26:0 presented oxidative DNA damage (measured by comet assay and endonuclease III repair enzyme), enzymatic oxidative imbalance (high catalase activity), nitrative stress [increased nitric oxide (NO) levels], inflammation [high Interleukin-1beta (IL-1β) levels], and induced lipid peroxidation (increased isoprostane levels) compared to native glial cells without C26:0 exposure. Furthermore, NAC, TRO, and RSV were capable to mitigate some damages caused by the C26:0 in glial cells. The present work yields experimental evidence that inflammation, oxidative, and nitrative stress may be induced by hexacosanoic acid, the main accumulated metabolite in X-ALD, and that antioxidants might be considered as an adjuvant therapy for this severe neurometabolic disease.
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Abbreviations
- BMT:
-
Bone marrow transplant
- CAT:
-
Catalase
- C22:0:
-
Docosanoic acid
- C24:0:
-
Tetracosanoic acid
- C26:0:
-
Hexacosanoic acid
- C27:0:
-
Heptacosanoic acid
- CCER:
-
Childhood cerebral form
- Endo III:
-
Endonuclease III
- GPx:
-
Glutathione peroxidase
- H2O2 :
-
Hydrogen peroxide
- HTZ:
-
Heterozygotes
- IL:
-
Interleukin
- IL-1β:
-
Interleukin-1beta
- LPS:
-
Lipopolysaccharide
- PBS:
-
Phosphate buffer saline
- NAC:
-
N-acetyl-l-cysteine
- NO:
-
Nitric oxide
- \({\text{NO}}_{3}^{ - }\) :
-
Nitrate
- \({\text{NO}}_{2}^{ - }\) :
-
Nitrite
- \({\text{O}}_{2}^{{\cdot - }}\) :
-
Superoxide anion
- SEM:
-
Standard error of mean
- RSV:
-
Rosuvastatin
- SOD:
-
Superoxide dismutase
- TRO:
-
Trolox
- VLCFA:
-
Very long-chain fatty acid
- X-ALD:
-
X-linked adrenoleukodystrophy
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Acknowledgements
This study was supported by Brazilian Foundation Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), and Fundo de Incentivo à Pesquisa e Eventos (FIPE/HCPA).
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The study was approved by the Ethics Committee of Hospital de Clínicas de Porto Alegre (Number 15-0487).
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Marchetti, D.P., Steffens, L., Jacques, C.E. et al. Oxidative Imbalance, Nitrative Stress, and Inflammation in C6 Glial Cells Exposed to Hexacosanoic Acid: Protective Effect of N-acetyl-l-cysteine, Trolox, and Rosuvastatin. Cell Mol Neurobiol 38, 1505–1516 (2018). https://doi.org/10.1007/s10571-018-0626-1
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DOI: https://doi.org/10.1007/s10571-018-0626-1